Research teams from around the world have made remarkable progress in the past decade in elucidating the genomic landscape of most types of childhood cancer. A decade ago it was possible to hope that targetable oncogenes, such as activated tyrosine kinases, might be identified in a high percentage of childhood cancers. However, it is now clear that the genomic landscape of childhood cancer is highly varied, and in many cases is quite distinctive from that of the common adult cancers.

There are examples of genomic lesions that have provided immediate therapeutic direction, including the following:

For some cancers, the genomic findings have been highly illuminating in the identification of genomically defined subsets of patients within histologies that have distinctive biological features and distinctive clinical characteristics (particularly in terms of prognosis). In some instances, identification of these subtypes has resulted in early clinical translation as exemplified by the WNT subgroup of medulloblastoma. Because of its excellent outcome, the WNT subgroup will be studied separately in future medulloblastoma clinical trials so that reductions in therapy can be evaluated with the goal of maintaining favorable outcome while reducing long-term morbidity. However, the prognostic significance of the recurring genomic lesions for some other cancers remains to be defined.

A key finding from genomic studies is the extent to which the molecular characteristics of childhood cancers correlate with their tissue (cell) of origin. As with most adult cancers, variants in childhood cancers do not arise at random, but rather are linked in specific constellations to disease categories. A few examples include the following:

Another theme across multiple childhood cancers is the contribution of variants of genes involved in normal development of the tissue of origin of the cancer and the contribution of genes involved in epigenomic regulation.

Structural variations play an important role for many childhood cancers. Translocations resulting in oncogenic fusion genes or overexpression of oncogenes play a central role, particularly for the leukemias and sarcomas. However, for other childhood cancers that are primarily characterized by structural variations, functional fusion genes are not produced. Mechanisms by which these recurring structural variations have oncogenic effects have been identified for osteosarcoma (translocations confined to the first intron of TP53) and medulloblastoma (structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements leading to transcriptional activation [enhancer hijacking]).[1,2] However, the oncogenic mechanisms of action for recurring structural variations of other childhood cancers (e.g., the segmental chromosomal alterations in neuroblastoma) need to be elucidated.

Understanding of the contribution of germline variants to childhood cancer etiology is being advanced by the application of whole-genome and exome sequencing to cohorts of children with cancer. Estimates for rates of pathogenic germline variants approaching 10% have emerged from studies applying these sequencing methods to childhood cancer cohorts.[3-5] In some cases, the pathogenic germline variants are clearly contributory to the patient’s cancer (e.g., TP53 variants arising in the context of Li-Fraumeni syndrome), whereas in other cases the contribution of the germline variant to the patient’s cancer is less clear (e.g., variants in adult cancer predisposition genes such as BRCA1 and BRCA2 that have an undefined role in childhood cancer predisposition).[4,5] The frequency of germline variants varies by tumor type (e.g., lower for neuroblastoma and higher for osteosarcoma),[5] and many of the identified germline variants fit into known predisposition syndromes (e.g., DICER1 for pleuropulmonary blastoma, SMARCB1 and SMARCA4 for rhabdoid tumor and small cell ovarian cancer, TP53 for adrenocortical carcinoma and Li-Fraumeni syndrome cancers, RB1 for retinoblastoma, etc.). The germline contribution to the development of specific cancers is discussed in the disease-specific sections that follow.

Each section of this document is meant to provide readers with a brief summary of current knowledge about the genomic landscape of specific childhood cancers, an understanding that is critical in considering how to apply precision medicine concepts to childhood cancers.

References

1. Northcott PA, Lee C, Zichner T, et al.: Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511 (7510): 428-34, 2014. [PUBMED Abstract]
2. Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014. [PUBMED Abstract]
3. Mody RJ, Wu YM, Lonigro RJ, et al.: Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA 314 (9): 913-25, 2015. [PUBMED Abstract]
4. Parsons DW, Roy A, Yang Y, et al.: Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. JAMA Oncol 2 (5): 616-624, 2016. [PUBMED Abstract]
5. Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015. [PUBMED Abstract]

Acute Lymphoblastic Leukemia (ALL)

Genomics of childhood ALL

The genomics of childhood acute lymphoblastic leukemia (ALL) has been extensively investigated, and multiple distinctive subtypes have been defined on the basis of cytogenetic and molecular characterizations, each with its own pattern of clinical and prognostic characteristics.[1,2] The discussion of the genomics of childhood ALL below is divided into three sections: the genomic alterations associated with B-ALL, followed by the genomic alterations associated with T-ALL and mixed phenotype acute leukemia (MPAL). Figures 1, 2, and 4 illustrate the distribution of B-ALL (stratified by National Cancer Institute [NCI] standard- and high-risk B-ALL) and T-ALL cases by cytogenetic/molecular subtypes.[1]

Throughout this section, the percentages of genomic subtypes from among all B-ALL and T-ALL cases are derived primarily from a report describing the genomic characterization of patients treated on several Children's Oncology Group (COG) and St. Jude Children's Research Hospital (SJCRH) clinical trials. Percentages by subtype are presented for NCI standard-risk and NCI high-risk patients with B-ALL (up to age 18 years).[1]

B-ALL cytogenetics/genomics

B-ALL is typified by genomic alterations that include: 1) gene fusions that lead to aberrant activity of transcription factors, 2) chromosomal gains and losses (e.g., hyperdiploidy or hypodiploidy), and 3) alterations leading to activation of tyrosine kinase genes.[1] Figures 1 and 2 illustrate the distribution of NCI standard-risk and high-risk B-ALL cases by 23 cytogenetic/molecular subtypes.[1] The two most common subtypes (hyperdiploid and ETV6::RUNX1 fusion) together account for approximately 60% of NCI standard-risk B-ALL cases, but only approximately 25% of NCI high-risk cases. Most other subtypes are much less common, with most occurring at frequencies less than 2% to 3% of B-ALL cases. The molecular and clinical characteristics of some of the subtypes are discussed below.

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The genomic landscape of B-ALL is characterized by a range of genomic alterations that disrupt normal B-cell development and, in some cases, by variants in genes that provide a proliferation signal (e.g., activating variants in RAS family genes or variants/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions), single nucleotide variants (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[3]

The genomic alterations in B-ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions and KMT2A-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within unique biological subtypes:

• IKZF1 deletions and variants are most commonly observed within cases of BCR::ABL1 ALL and BCR::ABL1-like ALL.[4,5]
• Intragenic ERG deletions occur within a distinctive subtype characterized by gene rearrangements involving DUX4.[6,7]
• TP53 variants, often germline, occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes.[8] TP53 variants are uncommon in other patients with B-ALL.

Activating single nucleotide variants in kinase genes are uncommon in high-risk B-ALL. JAK genes are the primary kinases that are found to be altered. These variants are generally observed in patients with BCR::ABL1-like ALL who have CRLF2 abnormalities, although JAK2 variants are also observed in approximately 25% of children with Down syndrome and ALL, occurring exclusively in cases with CRLF2 gene rearrangements.[5,9-11] Several kinase genes and cytokine receptor genes are activated by translocations, as described below in the discussion of BCR::ABL1 ALL and BCR::ABL1-like ALL. FLT3 variants occur in a minority of cases (approximately 10%) of hyperdiploid ALL and KMT2A-rearranged ALL, and are rare in other subtypes.[12]

Understanding of the genomics of B-ALL at relapse is less advanced than the understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[13] However, molecular subtype–defining lesions such as translocations and aneuploidy are almost always retained at relapse.[1,13] Of particular importance are new variants that arise at relapse that may be selected by specific components of therapy. As an example, variants in NT5C2 are not found at diagnosis, whereas specific variants in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-ALL with early relapse that were evaluated for this variant in two studies.[13,14] NT5C2 variants are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine and thioguanine.[14] Another gene that is found altered only at relapse is PRSP1, a gene involved in purine biosynthesis.[15] Variants were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 variants observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP variants are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[13,16] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing variants early and intervene before a frank relapse.

Several recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-ALL. Some chromosomal alterations are associated with more favorable outcomes, such as favorable trisomies (51–65 chromosomes) and the ETV6::RUNX1 fusion.[17][Level of evidence B4] Other alterations historically have been associated with a poorer prognosis, including the BCR::ABL1 fusion (Philadelphia chromosome–positive [Ph+]; t(9;22)(q34;q11.2)), rearrangements of the KMT2A gene, hypodiploidy, and intrachromosomal amplification of the RUNX1 gene (iAMP21).[18]

In recognition of the clinical significance of many of these genomic alterations, the 5th edition revision of the World Health Organization Classification of Haematolymphoid Tumours lists the following entities for B-ALL:[19]

• B-lymphoblastic leukemia/lymphoma, NOS.
• B-lymphoblastic leukemia/lymphoma with high hyperdiploidy.
• B-lymphoblastic leukemia/lymphoma with hypodiploidy.
• B-lymphoblastic leukemia/lymphoma with iAMP21.
• B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion.
• B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features.
• B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement.
• B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion.
• B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features.
• B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion.
• B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion.
• B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion.
• B-lymphoblastic leukemia/lymphoma with other defined genetic abnormalities.

The category of B-ALL with other defined genetic abnormalities includes potential novel entities, including B-ALL with DUX4, MEF2D, ZNF384 or NUTM1 rearrangements; B-ALL with IG::MYC fusions; and B-ALL with PAX5alt or PAX5 p.P80R (NP_057953.1) abnormalities.

These and other chromosomal and genomic abnormalities for childhood ALL are described below.

1. Chromosome number.
   • High hyperdiploidy (51–65 chromosomes).

     High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in approximately 33% of NCI standard-risk and 14% of NCI high-risk pediatric B-ALL cases.[1,20] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy.

     High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is an independent favorable prognostic factor.[20-22] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[22] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[23] which may explain the favorable outcome commonly observed in these cases.

     While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[24-26]

     Multiple reports have described the prognostic significance of specific chromosome trisomies among children with hyperdiploid B-ALL.

     • A study combining experience from the Children's Cancer Group and the Pediatric Oncology Group (POG) found that patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have a particularly favorable outcome.[27]; [17][Level of evidence B4]
     • A report using POG data found that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[28] COG protocols currently use double trisomies of chromosomes 4 and 10 to define favorable hyperdiploidy.
     • A retrospective analysis evaluated patients treated on two consecutive UKALL trials to identify and validate a profile to predict outcome in high hyperdiploid B-ALL. The investigators defined a good-risk group (approximately 80% of high hyperdiploidy patients) that was associated with a more favorable prognosis. Good-risk patients had either trisomies of both chromosomes 17 and 18 or trisomy of one of these two chromosomes along with absence of trisomies of chromosomes 5 and 20. All other patients were defined as poor risk and had a less favorable outcome. End-induction MRD and copy number alterations (such as IKZF1 deletion) were prognostically significant within each hyperdiploid risk group.[29]

     Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified on the basis of the prognostic significance of the translocation. For instance, in one study, 8% of patients with the BCR::ABL1 fusion also had high hyperdiploidy,[30] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-BCR::ABL1 high hyperdiploid patients.

     Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[31] Molecular technologies, such as single nucleotide polymorphism microarrays to detect widespread loss of heterozygosity, can be used to identify patients with masked hypodiploidy.[31] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes (hyperdiploidy with two and four copies of chromosomes rather than three copies). These patients have an unfavorable outcome, similar to those with hypodiploidy.[32]

     Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[33] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6::RUNX1 fusion.[33-35] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[33,35]

     The genomic landscape of hyperdiploid ALL is characterized by variants in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of variant profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL and may occur in utero, while variants in RTK/RAS pathway genes are late events in leukemogenesis and are often subclonal.[1,36]

   • Hypodiploidy (<44 chromosomes).

     B-ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying on the basis of modal chromosome number into the following four groups:[32]

     • Near-haploid: 24 to 29 chromosomes (n = 46).
     • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
     • High-hypodiploid: 40 to 43 chromosomes (n = 13).
     • Near-diploid: 44 chromosomes (n = 54).

     Near-haploid cases represent approximately 2% of NCI standard-risk and 2% of NCI high-risk pediatric B-ALL.[1]

     Low-hypodiploid cases represent approximately 0.5% of NCI standard-risk and 2.6% of NCI high-risk pediatric B-ALL cases.[1]

     Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[32,37] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[32] Several studies have shown that patients with high minimal residual disease (MRD) (≥0.01%) after induction do very poorly, with 5-year event-free survival (EFS) rates ranging from 25% to 47%. Although hypodiploid patients with low MRD after induction fare better (5-year EFS rates, 64%–75%), their outcomes are still inferior to most children with other types of ALL.[38-40]

     The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[8] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[41] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these variants are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[8] Approximately two-thirds of patients with ALL and germline pathogenic TP53 variants have hypodiploid ALL.[42]

2. Chromosomal translocations and gains/deletions of chromosomal segments.
   • ETV6::RUNX1 fusion (t(12;21)(p13.2;q22.1)).

     Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in approximately 27% of NCI standard-risk and 10% of NCI high-risk pediatric B-ALL cases.[1,34]

     The ETV6::RUNX1 fusion produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[43,44] Hispanic children with ALL have a lower incidence of ETV6::RUNX1 fusions than do White children.[45]

     Reports generally indicate favorable EFS and overall survival (OS) rates in children with the ETV6::RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[26,46-50]; [17][Level of evidence B4]

     • Early response to treatment.
     • NCI risk category (age and WBC count at diagnosis).
     • Treatment regimen.

     In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6::RUNX1 fusion status, to be independent prognostic factors.[46] However, another large trial only enrolled patients classified as having favorable-risk B-ALL, with low-risk clinical features, either trisomies of 4, 10, and 17 or ETV6::RUNX1 fusion, and end induction MRD less than 0.01%. Patients had a 5-year continuous complete remission rate of 93.7% and a 6-year OS rate of 98.2% for patients with ETV6::RUNX1.[17] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6::RUNX1 fusion.[50,51]

     There is a higher frequency of late relapses in patients with ETV6::RUNX1 fusions compared with other relapsed B-ALL patients.[46,52] Patients with the ETV6::RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[53] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[54] Some relapses in patients with ETV6::RUNX1 fusions may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6::RUNX1 translocation).[55,56]

   • BCR::ABL1 fusion (t(9;22)(q34.1;q11.2); Ph+).

     The BCR::ABL1 fusion leads to production of a BCR::ABL1 fusion protein with tyrosine kinase activity (see Figure 3).[1] The BCR::ABL1 fusion occurs in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1] The BCR::ABL1 fusion is also the leukemogenic driver for chronic myeloid leukemia (CML). The most common BCR breakpoint in CML is different from the most common BCR breakpoint in ALL. The breakpoint that typifies CML produces a larger fusion protein (termed p210) than the breakpoint most commonly observed for ALL (termed p190, a smaller fusion protein).

     Enlarge

     Ph+ ALL is more common in older children with B-ALL and high WBC counts, with the incidence of the BCR::ABL1 fusions increasing to about 25% in young adults with ALL.

     Historically, the BCR::ABL1 fusion was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplant (HSCT) in patients in first remission.[30,57-59] Inhibitors of the BCR::ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with BCR::ABL1 ALL.[60] A study by the Children's Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% (± 12%), which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era. This result eliminated the recommendation of HSCT for patients with a good early response to chemotherapy using a tyrosine kinase inhibitor.[61,62]

     The International Consensus Classification of acute lymphoblastic leukemia/lymphoma from 2022 divides BCR::ABL1–positive B-ALL into two subtypes: cases with lymphoid-only involvement and cases with multilineage involvement.[63] These subtypes differ in the timing of their transformation event. A multipotent progenitor serves as the target cell of origin for BCR::ABL1–positive B-ALL with multilineage involvement, and a later progenitor is the target cell of origin for BCR::ABL1–positive B-ALL with lymphoid-only involvement.

     • BCR::ABL1–positive B-ALL with lymphoid-only involvement is the predominate subtype. Only a minority of cases in children and adults have multilineage involvement (estimated at 15%–30%).[64]
     • BCR::ABL1–positive B-ALL cases with lymphoid-only involvement and cases with multilineage involvement have similar clinical presentations and immunophenotypes. In addition, both subtypes commonly have the p190 fusion protein.[64,65]
     • One way of distinguishing between patients with lymphoid-only and multilineage involvement is to detect the BCR::ABL1 fusion in normal non-ALL B cells, T cells, and myeloid cells.[65]
     • A second way of distinguishing between patients with lymphoid-only and multilineage involvement is to detect quantitative differences in MRD levels (typically 1 log) using measures that quantify BCR::ABL1 DNA or RNA, compared with measures based on flow cytometry, real-time quantitative polymerase chain reaction (PCR), or next-generation sequencing (NGS) quantitation of leukemia-specific immunoglobulin (IG) or T-cell receptor (TCR) rearrangements.[64-66]
       • For patients with lymphoid-only BCR::ABL1–positive B-ALL, MRD estimates for these methods will be correlated with each other.
       • For patients with multilineage involvement BCR::ABL1–positive B-ALL, posttreatment MRD estimates based on detection of BCR::ABL1 DNA or RNA will often be higher than estimates based on flow cytometry or quantitation of leukemia-specific IG/TCR rearrangements.
     • For patients with BCR::ABL1–positive B-ALL and multilineage involvement, levels of BCR::ABL1 transcripts and DNA may remain stable over time despite continued treatment with chemotherapy and tyrosine kinase inhibitors. In these situations, the persisting BCR::ABL1 DNA or RNA likely represents evidence of a residual preleukemic clone and not leukemia cells. Therefore, the term MRD is a misnomer.
     • A corollary of the difference in MRD detection by methods based on BCR::ABL1 DNA or RNA detection versus MRD detection based on flow cytometry or IG/TCR rearrangements is that the latter methods provide more reliable prognostication.[64,66,67] For example, the presence of MRD by BCR::ABL1 DNA or RNA detection in the absence of MRD detection by IG/TCR rearrangements does not confer inferior prognosis.
     • Based on the limited numbers of patients studied to date, prognosis appears similar in both adults and children with lymphoid-only versus multilineage involvement BCR::ABL1–positive B-ALL.[64,66]
     • There are case reports of patients with multilineage involvement BCR::ABL1–positive B-ALL who relapse years from their initial diagnosis. In addition, their relapsed leukemia has the same BCR::ABL1 breakpoint as their initial leukemia, but it has a different IG/TCR rearrangement.[66] These case reports suggest that patients with multilineage BCR::ABL1–positive B-ALL are at risk of a second leukemogenic event, leading to a second BCR::ABL1 leukemia.
     • There is no evidence that a specific monitoring schedule or prolonged treatment with a tyrosine kinase inhibitor provides clinical benefit for patients with multilineage involvement BCR::ABL1–positive B-ALL who have maintained presence of BCR::ABL1 transcripts or DNA at the completion of a standard-duration course of leukemia therapy.
   • KMT2A-rearranged ALL (t(v;11q23.3)).

     Rearrangements involving the KMT2A gene with more than 100 translocation partner genes result in the production of fusion oncoproteins. KMT2A gene rearrangements occur in up to 80% of infants with ALL. Beyond infancy, approximately 1% of NCI standard-risk and 4% of NCI high-risk pediatric B-ALL cases have KMT2A rearrangements.[1]

     These rearrangements are generally associated with an increased risk of treatment failure, particularly in infants.[68-71] The KMT2A::AFF1 fusion (t(4;11)(q21;q23)) is the most common rearrangement involving the KMT2A gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[69,72]

     Patients with KMT2A::AFF1 fusions are usually infants with high WBC counts. These patients are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[73] While both infants and adults with the KMT2A::AFF1 fusion are at high risk of treatment failure, children with the KMT2A::AFF1 fusion appear to have a better outcome.[68,69,74] Irrespective of the type of KMT2A gene rearrangement, infants with KMT2A-rearranged ALL have much worse event-free survival rates than non-infant pediatric patients with KMT2A-rearranged ALL.[68,69,74]

     Whole-genome sequencing has determined that cases of infant ALL with KMT2A gene rearrangements have frequent subclonal NRAS or KRAS variants and few additional genomic alterations, none of which have clear clinical significance.[12,75] Deletion of the KMT2A gene has not been associated with an adverse prognosis.[76]

     Of interest, the KMT2A::MLLT1 fusion (t(11;19)(q23;p13.3)) occurs in approximately 1% of ALL cases and occurs in both early B-lineage ALL and T-ALL.[77] Outcome for infants with the KMT2A::MLLT1 fusion is poor, but outcome appears relatively favorable in older children with T-ALL and the KMT2A::MLLT1 fusion.[77]

   • TCF3::PBX1 fusion (t(1;19)(q23;p13.3)) and TCF3::HLF fusion (t(17;19)(q22;p13)).

     Fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1 is present in approximately 4% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1,78,79] The TCF3::PBX1 fusion may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B–ALL immunophenotype (cytoplasmic immunoglobulin positive).[80] Black children are relatively more likely than White children to have pre-B–ALL with the TCF3::PBX1 fusion.[81]

     The TCF3::PBX1 fusion had been associated with inferior outcome in the context of antimetabolite-based therapy,[82] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[79,83] More specifically, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) in which all patients were treated without cranial radiation, patients with the TCF3::PBX1 fusion had an overall outcome comparable to children lacking this translocation, but with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[84,85]

     The TCF3::HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3::HLF fusion is associated with disseminated intravascular coagulation and hypercalcemia at diagnosis. Outcome is very poor for children with the TCF3::HLF fusion, with a literature review noting mortality for 20 of 21 cases reported.[86] In addition to the TCF3::HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by variants in RAS pathway genes (NRAS, KRAS, and PTPN11).[80]

   • DUX4-rearranged ALL with frequent ERG deletions.

     Approximately 3% of NCI standard-risk and 6% of NCI high-risk pediatric B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[1,6,7] East Asian ancestry was linked to an increased prevalence of DUX4-rearranged ALL (favorable).[87] The most common rearrangement produces IGH::DUX4 fusions, with ERG::DUX4 fusions also observed.[88] DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with focal deletions in ERG,[88-91] and one-half to more than two-thirds of these cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes.[6,88] ERG deletions often appear to be clonal, but using sensitive detection methodology, it appears that most cases are polyclonal.[88] IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[6,7]

     ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%. Even when the IZKF1 deletion is present, prognosis remains highly favorable.[89-92] While patients with DUX4-rearranged ALL have an overall favorable prognosis, there is uncertainty as to whether this applies to both ERG-deleted and ERG-intact cases. In a study of 50 patients with DUX4-rearranged ALL, patients with an ERG deletion detected by genomic PCR (n = 33) had a more favorable EFS rate of approximately 90% than did patients with intact ERG (n = 17), with an EFS rate of approximately 70%.[90]

   • MEF2D-rearranged ALL.

     Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 0.3% of NCI standard-risk and 3% of NCI high-risk pediatric B-ALL cases.[1,93,94]

     Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[93,95] The interstitial deletion producing the MEF2D::BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D::CSFR1 that have a BCR::ABL1-like gene expression profile.[93,96]

     The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[93,94] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS rate was 72% (standard error, ± 10%), which was inferior to that for other patients.[93]

   • ZNF384-rearranged ALL.

     ZNF384 is a transcription factor that is rearranged in approximately 0.3% of NCI standard-risk and 2.7% of NCI high-risk pediatric B-ALL cases.[1,93,97,98]

     East Asian ancestry was associated with an increased prevalence of ZNF384.[87] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[93,97,98] ZNF384 rearrangement does not appear to confer independent prognostic significance.[93,97,98] However, within the subset of patients with ZNF384 rearrangements, patients with EP300::ZNF384 fusions have lower relapse rates than patients with other ZNF384 fusion partners.[99] The immunophenotype of B-ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[97,98] Cases of mixed phenotype acute leukemia (MPAL) (B/myeloid) that have ZNF384 gene fusions have been reported,[100,101] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.[102]

   • NUTM1-rearranged B-ALL.

     NUTM1-rearranged B-ALL is most commonly observed in infants, representing 3% to 5% of overall cases of B-ALL in this age group and approximately 20% of infant B-ALL cases lacking the KMT2A rearrangement.[103] The frequency of NUTM1 rearrangement is lower in children after infancy (<1% of cases).[1,103]

     The NUTM1 gene is located on chromosome 15q14, and some cases of B-ALL with NUTM1 rearrangements show chromosome 15q aberrations, but other cases are cryptic and have no cytogenetic abnormalities.[104] RNA sequencing, as well as break-apart FISH, can be used to detect the presence of the NUTM1 rearrangement.[103]

     The NUTM1 rearrangement appears to be associated with a favorable outcome.[103,105] Among 35 infants with NUTM1-rearranged B-ALL who were treated on Interfant protocols, all patients achieved remission and no relapses were observed.[103] For the 32 children older than 12 months with NUTM1-rearranged B-ALL, the 4-year EFS and OS rates were 92% and 100%, respectively.

   • IGH::IL3 fusion (t(5;14)(q31.1;q32.3)).

     This entity is included in the 2016 revision of the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues.[106] The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IGH::IL3 fusion as the underlying genetic basis for the condition.[107,108] The joining of the IGH locus to the promoter region of the IL3 gene leads to dysregulation of IL3 expression.[109] Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IGH::IL3 fusion.[110]

     The number of cases of IGH::IL3 ALL described in the published literature is too small to assess the prognostic significance of the IGH::IL3 fusion. Diagnosis of cases of IGH::IL3 ALL may be delayed because the ALL clone in the bone marrow may be small, and because it can present with hypereosinophilia in the absence of cytopenias and circulating blasts.[106]

   • Intrachromosomal amplification of chromosome 21 (iAMP21).

     iAMP21 occurs in approximately 5% of NCI standard-risk and 7% of NCI high-risk pediatric B-ALL cases.[1] iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome).[106] iAMP21 can also be identified by chromosomal microarray analysis. Uncommonly, iAMP21 with an atypical genomic pattern (e.g., amplification of the genomic region but with less than 5 RUNX1 signals or having at least 5 RUNX1 signals with some located apart from the abnormal iAMP21-chromosome) is identified by microarray but not RUNX1 FISH.[111] The prognostic significance of iAMP21 defined only by microarray has not been characterized.

     iAMP21 is associated with older age (median, approximately 10 years), presenting WBC count of less than 50 × 109/L, a slight female preponderance, and high end-induction MRD.[112-114] Analysis of variant signatures indicates that gene amplifications in iAMP21 occur later in leukemogenesis, which is in contrast to those of hyperdiploid ALL that can arise early in life and even in utero.[1]

     The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS rate, 29%).[18] In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS rate, 78%).[113] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS rate, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS rate, 73% vs. 80%).[112] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[112] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for HSCT in first remission.[114]

   • PAX5 alterations.

     Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, called PAX5alt and PAX5 p.P80R (NP_057953.1).[115] The alterations in the PAX5alt subtype included rearrangements, sequence variants, and focal intragenic amplifications.

     PAX5alt. PAX5 rearrangements have been reported to represent approximately 3% of NCI standard-risk and 11% of NCI high-risk pediatric B-ALL cases.[1] More than 20 partner genes for PAX5 have been described,[115] with PAX5::ETV6, the primary genomic alteration in dic(9;12)(p13;p13),[116] being the most common gene fusion.[115]

     Intragenic amplification of PAX5 was identified in approximately 1% of B-ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations.[117] Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5 amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%–61%), and the OS rate was 67% (95% CI, 54%–77%), suggesting a relatively poor prognosis for patients with this B-ALL subtype.

     PAX5 p.P80R (NP_057953.1). PAX5 with a p.P80R variant shows a gene expression profile distinctive from that of other cases with PAX5 alterations.[115] Cases with PAX5 p.P80R represent approximately 0.3% of NCI standard-risk and 1.8% of NCI high-risk pediatric B-ALL.[1] PAX5 p.P80R B-ALL appears to occur more frequently in the adolescent and young adult (AYA) and adult populations (3.1% and 4.2%, respectively).[115]

     Outcome for the pediatric patients with PAX5 p.P80R and PAX5alt treated in a COG clinical trial appears to be intermediate (5-year EFS rate, approximately 75%).[115] PAX5alt rearrangements have also been detected in infant patients with ALL, with a reported outcome similar to KMT2A-rearranged infant ALL.[105]

   • BCR::ABL1-like (Ph-like).

     BCR::ABL1-negative patients with a gene expression profile similar to BCR::ABL1-positive patients have been referred to as Ph-like,[118-120] and are now referred to as BCR::ABL1-like.[19] This occurs in 10% to 20% of pediatric B-ALL patients, increasing in frequency with age, and has been associated with an IKZF1 deletion or variant.[1,9,118,119,121,122]

     Retrospective analyses have indicated that patients with BCR::ABL1-like ALL have a poor prognosis.[5,118] In one series, the 5-year EFS rate for NCI high-risk children and adolescents with BCR::ABL1-like ALL was 58% and 41%, respectively.[5] While it is more frequent in older and higher-risk patients, the BCR::ABL1-like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-ALL patients were found to have BCR::ABL1-like ALL; these patients had an inferior EFS rate compared with non–BCR::ABL1-like standard-risk patients (82% vs. 91%), although no difference in OS rate (93% vs. 96%) was noted.[123] In one study of 40 BCR::ABL1-like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.[124]

     The hallmark of BCR::ABL1-like ALL is activated kinase signaling, with approximately 35% to 50% containing CRLF2 genomic alterations [1,120,125] and half of those cases containing concomitant JAK variants.[126]

     Many of the remaining cases of BCR::ABL1-like ALL have been noted to have a series of translocations involving tyrosine-kinase encoding ABL-class fusion genes, including ABL1, ABL2, CSF1R, and PDGFRB.[5,121,127] Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo,[121,128] suggesting potential therapeutic strategies for these patients. Preclinical drug sensitivity assays have suggested that sensitivity to different tyrosine kinase inhibitors (TKIs) may vary by the specific ABL-class gene involved in the fusion. In one study of ex vivo TKI sensitivity, samples from patients with PDGFRB fusions were sensitive to imatinib. However, these samples were less sensitive to dasatinib and bosutinib than samples from patients with ABL1 fusions (including BCR::ABL1).[128] Clinical studies have not yet confirmed the differing responses to various TKIs by type of ABL-class fusion.

     BCR::ABL1-like ALL cases with non-CRLF2 genomic alterations represent approximately 3% of NCI standard-risk and 8% of NCI high-risk pediatric B-ALL cases.[1] In a retrospective study of 122 pediatric patients (aged 1–18 years) with ABL-class fusions (all treated without tyrosine kinase inhibitors), the 5-year EFS rate was 59%, and the OS rate was 76%.[129]

     Approximately 9% of BCR::ABL1-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[130] The C-terminal region of the receptor that is lost is the region that is altered in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development. Single nucleotide variants in kinase genes, aside from those in JAK1 and JAK2, are uncommon in patients with BCR::ABL1-like ALL.[9]

     CRLF2. Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-ALL. These alterations represent approximately 50% of cases of BCR::ABL1-like ALL.[131-133] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IGH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8::CRLF2 fusion.[9,125,131,132] These two genomic alterations are associated with distinctive clinical and biological characteristics.

     BCR::ABL1-like B-ALL with CRLF2 genomic alterations is observed in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1]

     ALL with genomic alterations in CRLF2 occurs at a higher incidence in children with Hispanic or Latino genetic ancestry [125,134,135] and American Indian genetic ancestry.[87] In a study of 205 children with high-risk B-ALL, 18 of 51 (35.3%) Hispanic or Latino patients had CRLF2 rearrangements, compared with 11 of 154 (7.1%) cases of other declared ethnicity.[125] In a second study, the frequency of IGH::CRLF2 fusions was increased in Hispanic or Latino children compared with non-Hispanic or non-Latino children with B-ALL (13.2% vs. 3.6%).[134,135] In this study, the percentage of B-ALL with P2RY8::CRLF2 fusions was approximately 6% and was not affected by ethnicity.

     The P2RY8::CRLF2 fusion is observed in 70% to 75% of pediatric patients with CRLF2 genomic alterations, and it occurs in younger patients (median age, approximately 4 years vs. 14 years for patients with IGH::CRLF2).[136,137] P2RY8::CRLF2 occurs not infrequently with established chromosomal abnormalities (e.g., hyperdiploidy, iAMP21, dic(9;20)), while IGH::CRLF2 is generally mutually exclusive with known cytogenetic subgroups. CRLF2 genomic alterations are observed in approximately 60% of patients with Down syndrome and ALL, with P2RY8::CRLF2 fusions being more common than IGH::CRLF2 (approximately 80%–85% vs. 15%–20%).[132,136]

     IGH::CRLF2 and P2RY8::CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence.[138] However, in some cases they appear to be a late event and show subclonal prevalence.[138] Loss of the CRLF2 genomic abnormality in some cases at relapse confirms the subclonal nature of the alteration in these cases.[136,139]

     CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions. Deletions of IKZF1 are more common in cases with IGH::CRLF2 fusions than in cases with P2RY8::CRLF2 fusions.[137] Hispanic and Latino children have a higher frequency of CRLF2 rearrangements with IKZF1 deletions than non-Hispanic children.[135]

     Other recurring genomic alterations found in association with CRLF2 alterations include deletions in genes associated with B-cell differentiation (e.g., PAX5, BTG1, EBF1, etc.) and cell cycle control (CDKN2A), as well as genomic alterations activating JAK-STAT pathway signaling (e.g., IL7R and JAK variants).[5,125,126,132,140]

     Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance in univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[125,131,132,141,142] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR::ABL1-like expression signatures were associated with unfavorable outcome.[122] Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed on the basis of CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[141,142]

   • IKZF1 deletions.

     IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of B-ALL cases. Less commonly, IKZF1 can be inactivated by deleterious single nucleotide variants.[119]

     Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore more common in NCI high-risk patients than in NCI standard-risk patients.[3,119,140,143,144] A high proportion of BCR::ABL1-positive cases have a deletion of IKZF1,[4,140] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[145] IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in BCR::ABL1-like ALL cases.[89,118,140] IKZF1 deletions also occur more commonly in Hispanic children. In one study from a single cancer center, IKZF1 deletions were observed in 29% of Hispanic children, compared with 11% of non-Hispanic children (P = .001).[135]

     Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome in multivariate analyses.[89,118,119,122,140,146-153]; [154][Level of evidence B4] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERG deletions.[89-91] Similarly, the prognostic significance of the IKZF1 deletion also appeared to be minimized in a cohort of COG patients with DUX4-rearranged ALL and with ERG transcriptional dysregulation that frequently occurred by ERG deletion.[7] The Associazione Italiana di Ematologia e Oncologia Pediatrica–Berlin-Frankfurt-Münster group reported that IKZF1 deletions were significant adverse prognostic factors only in B-ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.[155] This combination of IKZF1 deletion with accompanying deletion of select other genes is termed IKZF1PLUS.[155] In a single-center study, the IKZF1PLUS profile was more commonly observed in Hispanic children than in non-Hispanic children (20% vs. 5%, P = .001).[135]

     The poor prognosis associated with IKZF1 alterations appears to be enhanced by the concomitant finding of deletion of 22q11.22. In a study of 1,310 patients with B-ALL, approximately one-half of the patients with IKZF1 alterations also had deletion of 22q11.22. The 5-year EFS rate was 43.3% for those with both abnormalities, compared with 68.5% for patients with IKZF1 alterations and wild-type 22q11.22 (P < .001).[156]

     There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[157][Level of evidence B4]

     In the Dutch ALL11 study, patients with IKZF1 deletions had maintenance therapy extended by 1 year, with the goal of improving outcomes.[158] The landmark analysis demonstrated an almost threefold reduction in relapse rate and an improvement in the 2-year EFS rate (from 74.4% to 91.2%), compared with historical controls.

   • MYC-rearranged ALL (8q24).

     MYC gene rearrangements are a rare but recurrent finding in pediatric patients with B-ALL. Patients with rearrangements of the MYC gene and the IGH2, IGK, and IGL genes at 14q32, 2p12, and 22q11.2, respectively, have been reported.[159-161] The lymphoblasts typically exhibit a precursor B-cell immunophenotype, with a French-American-British (FAB) L2 or L3 morphology, with no expression of surface immunoglobulin and kappa or lambda light chains. Concurrent MYC gene rearrangements have been observed along with additional cytogenetic rearrangements such as IGH::BCL2 or KMT2A.[161] Patients reported in the literature have been variably treated with ALL therapy or with mature B leukemia/lymphoma treatment protocols, and the optimal treatment for this patient group remains uncertain.[161]

Genomics of ALL in children with Down syndrome

The largest study that examined the genomic landscape of ALL arising in children with Down syndrome included 295 patients enrolled in COG clinical trials.[11]

• Almost all cases of ALL in children with Down syndrome are B-ALL. T-ALL is uncommon.
• The common recurring genomic alterations found in non-Down syndrome ALL (e.g., high hyperdiploidy and ETV6::RUNX1) occur much less often in children with Down syndrome and ALL. Other alterations occur more often in children with Down syndrome and ALL.
• Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.
  • Approximately one-half of CRLF2-rearranged cases have JAK2 variants, which are not seen in children with Down syndrome and ALL who do not have CRLF2 rearrangements.
  • IKZF1 alterations occur in approximately 30% of cases with CRLF2 rearrangements but in only approximately 10% of cases without CRLF2 rearrangements.
  • Twenty-five percent of CRLF2-rearranged cases in patients with Down syndrome are classified by gene expression as BCR::ABL1-like, compared with 54% of CRLF2-rearranged non-Down syndrome ALL cases.
  • Overall, patients with CRLF2-rearranged ALL and Down syndrome have an intermediate prognosis. However, patients with a BCR::ABL1-like gene expression signature have worse outcomes than those without a BCR::ABL1-like gene expression signature and CRLF2 rearrangements (EFS rates, 39.5% ± 8.1% vs. 82% ± 4.4%; OS rates, 70.3% ± 8.7% vs. 86.9% ± 4.8%).
• The IGH::IGF2BP1 gene fusion occurs in approximately 3% of patients with Down syndrome. This gene fusion is rare in patients with ALL who do not have Down syndrome. In one retrospective analysis, this fusion was associated with a relatively favorable outcome (EFS rate, 87.5% ± 11.7%).
• C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).
  • Rearrangements of CEBPD are the most common C/EBPalt lesion, occurring in 7.5% of Down syndrome ALL cases. The fusion partner for more than 80% of CEBPD rearrangements is IGH. Less common fusion partners include MME, TPM4, 9p13.2, and 6q25.3.
  • Another 4% to 5% of Down syndrome ALL is characterized by alterations in other C/EBP family members, such as CEBPA and CEBPE.
  • C/EBPalt cases commonly harbor concomitant variants of FLT3, KDM6A, and SETD2.
  • C/EBPalt was associated with high rates of MRD-negative remission at the end of induction therapy (87.1%) and an intermediate outcome (10-year EFS rate, 73.9% ± 9.9%; 10-year OS rate, 76.7% ± 12.8%).

T-ALL cytogenetics/genomics

T-ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with variants in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway.[162] Cytogenetic abnormalities common in B-ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-ALL.[163,164]

In Figure 4 below, pediatric T-ALL cases are divided into 10 molecular subtypes based on their RNA expression and gene variant status. These cases were derived from patients enrolled in SJCRH and COG clinical trials.[1] Each subtype is associated with dysregulation of specific genes involved in T-cell development. Within a subtype, multiple mechanisms may drive expression of the dysregulated gene. For example, for the largest subtype, TAL1, overexpression of TAL1 can result from the STIL::TAL1 fusion and a noncoding insertion variant upstream of the TAL1 locus that creates a MYB-binding site.[162,165] As another example, within the HOXA group, overexpression of HOXA9 can result from multiple gene fusions, including KMT2A rearrangements, MLLT10 rearrangements, and SET::NUP214 fusions.[1,162,166] In contrast to the molecular subtypes of B-ALL, the molecular subtypes of T-ALL are not used to define treatment interventions based on their prognostic significance or therapeutic implications.

Enlarge

• Notch pathway signaling.

  Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene variants in T-ALL, and these are the most commonly altered genes in pediatric T-ALL.[162,167] NOTCH1-activating gene variants occur in approximately 50% to 60% of T-ALL cases, and FBXW7-inactivating gene variants occur in approximately 15% of cases. Approximately 60% of T-ALL cases have Notch pathway activation by variants in at least one of these genes.[168,169]

  The prognostic significance of NOTCH1 and FBXW7 variants may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia reported that patients having altered NOTCH1 or FBXW7 and wild-type PTEN and RAS constituted a favorable-risk group (i.e., low-risk group), while patients with PTEN or RAS variants, regardless of NOTCH1 and FBXW7 status, have a significantly higher risk of treatment failure (i.e., high-risk group).[170,171] In the FRALLE study, the 5-year disease-free survival rate was 88% for the genetic low-risk group of patients and 60% for the genetic high-risk group of patients.[170] However, using the same criteria to define the genetic risk group, the Dana-Farber Cancer Institute consortium was unable to replicate these results. They reported a 5-year EFS rate of 86% for genetic low-risk patients and 79% for the genetic high-risk patients, a difference that was not statistically significant (P = .26).[169]

• Chromosomal translocations.

  Multiple chromosomal translocations have been identified in T-ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1, TAL2, LMO1, LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[162,163,172-176] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including FISH or PCR.[163] Variants in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-ALL.[165]

  Translocations resulting in chimeric fusion proteins are also observed in T-ALL.[170]

  • A NUP214::ABL1 fusion has been noted in 4% to 6% of T-ALL cases and is observed in both adults and children, with a male predominance.[177-179] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or, more rarely, as a small homogeneous staining region.[179] T-ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[179] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may demonstrate therapeutic benefits in this T-ALL subtype,[177,178,180] although clinical experience with this strategy is very limited.[181-183]
  • Gene fusions involving SPI1 (encoding the transcription factor PU.1) were reported in 4% of Japanese children with T-ALL.[184] Fusion partners included STMN1 and TCF7. T-ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.
  • BCL11B is a zinc finger transcription factor that plays a dual role as a transcription activator and repressor. It is known to play a critical role in T-cell differentiation. In T-ALL, the BCL11B gene is involved in a t(5;14)(q35;q32) translocation where a distal BCL11B enhancer drives aberrant expression of TLX3 (or NKX2-5).[185] In the process of donating its enhancer, one allele of BCL11B is inactivated. However, the resulting haploinsufficient state itself may also play a role in tumor pathogenesis. The role of BCL11B as a tumor suppressor gene is supported by the finding that about 16% of patients have T-ALL that harbors deletions or missense variants.[162,186] As described in the sections for early T-cell precursor (ETP) and T/myeloid mixed phenotype acute leukemia (T/M MPAL), BCL11B may also be leukemogenic through overexpression.
  • Other recurring gene fusions in T-ALL patients include those involving MLLT10, KMT2A, NUP214, and NUP98.[162,166]
• Ploidy.
  • Recurrent abnormalities in chromosome number are much less common in T-ALL than in B-ALL. One study included 2,250 pediatric patients with T-ALL who were treated in Associazione Italiana di Ematologia e Oncologia Pediatrica/Berlin-Frankfurt-Münster protocols. The study found that near tetraploidy (DNA index, 1.79–2.28 or 81–103 chromosomes), observed in 1.4% of patients, was associated with favorable disease features and outcomes.[187]

Early T-cell precursor (ETP) ALL cytogenetics/genomics

Detailed molecular characterization of ETP ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by variant or copy number alteration in more than one-third of cases.[188] Compared with other T-ALL cases, the ETP group had a lower rate of NOTCH1 variants and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of ETP ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[188]

Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL.[189,190] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of ETP phenotype.

Allele-specific, generally high expression of BCL11B plays an oncogenic role in a subset of cases identified as ETP ALL (7 of 58 in one study) as well as in up to 30% to 40% of lineage ambiguous leukemia T/M mixed phenotype acute leukemia (T/M MPAL).[191,192] The dysregulated expression of BCL11B can occur by multiple mechanisms.

• One such alteration is t(2;14)(q22;q32), which produces an in-frame ZEB2::BCL11B fusion gene.
• Other structural variants leading to allele-specific deregulated BCL11B expression include structural variants that juxtapose regulatory sequences of active genes (e.g., ARID1B [chromosome 6], BENC [chromosome 7], and CDK6 [chromosome 7]) upstream or downstream of the BCL11B locus leading to aberrant expression in a process called enhancer hijacking.
• Finally, in about 20% of cases with deregulated BCL11B expression, a translocation cannot be identified. In many such cases, amplification of a downstream enhancer, BCL11B enhancer tandem amplification (BETA), leads to BCL11B promoter driven transcription.
• There is a high prevalence of FLT3 alterations and JAK/STAT activation in acute leukemias driven by genomic alterations leading to BCL11B expression.[191]

Mixed phenotype acute leukemia (MPAL) cytogenetics/genomics

For acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[193,194] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 2.[106]

Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa

Condition	Definition
MPAL = mixed phenotype acute leukemia; NOS = not otherwise specified.
aAdapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[193] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.
Acute undifferentiated leukemia	Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
MPAL with BCR::ABL1 (t(9;22)(q34;q11.2))	Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have the (9;22) translocation or the BCR::ABL1 rearrangement
MPAL with KMT2A (t(v;11q23))	Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have a translocation involving the KMT2A gene
MPAL, B/myeloid, NOS (B/M MPAL)	Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A
MPAL, T/myeloid, NOS (T/M MPAL)	Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR::ABL1 or KMT2A
MPAL, B/myeloid, NOS—rare types	Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemias	Natural killer–cell lymphoblastic leukemia/lymphoma

Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa

Lineage	Criteria
aAdapted from Arber et al.[106]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineage	Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineage	Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B lineage	Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

The classification system for MPAL includes two entities that are defined by their primary molecular alteration: MPAL with BCR::ABL1 translocation and MPAL with KMT2A rearrangement. The genomic alterations associated with the MPAL, B/myeloid, NOS (B/M MPAL) and MPAL, T/myeloid, NOS (T/M MPAL) entities are distinctive, as described below:

• B/M MPAL.
  • Among 115 MPAL cases for which genomic characterization was performed, 35 (30%) were B/M MPAL. There were an additional 16 MPAL cases (14%) with KMT2A rearrangements, 15 of whom showed a B/myeloid immunophenotype.
  • Approximately one-half of B/M MPAL cases had rearrangements of ZNF384 with recurrent fusion partners, including TCF3 and EP300. These cases had gene expression profiles indistinguishable from B-ALL cases with ZNF384 rearrangements.[102]
  • Approximately two-thirds of B/M MPAL cases had RAS pathway alterations, with NRAS and PTPN11 being the most commonly altered genes.[102]
  • Genes encoding epigenetic regulators (e.g., MLLT3, KDM6A, EP300, and CREBBP) are altered in approximately two-thirds of B/M MPAL cases.[102]
• T/M MPAL.
  • Among 115 MPAL cases for which genomic characterization was performed, 49 (43%) were T/M MPAL.[102] The genomic features of the T/M MPAL cases shared commonalities with those of ETP ALL, suggesting that T/M MPAL and ETP ALL are similar entities along the spectrum of immature leukemias.
  • Compared with T-ALL, T/M MPAL showed a lower rate of alterations in the core T-ALL transcription factors (TAL1, TAL2, TLX1, TLX3, LMO1, LMO2, NKX2-1, HOXA10, and LYL1) (63% vs. 16%, respectively).[102] A similar lower rate was also observed for ETP ALL.
  • CDKN2A, CDKN2B, and NOTCH1 variants, which are present in approximately two-thirds of T-ALL cases, were much less common in T/M MPAL cases. By contrast, WT1 variants occurred in approximately 40% of T/M MPAL, but in less than 10% of T-ALL cases.[102]
  • One-third of T/M MPAL cases have genomic alterations associated with BCL11B that lead to allele-specific, generally high expression of BCL11B.[191,192]
    • One such alteration is t(2;14)(q22;q32), which produces an in-frame ZEB2::BCL11B fusion gene that leads to deregulated expression of BCL11B.
    • Other alterations leading to allele-specific deregulated BCL11B expression include structural variants that juxtapose regulatory sequences of active genes (e.g., ARID1B [chromosome 6], BENC [chromosome 7], and CDK6 [chromosome 7]) upstream or downstream of the BCL11B locus in a process called enhancer hijacking.
    • Finally, a translocation cannot be identified in about 20% of cases with deregulated BCL11B overexpression. In such cases, amplification of a downstream enhancer, BCL11B enhancer tandem amplification (BETA), leads to BCL11B promoter driven transcription.
    • There is a high prevalence of FLT3 alterations and JAK/STAT activation in acute leukemias driven by genomic alterations leading to BCL11B overexpression.
  • RAS and JAK-STAT pathway variants were common in the T/M MPAL and ETP ALL cases, while the PI3K signaling pathway is more commonly altered in T-ALL.[102] For T/M MPAL, the most commonly altered signaling pathway gene was FLT3 (43% of cases). FLT3 variants tended to be mutually exclusive with RAS pathway variants.
  • Genes encoding epigenetic regulators (e.g., EZH2 and PHF6) were altered in approximately two-thirds of T/M MPAL cases.[102]

Gene polymorphisms in drug metabolic pathways

Several polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[195-197]

• TPMT.

  Patients with variant phenotypes of TPMT (a gene involved in the metabolism of thiopurines such as mercaptopurine) appear to have more favorable outcomes,[198] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression, infection, and second malignancies.[199,200] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this variant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[201,202]

• NUDT15.

  Germline variants in NUDT15 that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[201,203] The NUDT15 variants are most common in East Asian and Hispanic patients, and they are rare in European and African patients. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[201,204]

• CEP72.

  Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[205]

• Single nucleotide polymorphisms.

  Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of interleukin-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[206] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[207,208] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations. It is unknown whether individualized dose modification on the basis of these findings will improve outcomes.

For information about the treatment of childhood ALL, see Childhood Acute Lymphoblastic Leukemia Treatment.

Juvenile Myelomonocytic Leukemia (JMML)

Molecular Features of JMML

The genomic landscape of JMML is characterized by variants in one of five genes of the RAS pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[405-407] In a series of 118 consecutively diagnosed JMML cases with RAS pathway–activating variants, PTPN11 was the most commonly altered gene, accounting for 51% of cases (19% germline and 32% somatic) (see Figure 5).[405] Patients with NRAS variants accounted for 19% of cases, and patients with KRAS variants accounted for 15% of cases. NF1 variants accounted for 8% of cases, and CBL variants accounted for 11% of cases. Although variants among these five genes are generally mutually exclusive, 4% to 17% of cases have variants in two of these RAS pathway genes,[405-407] a finding that is associated with poorer prognosis.[405,407]

The variant rate in JMML leukemia cells is very low, but additional variants beyond those of the five RAS pathway genes described above are observed.[405-407] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was altered in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also altered at low rates in JMML (e.g., SETBP1 was altered in 6%–9% of cases).[405-408] JAK3 variants are also observed in a small percentage (4%–12%) of JMML cases.[405-408] Cases with germline PTPN11 and germline CBL variants showed low rates of additional variants (see Figure 5).[405] The presence of variants beyond disease-defining RAS pathway variants is associated with an inferior prognosis.[405,406]

A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical RAS pathway variants. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1::ALK, RANBP2::ALK, and TBL1XR1::ROS1 gene fusions). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK gene fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplant.[407]

Enlarge

Genomic and Molecular Prognostic Factors

Several genomic factors affect the prognosis of patients with JMML, including the following:

1. Number of non–RAS pathway variants. A predictor of prognosis for children with JMML is the number of variants beyond the disease-defining RAS pathway variants.[405,406]
   • One study observed that zero or one somatic alteration (pathogenic variant or monosomy 7) was identified in 64 patients (65.3%) at diagnosis, whereas two or more alterations were identified in 34 patients (34.7%).[406] In multivariate analysis, variant number (2 or more vs. 0 or 1) maintained significance as a predictor of inferior event-free survival (EFS) and overall survival (OS). A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 variants.[406]
   • Another study observed that approximately 60% of patients had one or more additional variants beyond their disease-defining RAS pathway variant. These patients had an inferior OS compared with patients who had no additional variants (3-year OS rate, 61% vs. 85%, respectively).[405]
   • A third study observed a trend for an inferior OS for patients with two or more variants compared with patients with zero or one variant.[407]
2. RAS pathway double variants. Although variants in the five canonical RAS pathway genes associated with JMML (NF1, NRAS, KRAS, PTPN11, and CBL) are generally mutually exclusive, 4% to 17% of cases have variants in two of these RAS pathway genes.[405,406] This finding has been associated with a poorer prognosis.[405,406]
   • Two RAS pathway variants were identified in 11% of JMML patients in one report, and these patients had a significantly inferior EFS rate (14%) compared with patients who had a single RAS pathway variant (62%). Patients with Noonan syndrome were excluded from the analyses.[406]
   • Similar findings for RAS pathway variants were reported in a second study. This study observed that patients with RAS pathway double variants (15 of 96 patients) had lower survival rates than did patients with either no additional variants or with additional variants beyond the RAS pathway variant.[405]
3. DNA methylation profile.
   • One study applied DNA methylation profiling to a discovery cohort of 39 patients with JMML and to a validation cohort of 40 patients. Distinctive subsets of JMML with either high, intermediate, or low methylation levels were observed in both cohorts. Patients with the lowest methylation levels had the highest survival rates, and all but 1 of 15 patients experienced spontaneous resolution in the low methylation cohort. High methylation status was associated with lower EFS rates.[409]
   • Another study applied DNA methylation profiling to a cohort of 106 patients with JMML. The study observed one subgroup of patients with a hypermethylation profile and one subgroup of patients with a hypomethylation profile. Patients in the hypermethylation group had a significantly lower OS rate than did patients in the hypomethylation group (5-year OS rate, 46% vs. 73%, respectively). Patients in the hypermethylation group also had a significantly poorer 5-year transplant-free survival rate than did patients in the hypomethylation group (2.2%; 95% CI, 0.2%–10.1% vs. 41.2%; 95% CI, 27.1%–54.8%). Hypermethylation status was associated with two or more variants, higher fetal hemoglobin levels, older age, and lower platelet count at diagnosis. All patients with Noonan syndrome were in the hypomethylation group.[407]
   • A study examined 33 patients with JMML who had CBL variants. The study identified 31 patients with low methylation and 2 patients with intermediate methylation. Both of the children with intermediate methylation relapsed after undergoing HSCT. Because treatment, which included observation only, varied among the 31 patients with low methylation, the impact of the methylation profile on therapeutic decisions and outcomes could not be fully assessed. However, the methylation status was not prognostic of spontaneous resolution.[410]
4. LIN28B overexpression. LIN28B overexpression, which is present in approximately one-half of children with JMML, identifies a biologically distinctive subset of JMML. LIN28B is an RNA-binding protein that regulates stem cell renewal.[411]
   • LIN28B overexpression was positively correlated with high blood fetal hemoglobin level and age (both of which are associated with poor prognosis), and it was negatively correlated with presence of monosomy 7 (also associated with inferior prognosis). Although LIN28B overexpression identifies a subset of patients with increased risk of treatment failure, it was not found to be an independent prognostic factor when other factors such as age and monosomy 7 status are considered.[411]
   • Another study also observed a subset of JMML patients with elevated LIN28B expression. The study identified LIN28B as the gene for which expression was most strongly associated with hypermethylation status.[407]

For information about the treatment of JMML, see Juvenile Myelomonocytic Leukemia Treatment.

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185. Nagel S, Scherr M, Kel A, et al.: Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3'-BCL11B enhancers and coregulation by PU.1 and HMGA1. Cancer Res 67 (4): 1461-71, 2007. [PUBMED Abstract]
186. Gutierrez A, Kentsis A, Sanda T, et al.: The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood 118 (15): 4169-73, 2011. [PUBMED Abstract]
187. Ceppi F, Gotti G, Möricke A, et al.: Near-tetraploid T-cell acute lymphoblastic leukaemia in childhood: Results of the AIEOP-BFM ALL studies. Eur J Cancer 175: 120-124, 2022. [PUBMED Abstract]
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189. Gutierrez A, Dahlberg SE, Neuberg DS, et al.: Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. J Clin Oncol 28 (24): 3816-23, 2010. [PUBMED Abstract]
190. Yang YL, Hsiao CC, Chen HY, et al.: Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer 58 (6): 846-51, 2012. [PUBMED Abstract]
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194. Borowitz MJ, Béné MC, Harris NL, et al.: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 179-87.
195. Davies SM, Bhatia S, Ross JA, et al.: Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 100 (1): 67-71, 2002. [PUBMED Abstract]
196. Krajinovic M, Costea I, Chiasson S: Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 359 (9311): 1033-4, 2002. [PUBMED Abstract]
197. Krajinovic M, Lemieux-Blanchard E, Chiasson S, et al.: Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4 (1): 66-72, 2004. [PUBMED Abstract]
198. Schmiegelow K, Forestier E, Kristinsson J, et al.: Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 23 (3): 557-64, 2009. [PUBMED Abstract]
199. Relling MV, Hancock ML, Boyett JM, et al.: Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93 (9): 2817-23, 1999. [PUBMED Abstract]
200. Stanulla M, Schaeffeler E, Flohr T, et al.: Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293 (12): 1485-9, 2005. [PUBMED Abstract]
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202. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-8, 1999. [PUBMED Abstract]
203. Moriyama T, Nishii R, Perez-Andreu V, et al.: NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 48 (4): 367-73, 2016. [PUBMED Abstract]
204. Tanaka Y, Kato M, Hasegawa D, et al.: Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol 171 (1): 109-15, 2015. [PUBMED Abstract]
205. Diouf B, Crews KR, Lew G, et al.: Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 313 (8): 815-23, 2015. [PUBMED Abstract]
206. Yang JJ, Cheng C, Yang W, et al.: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301 (4): 393-403, 2009. [PUBMED Abstract]
207. Gregers J, Christensen IJ, Dalhoff K, et al.: The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 115 (23): 4671-7, 2010. [PUBMED Abstract]
208. Radtke S, Zolk O, Renner B, et al.: Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood 121 (26): 5145-53, 2013. [PUBMED Abstract]
209. Grimwade D, Walker H, Oliver F, et al.: The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92 (7): 2322-33, 1998. [PUBMED Abstract]
210. Harrison CJ, Hills RK, Moorman AV, et al.: Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol 28 (16): 2674-81, 2010. [PUBMED Abstract]
211. von Neuhoff C, Reinhardt D, Sander A, et al.: Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol 28 (16): 2682-9, 2010. [PUBMED Abstract]
212. Grimwade D, Hills RK, Moorman AV, et al.: Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116 (3): 354-65, 2010. [PUBMED Abstract]
213. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, et al.: Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 120 (16): 3187-205, 2012. [PUBMED Abstract]
214. Brown P, McIntyre E, Rau R, et al.: The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 110 (3): 979-85, 2007. [PUBMED Abstract]
215. Hollink IH, Zwaan CM, Zimmermann M, et al.: Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia 23 (2): 262-70, 2009. [PUBMED Abstract]
216. Ho PA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood 113 (26): 6558-66, 2009. [PUBMED Abstract]
217. Meshinchi S, Alonzo TA, Stirewalt DL, et al.: Clinical implications of FLT3 mutations in pediatric AML. Blood 108 (12): 3654-61, 2006. [PUBMED Abstract]
218. Tarlock K, Meshinchi S: Pediatric acute myeloid leukemia: biology and therapeutic implications of genomic variants. Pediatr Clin North Am 62 (1): 75-93, 2015. [PUBMED Abstract]
219. Bolouri H, Farrar JE, Triche T, et al.: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med 24 (1): 103-112, 2018. [PUBMED Abstract]
220. Zarnegar-Lumley S, Alonzo TA, Gerbing RB, et al.: Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, and ECOG analysis. Blood Adv 7 (19): 5941-5953, 2023. [PUBMED Abstract]
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222. Pfister SM, Reyes-Múgica M, Chan JKC, et al.: A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era. Cancer Discov 12 (2): 331-355, 2022. [PUBMED Abstract]
223. Khoury JD, Solary E, Abla O, et al.: The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 36 (7): 1703-1719, 2022. [PUBMED Abstract]
224. Klein K, Kaspers G, Harrison CJ, et al.: Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group. J Clin Oncol 33 (36): 4247-58, 2015. [PUBMED Abstract]
225. Creutzig U, Zimmermann M, Ritter J, et al.: Definition of a standard-risk group in children with AML. Br J Haematol 104 (3): 630-9, 1999. [PUBMED Abstract]
226. Raimondi SC, Chang MN, Ravindranath Y, et al.: Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood 94 (11): 3707-16, 1999. [PUBMED Abstract]
227. Lie SO, Abrahamsson J, Clausen N, et al.: Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials. Br J Haematol 122 (2): 217-25, 2003. [PUBMED Abstract]
228. Duployez N, Marceau-Renaut A, Boissel N, et al.: Comprehensive mutational profiling of core binding factor acute myeloid leukemia. Blood 127 (20): 2451-9, 2016. [PUBMED Abstract]
229. Faber ZJ, Chen X, Gedman AL, et al.: The genomic landscape of core-binding factor acute myeloid leukemias. Nat Genet 48 (12): 1551-1556, 2016. [PUBMED Abstract]
230. Chen W, Xie H, Wang H, et al.: Prognostic Significance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis. PLoS One 11 (1): e0146614, 2016. [PUBMED Abstract]
231. Shih LY, Liang DC, Huang CF, et al.: Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia 22 (2): 303-7, 2008. [PUBMED Abstract]
232. Goemans BF, Zwaan CM, Miller M, et al.: Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 19 (9): 1536-42, 2005. [PUBMED Abstract]
233. Pollard JA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood 115 (12): 2372-9, 2010. [PUBMED Abstract]
234. Shimada A, Taki T, Tabuchi K, et al.: KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood 107 (5): 1806-9, 2006. [PUBMED Abstract]
235. Manara E, Bisio V, Masetti R, et al.: Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002/01 trial: screening and prognostic impact of c-KIT mutations. Leukemia 28 (5): 1132-4, 2014. [PUBMED Abstract]
236. Chen X, Dou H, Wang X, et al.: KIT mutations correlate with adverse survival in children with core-binding factor acute myeloid leukemia. Leuk Lymphoma 59 (4): 829-836, 2018. [PUBMED Abstract]
237. Tokumasu M, Murata C, Shimada A, et al.: Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial. Leukemia 29 (12): 2438-41, 2015. [PUBMED Abstract]
238. Tarlock K, Alonzo TA, Wang YC, et al.: Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia. Clin Cancer Res 25 (16): 5038-5048, 2019. [PUBMED Abstract]
239. Srinivasan S, Dhamne C, Patkar N, et al.: KIT exon 17 mutations are predictive of inferior outcome in pediatric acute myeloid leukemia with RUNX1::RUNX1T1. Pediatr Blood Cancer 71 (2): e30791, 2024. [PUBMED Abstract]
240. Jahn N, Agrawal M, Bullinger L, et al.: Incidence and prognostic impact of ASXL2 mutations in adult acute myeloid leukemia patients with t(8;21)(q22;q22): a study of the German-Austrian AML Study Group. Leukemia 31 (4): 1012-1015, 2017. [PUBMED Abstract]
241. Yamato G, Shiba N, Yoshida K, et al.: ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis. Genes Chromosomes Cancer 56 (5): 382-393, 2017. [PUBMED Abstract]
242. Döhner K, Schlenk RF, Habdank M, et al.: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106 (12): 3740-6, 2005. [PUBMED Abstract]
243. Verhaak RG, Goudswaard CS, van Putten W, et al.: Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106 (12): 3747-54, 2005. [PUBMED Abstract]
244. Schnittger S, Schoch C, Kern W, et al.: Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106 (12): 3733-9, 2005. [PUBMED Abstract]
245. Falini B, Mecucci C, Tiacci E, et al.: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352 (3): 254-66, 2005. [PUBMED Abstract]
246. Schlenk RF, Döhner K, Krauter J, et al.: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358 (18): 1909-18, 2008. [PUBMED Abstract]
247. Gale RE, Green C, Allen C, et al.: The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111 (5): 2776-84, 2008. [PUBMED Abstract]
248. Cazzaniga G, Dell'Oro MG, Mecucci C, et al.: Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood 106 (4): 1419-22, 2005. [PUBMED Abstract]
249. Balgobind BV, Hollink IH, Arentsen-Peters ST, et al.: Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia. Haematologica 96 (10): 1478-87, 2011. [PUBMED Abstract]
250. Staffas A, Kanduri M, Hovland R, et al.: Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood 118 (22): 5905-13, 2011. [PUBMED Abstract]
251. Tarlock K, Gerbing RB, Ries RE, et al.: Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia. Blood Adv 8 (9): 2094-2103, 2024. [PUBMED Abstract]
252. Tawana K, Wang J, Renneville A, et al.: Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126 (10): 1214-23, 2015. [PUBMED Abstract]
253. Tarlock K, Lamble AJ, Wang YC, et al.: CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group. Blood 138 (13): 1137-1147, 2021. [PUBMED Abstract]
254. Marcucci G, Maharry K, Radmacher MD, et al.: Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol 26 (31): 5078-87, 2008. [PUBMED Abstract]
255. Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, et al.: Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 113 (13): 3088-91, 2009. [PUBMED Abstract]
256. Dufour A, Schneider F, Metzeler KH, et al.: Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol 28 (4): 570-7, 2010. [PUBMED Abstract]
257. Taskesen E, Bullinger L, Corbacioglu A, et al.: Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 117 (8): 2469-75, 2011. [PUBMED Abstract]
258. Fasan A, Haferlach C, Alpermann T, et al.: The role of different genetic subtypes of CEBPA mutated AML. Leukemia 28 (4): 794-803, 2014. [PUBMED Abstract]
259. Wakita S, Sakaguchi M, Oh I, et al.: Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia. Blood Adv 6 (1): 238-247, 2022. [PUBMED Abstract]
260. Taube F, Georgi JA, Kramer M, et al.: CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome. Blood 139 (1): 87-103, 2022. [PUBMED Abstract]
261. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, et al.: Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica 96 (3): 384-92, 2011. [PUBMED Abstract]
262. Tarlock K, Alonzo T, Wang YC, et al.: Prognostic impact of CSF3R mutations in favorable risk childhood acute myeloid leukemia. Blood 135 (18): 1603-1606, 2020. [PUBMED Abstract]
263. Tawana K, Rio-Machin A, Preudhomme C, et al.: Familial CEBPA-mutated acute myeloid leukemia. Semin Hematol 54 (2): 87-93, 2017. [PUBMED Abstract]
264. Pui CH, Relling MV, Rivera GK, et al.: Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 9 (12): 1990-6, 1995. [PUBMED Abstract]
265. Inaba H, Zhou Y, Abla O, et al.: Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood 126 (13): 1575-84, 2015. [PUBMED Abstract]
266. de Rooij JD, Branstetter C, Ma J, et al.: Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 49 (3): 451-456, 2017. [PUBMED Abstract]
267. Balgobind BV, Raimondi SC, Harbott J, et al.: Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 114 (12): 2489-96, 2009. [PUBMED Abstract]
268. Swansbury GJ, Slater R, Bain BJ, et al.: Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants. Leukemia 12 (5): 792-800, 1998. [PUBMED Abstract]
269. Pollard JA, Guest E, Alonzo TA, et al.: Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol 39 (28): 3149-3160, 2021. [PUBMED Abstract]
270. van Weelderen RE, Klein K, Harrison CJ, et al.: Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group. J Clin Oncol 41 (16): 2963-2974, 2023. [PUBMED Abstract]
271. van Weelderen RE, Harrison CJ, Klein K, et al.: Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia. Blood Adv 8 (12): 3200-3213, 2024. [PUBMED Abstract]
272. Gröschel S, Sanders MA, Hoogenboezem R, et al.: A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157 (2): 369-81, 2014. [PUBMED Abstract]
273. Yamazaki H, Suzuki M, Otsuki A, et al.: A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 25 (4): 415-27, 2014. [PUBMED Abstract]
274. Mrózek K, Heerema NA, Bloomfield CD: Cytogenetics in acute leukemia. Blood Rev 18 (2): 115-36, 2004. [PUBMED Abstract]
275. Lugthart S, Gröschel S, Beverloo HB, et al.: Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol 28 (24): 3890-8, 2010. [PUBMED Abstract]
276. Balgobind BV, Lugthart S, Hollink IH, et al.: EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 24 (5): 942-9, 2010. [PUBMED Abstract]
277. Elsherif M, Hammad M, Hafez H, et al.: MECOM gene overexpression in pediatric patients with acute myeloid leukemia. Acta Oncol 61 (4): 516-522, 2022. [PUBMED Abstract]
278. Baldazzi C, Luatti S, Zuffa E, et al.: Complex chromosomal rearrangements leading to MECOM overexpression are recurrent in myeloid malignancies with various 3q abnormalities. Genes Chromosomes Cancer 55 (4): 375-88, 2016. [PUBMED Abstract]
279. Lim G, Choi JR, Kim MJ, et al.: Detection of t(3;5) and NPM1/MLF1 rearrangement in an elderly patient with acute myeloid leukemia: clinical and laboratory study with review of the literature. Cancer Genet Cytogenet 199 (2): 101-9, 2010. [PUBMED Abstract]
280. Dumézy F, Renneville A, Mayeur-Rousse C, et al.: Acute myeloid leukemia with translocation t(3;5): new molecular insights. Haematologica 98 (4): e52-4, 2013. [PUBMED Abstract]
281. Ageberg M, Drott K, Olofsson T, et al.: Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis. Genes Chromosomes Cancer 47 (4): 276-87, 2008. [PUBMED Abstract]
282. Shiba N, Ichikawa H, Taki T, et al.: NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia. Genes Chromosomes Cancer 52 (7): 683-93, 2013. [PUBMED Abstract]
283. Slovak ML, Gundacker H, Bloomfield CD, et al.: A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies. Leukemia 20 (7): 1295-7, 2006. [PUBMED Abstract]
284. Alsabeh R, Brynes RK, Slovak ML, et al.: Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am J Clin Pathol 107 (4): 430-7, 1997. [PUBMED Abstract]
285. Sandahl JD, Coenen EA, Forestier E, et al.: t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients. Haematologica 99 (5): 865-72, 2014. [PUBMED Abstract]
286. Tarlock K, Alonzo TA, Moraleda PP, et al.: Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: a report from the Children's Oncology Group. Br J Haematol 166 (2): 254-9, 2014. [PUBMED Abstract]
287. Lamble AJ, Hagiwara K, Gerbing RB, et al.: CREBBP alterations are associated with a poor prognosis in de novo AML. Blood 141 (17): 2156-2159, 2023. [PUBMED Abstract]
288. Coenen EA, Zwaan CM, Reinhardt D, et al.: Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood 122 (15): 2704-13, 2013. [PUBMED Abstract]
289. Wong KF, Yuen HL, Siu LL, et al.: t(8;16)(p11;p13) predisposes to a transient but potentially recurring neonatal leukemia. Hum Pathol 39 (11): 1702-7, 2008. [PUBMED Abstract]
290. Wu X, Sulavik D, Roulston D, et al.: Spontaneous remission of congenital acute myeloid leukemia with t(8;16)(p11;13). Pediatr Blood Cancer 56 (2): 331-2, 2011. [PUBMED Abstract]
291. Terui K, Sato T, Sasaki S, et al.: Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13). Haematologica 93 (10): 1591-3, 2008. [PUBMED Abstract]
292. Noort S, Zimmermann M, Reinhardt D, et al.: Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: a retrospective study by the I-BFM Study Group. Blood 132 (15): 1584-1592, 2018. [PUBMED Abstract]
293. Gruber TA, Larson Gedman A, Zhang J, et al.: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell 22 (5): 683-97, 2012. [PUBMED Abstract]
294. Thiollier C, Lopez CK, Gerby B, et al.: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. J Exp Med 209 (11): 2017-31, 2012. [PUBMED Abstract]
295. de Rooij JD, Hollink IH, Arentsen-Peters ST, et al.: NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia 27 (12): 2280-8, 2013. [PUBMED Abstract]
296. Masetti R, Pigazzi M, Togni M, et al.: CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype. Blood 121 (17): 3469-72, 2013. [PUBMED Abstract]
297. Masetti R, Rondelli R, Fagioli F, et al.: Infants with acute myeloid leukemia treated according to the Associazione Italiana di Ematologia e Oncologia Pediatrica 2002/01 protocol have an outcome comparable to that of older children. Haematologica 99 (8): e127-9, 2014. [PUBMED Abstract]
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330. Abla O, Ries RE, Triche T, et al.: Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia. Blood Adv 8 (8): 2005-2017, 2024. [PUBMED Abstract]
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332. Schnittger S, Schoch C, Dugas M, et al.: Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100 (1): 59-66, 2002. [PUBMED Abstract]
333. Thiede C, Steudel C, Mohr B, et al.: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99 (12): 4326-35, 2002. [PUBMED Abstract]
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335. Meshinchi S, Stirewalt DL, Alonzo TA, et al.: Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 102 (4): 1474-9, 2003. [PUBMED Abstract]
336. Zwaan CM, Meshinchi S, Radich JP, et al.: FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 102 (7): 2387-94, 2003. [PUBMED Abstract]
337. Voigt AP, Brodersen LE, Alonzo TA, et al.: Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children's Oncology Group protocol AAML0531. Haematologica 102 (12): 2058-2068, 2017. [PUBMED Abstract]
338. Berman JN, Gerbing RB, Alonzo TA, et al.: Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children's Oncology Group. Leukemia 25 (6): 1039-42, 2011. [PUBMED Abstract]
339. Kühn MW, Radtke I, Bullinger L, et al.: High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. Blood 119 (10): e67-75, 2012. [PUBMED Abstract]
340. Lion T, Haas OA: Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma 11 (1-2): 15-20, 1993. [PUBMED Abstract]
341. Duchayne E, Fenneteau O, Pages MP, et al.: Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Français d'Hématologie Cellulaire (GFHC). Leuk Lymphoma 44 (1): 49-58, 2003. [PUBMED Abstract]
342. Ma Z, Morris SW, Valentine V, et al.: Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28 (3): 220-1, 2001. [PUBMED Abstract]
343. Mercher T, Coniat MB, Monni R, et al.: Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci U S A 98 (10): 5776-9, 2001. [PUBMED Abstract]
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345. Hammer ASB, Juul-Dam KL, Sandahl JD, et al.: Hypodiploidy has unfavorable impact on survival in pediatric acute myeloid leukemia: an I-BFM Study Group collaboration. Blood Adv 7 (6): 1045-1055, 2023. [PUBMED Abstract]
346. Umeda M, Ma J, Huang BJ, et al.: Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia. Blood Cancer Discov 3 (3): 194-207, 2022. [PUBMED Abstract]
347. Ryland GL, Umeda M, Holmfeldt L, et al.: Description of a novel subtype of acute myeloid leukemia defined by recurrent CBFB insertions. Blood 141 (7): 800-805, 2023. [PUBMED Abstract]
348. Rungjirajittranon T, Siriwannangkul T, Kungwankiattichai S, et al.: Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis. Cancers (Basel) 14 (21): , 2022. [PUBMED Abstract]
349. Yamato G, Shiba N, Yoshida K, et al.: RUNX1 mutations in pediatric acute myeloid leukemia are associated with distinct genetic features and an inferior prognosis. Blood 131 (20): 2266-2270, 2018. [PUBMED Abstract]
350. Sendker S, Awada A, Domagalla S, et al.: RUNX1 mutation has no prognostic significance in paediatric AML: a retrospective study of the AML-BFM study group. Leukemia 37 (7): 1435-1443, 2023. [PUBMED Abstract]
351. Paschka P, Marcucci G, Ruppert AS, et al.: Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 26 (28): 4595-602, 2008. [PUBMED Abstract]
352. Virappane P, Gale R, Hills R, et al.: Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 26 (33): 5429-35, 2008. [PUBMED Abstract]
353. Gaidzik VI, Schlenk RF, Moschny S, et al.: Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 113 (19): 4505-11, 2009. [PUBMED Abstract]
354. Renneville A, Boissel N, Zurawski V, et al.: Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer 115 (16): 3719-27, 2009. [PUBMED Abstract]
355. Ho PA, Zeng R, Alonzo TA, et al.: Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood 116 (5): 702-10, 2010. [PUBMED Abstract]
356. Hollink IH, van den Heuvel-Eibrink MM, Zimmermann M, et al.: Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood 113 (23): 5951-60, 2009. [PUBMED Abstract]
357. Ley TJ, Ding L, Walter MJ, et al.: DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363 (25): 2424-33, 2010. [PUBMED Abstract]
358. Yan XJ, Xu J, Gu ZH, et al.: Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43 (4): 309-15, 2011. [PUBMED Abstract]
359. Thol F, Damm F, Lüdeking A, et al.: Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 29 (21): 2889-96, 2011. [PUBMED Abstract]
360. Ho PA, Kutny MA, Alonzo TA, et al.: Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group. Pediatr Blood Cancer 57 (2): 204-9, 2011. [PUBMED Abstract]
361. Green CL, Evans CM, Hills RK, et al.: The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood 116 (15): 2779-82, 2010. [PUBMED Abstract]
362. Paschka P, Schlenk RF, Gaidzik VI, et al.: IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 28 (22): 3636-43, 2010. [PUBMED Abstract]
363. Abbas S, Lugthart S, Kavelaars FG, et al.: Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood 116 (12): 2122-6, 2010. [PUBMED Abstract]
364. Marcucci G, Maharry K, Wu YZ, et al.: IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 28 (14): 2348-55, 2010. [PUBMED Abstract]
365. Wagner K, Damm F, Göhring G, et al.: Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 28 (14): 2356-64, 2010. [PUBMED Abstract]
366. Figueroa ME, Abdel-Wahab O, Lu C, et al.: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18 (6): 553-67, 2010. [PUBMED Abstract]
367. Ward PS, Patel J, Wise DR, et al.: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17 (3): 225-34, 2010. [PUBMED Abstract]
368. Dang L, White DW, Gross S, et al.: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462 (7274): 739-44, 2009. [PUBMED Abstract]
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370. Oki K, Takita J, Hiwatari M, et al.: IDH1 and IDH2 mutations are rare in pediatric myeloid malignancies. Leukemia 25 (2): 382-4, 2011. [PUBMED Abstract]
371. Pigazzi M, Ferrari G, Masetti R, et al.: Low prevalence of IDH1 gene mutation in childhood AML in Italy. Leukemia 25 (1): 173-4, 2011. [PUBMED Abstract]
372. Ho PA, Alonzo TA, Kopecky KJ, et al.: Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia 24 (5): 909-13, 2010. [PUBMED Abstract]
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374. Maxson JE, Ries RE, Wang YC, et al.: CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood 127 (24): 3094-8, 2016. [PUBMED Abstract]
375. Germeshausen M, Kratz CP, Ballmaier M, et al.: RAS and CSF3R mutations in severe congenital neutropenia. Blood 114 (16): 3504-5, 2009. [PUBMED Abstract]
376. Skokowa J, Steinemann D, Katsman-Kuipers JE, et al.: Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123 (14): 2229-37, 2014. [PUBMED Abstract]
377. Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999. [PUBMED Abstract]
378. Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009. [PUBMED Abstract]
379. Falini B, Flenghi L, Fagioli M, et al.: Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood 90 (10): 4046-53, 1997. [PUBMED Abstract]
380. Gomis F, Sanz J, Sempere A, et al.: Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia. Ann Hematol 83 (11): 687-90, 2004. [PUBMED Abstract]
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388. Sukhai MA, Wu X, Xuan Y, et al.: Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Oncogene 23 (3): 665-78, 2004. [PUBMED Abstract]
389. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11 (7): 1014-6, 1997. [PUBMED Abstract]
390. Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17 (1): 109-13, 1997. [PUBMED Abstract]
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392. Chen X, Wang F, Zhou X, et al.: Torque teno mini virus driven childhood acute promyelocytic leukemia: The third case report and sequence analysis. Front Oncol 12: 1074913, 2022. [PUBMED Abstract]
393. Sala-Torra O, Beppu LW, Abukar FA, et al.: TTMV-RARA fusion as a recurrent cause of AML with APL characteristics. Blood Adv 6 (12): 3590-3592, 2022. [PUBMED Abstract]
394. Callens C, Chevret S, Cayuela JM, et al.: Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19 (7): 1153-60, 2005. [PUBMED Abstract]
395. Gale RE, Hills R, Pizzey AR, et al.: Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106 (12): 3768-76, 2005. [PUBMED Abstract]
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397. Noguera NI, Breccia M, Divona M, et al.: Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16 (11): 2185-9, 2002. [PUBMED Abstract]
398. Tallman MS, Kim HT, Montesinos P, et al.: Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood 116 (25): 5650-9, 2010. [PUBMED Abstract]
399. Iland HJ, Bradstock K, Supple SG, et al.: All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120 (8): 1570-80; quiz 1752, 2012. [PUBMED Abstract]
400. Kutny MA, Moser BK, Laumann K, et al.: FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (4): 662-7, 2012. [PUBMED Abstract]
401. Kutny MA, Alonzo TA, Abla O, et al.: Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial. JAMA Oncol 8 (1): 79-87, 2022. [PUBMED Abstract]
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403. Loghavi S, Kanagal-Shamanna R, Khoury JD, et al.: Fifth Edition of the World Health Classification of Tumors of the Hematopoietic and Lymphoid Tissue: Myeloid Neoplasms. Mod Pathol 37 (2): 100397, 2024. [PUBMED Abstract]
404. Wang W, Cortes JE, Tang G, et al.: Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood 127 (22): 2742-50, 2016. [PUBMED Abstract]
405. Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 (11): 1334-40, 2015. [PUBMED Abstract]
406. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
407. Murakami N, Okuno Y, Yoshida K, et al.: Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131 (14): 1576-1586, 2018. [PUBMED Abstract]
408. Sakaguchi H, Okuno Y, Muramatsu H, et al.: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45 (8): 937-41, 2013. [PUBMED Abstract]
409. Stieglitz E, Mazor T, Olshen AB, et al.: Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun 8 (1): 2127, 2017. [PUBMED Abstract]
410. Hecht A, Meyer JA, Behnert A, et al.: Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia. Haematologica 107 (1): 178-186, 2022. [PUBMED Abstract]
411. Helsmoortel HH, Bresolin S, Lammens T, et al.: LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. Blood 127 (9): 1163-72, 2016. [PUBMED Abstract]
412. Schwartz JR, Ma J, Lamprecht T, et al.: The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8 (1): 1557, 2017. [PUBMED Abstract]
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414. Collin M, Dickinson R, Bigley V: Haematopoietic and immune defects associated with GATA2 mutation. Br J Haematol 169 (2): 173-87, 2015. [PUBMED Abstract]
415. Wlodarski MW, Hirabayashi S, Pastor V, et al.: Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 127 (11): 1387-97; quiz 1518, 2016. [PUBMED Abstract]
416. Wlodarski MW, Collin M, Horwitz MS: GATA2 deficiency and related myeloid neoplasms. Semin Hematol 54 (2): 81-86, 2017. [PUBMED Abstract]
417. Davidsson J, Puschmann A, Tedgård U, et al.: SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. Leukemia 32 (5): 1106-1115, 2018. [PUBMED Abstract]
418. Schwartz JR, Wang S, Ma J, et al.: Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia 31 (8): 1827-1830, 2017. [PUBMED Abstract]
419. Narumi S, Amano N, Ishii T, et al.: SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 48 (7): 792-7, 2016. [PUBMED Abstract]
420. Chen DH, Below JE, Shimamura A, et al.: Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet 98 (6): 1146-1158, 2016. [PUBMED Abstract]
421. Wong JC, Bryant V, Lamprecht T, et al.: Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. JCI Insight 3 (14): , 2018. [PUBMED Abstract]
422. Göhring G, Michalova K, Beverloo HB, et al.: Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 116 (19): 3766-9, 2010. [PUBMED Abstract]
423. Haase D, Germing U, Schanz J, et al.: New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110 (13): 4385-95, 2007. [PUBMED Abstract]
424. Arber DA, Vardiman JW, Brunning RD: Acute myeloid leukaemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 110-23.
425. Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003. [PUBMED Abstract]
426. Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003. [PUBMED Abstract]
427. Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006. [PUBMED Abstract]
428. Groet J, McElwaine S, Spinelli M, et al.: Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361 (9369): 1617-20, 2003. [PUBMED Abstract]
429. Rainis L, Bercovich D, Strehl S, et al.: Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102 (3): 981-6, 2003. [PUBMED Abstract]
430. Wechsler J, Greene M, McDevitt MA, et al.: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32 (1): 148-52, 2002. [PUBMED Abstract]
431. Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005. [PUBMED Abstract]
432. Sato T, Yoshida K, Toki T, et al.: Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms. Blood 143 (25): 2627-2643, 2024. [PUBMED Abstract]

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62. Tsuyama N, Sakamoto K, Sakata S, et al.: Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects. J Clin Exp Hematop 57 (3): 120-142, 2017. [PUBMED Abstract]
63. Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008. [PUBMED Abstract]
64. Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008. [PUBMED Abstract]
65. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000. [PUBMED Abstract]
66. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011. [PUBMED Abstract]
67. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014. [PUBMED Abstract]
68. Jaffe ES, Harris NL, Siebert R: Paediatric-type follicular lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 278-9.
69. Launay E, Pangault C, Bertrand P, et al.: High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 26 (3): 559-62, 2012. [PUBMED Abstract]
70. Schmidt J, Gong S, Marafioti T, et al.: Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. Blood 128 (8): 1101-11, 2016. [PUBMED Abstract]
71. Louissaint A, Schafernak KT, Geyer JT, et al.: Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. Blood 128 (8): 1093-100, 2016. [PUBMED Abstract]
72. Schmidt J, Ramis-Zaldivar JE, Nadeu F, et al.: Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 130 (3): 323-327, 2017. [PUBMED Abstract]
73. Ozawa MG, Bhaduri A, Chisholm KM, et al.: A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma. Mod Pathol 29 (10): 1212-20, 2016. [PUBMED Abstract]
74. Lim S, Lim KY, Koh J, et al.: Pediatric-Type Indolent B-Cell Lymphomas With Overlapping Clinical, Pathologic, and Genetic Features. Am J Surg Pathol 46 (10): 1397-1406, 2022. [PUBMED Abstract]

For information about the treatment of childhood Hodgkin lymphoma, see Childhood Hodgkin Lymphoma Treatment.

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22. Stein H, Marafioti T, Foss HD, et al.: Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97 (2): 496-501, 2001. [PUBMED Abstract]
23. Braeuninger A, Küppers R, Strickler JG, et al.: Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 94 (17): 9337-42, 1997. [PUBMED Abstract]
24. Falini B, Bigerna B, Pasqualucci L, et al.: Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease. Blood 87 (2): 465-71, 1996. [PUBMED Abstract]
25. Huppmann AR, Nicolae A, Slack GW, et al.: EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38 (3): 316-24, 2014. [PUBMED Abstract]
26. Prakash S, Fountaine T, Raffeld M, et al.: IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol 30 (5): 585-92, 2006. [PUBMED Abstract]
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Central nervous system (CNS) tumors include gliomas (including astrocytomas), glioneuronal tumors, neuronal tumors, CNS atypical teratoid/rhabdoid tumors, medulloblastomas, nonmedulloblastoma embryonal tumors, pineal tumors, and ependymomas.

The terminology of the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System is used below. The 2021 WHO CNS classification advances the role of molecular diagnostics in CNS tumor classification, and it includes multiple major changes from the previous 2016 WHO classification.[1]

Ependymomas

Molecular Subgroups of Ependymoma

Molecular characterization studies have previously identified nine molecular subgroups of ependymoma, six of which predominate in childhood. The subgroups are determined by their distinctive DNA methylation and gene expression profiles and unique spectrum of genomic alterations (see Figure 6).[166-169]

One new molecularly defined ependymoma was added to the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System: spinal ependymoma with MYCN amplification. The 2021 classification further described ependymal tumors defined by anatomical location and histology but not by molecular alteration. These tumors are called posterior fossa ependymoma (PF-EPN), supratentorial ependymoma (ST-EPN), and spinal ependymoma (SP-EPN). These tumors either contain a unique molecular alteration (not elsewhere classified [NEC]) or their molecular analysis failed or was not obtained (not otherwise specified [NOS]).[78]

• Infratentorial tumors.
  • Posterior fossa ependymoma (PF-EPN).
  • Posterior fossa A (PF-EPN-A), loss of H3 K27 trimethylation mark.
  • Posterior fossa B (PF-EPN-B), retained H3 K27 trimethylation mark.
• Supratentorial tumors.
  • Supratentorial ependymoma (ST-EPN).
  • ZFTA fusion–positive ependymoma (ST-EPN-ZFTA). This was previously called RELA fusion–positive ependymoma (ST-EPN-RELA), but it was renamed because ZFTA is the new designation for C11orf95, and ZFTA may be fused with a partner gene other than RELA.[170]
  • YAP1 fusion–positive ependymoma (ST-EPN-YAP1).
• Spinal tumors.
  • Spinal ependymoma (SP-EPN).
  • Spinal ependymoma, MYCN-amplified (SP-EPN-MYCN).
  • Myxopapillary ependymoma (SP-EPN-MPE).

Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the remaining three molecular variants, and it is rarely, if ever, seen in children.

Enlarge

Infratentorial tumors

Posterior fossa A ependymoma (PF-EPN-A)

The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:

• Presentation in young children (median age, 3 years).[166,171]
• Low rates of variants that affect protein structure, approximately five per genome.[167]
• Gain of chromosome 1q, a known poor prognostic factor for patients with ependymoma,[172] in approximately 25% of cases.[166,168,173]
• Loss of chromosome 6q, reported to be a poor prognostic factor for patients with PF-EPN-A, in 8% to 10% of cases.[174]
• A balanced chromosomal profile with few chromosomal gains or losses.[166,167]
• Loss of the H3 K27 trimethylation mark and globally hypomethylated DNA.[175] A prospective multi-institutional study analyzed 147 patients with ependymoma. The study reported high sensitivity and specificity for immunohistochemical detection of loss of the H3 K27 trimethylation mark in identifying PF-EPN-A cases.[176] Loss of this mark occurs through multiple mechanisms, including the following:
  • Recurrent variants of EZHIP in 10% of cases, with high EZHIP mRNA expression across almost all PF-EPN-A.[46,177] EZHIP expression (with or without alteration) results in inhibition of the methyltransferase EZH2 leading to loss of the H3 K27 trimethylation mark.[45,46]
  • Recurrent K27M variants in histone H3 variants in a small proportion of cases.[178,179] Unlike diffuse midline gliomas, variants in H3.1 (H3C2 and H3C3) are more common than variants in H3.3 (H3-3A).[177] Histone variants are mutually exclusive with high expression of EZHIP,[177] and they also lead to loss of the H3 K27 trimethylation mark through EZH2 inhibition.

A study that included over 600 cases of PF-EPN-A used methylation array profiling to divide this population into two distinctive subgroups, PFA-1 and PFA-2.[177] Gene expression profiling suggested that these two subtypes may arise in different anatomical locations in the hindbrain. Within both PFA-1 and PFA-2 groups, distinctive minor subtypes could be identified, suggesting the presence of heterogeneity. Additional study will be required to define the clinical significance of these subtypes.

Posterior fossa B ependymoma (PF-EPN-B)

The PF-EPN-B subgroup is less common than the PF-EPN-A subgroup, representing 15% to 20% of all posterior fossa ependymomas in children. PF-EPN-B is characterized by the following:

• Presentation primarily in adolescents and young adults (median age, 30 years).[166,171]
• Low rates of variants that affect protein structure (approximately five per genome), with no recurring variants.[168]
• Numerous cytogenetic abnormalities, primarily involving the gain/loss of whole chromosomes.[166,168]
• Retained H3 K27 trimethylation.[175]
• 1q gain and 6q loss occur in PF-EPN-B but have not been reported as prognostic in this subgroup (unlike in PF-EPN-A).[180]

Supratentorial tumors

Supratentorial ependymomas with ZFTA fusions (ST-EPN-ZFTA)

ST-EPN-ZFTA is the largest subset of pediatric supratentorial ependymomas and is predominantly characterized by gene fusions involving RELA,[181,182] a transcriptional factor important in NF-κB pathway activity. ST-EPN-ZFTA is characterized by the following:

• Represents approximately 70% of supratentorial ependymomas in children,[181,182] and presents at a median age of 8 years.[166]
• Presence of ZFTA fusions result from chromothripsis involving chromosome 11q13.1.[181]
• Low rates of variants that affect protein structure and near absence of recurring variants outside of ZFTA::RELA fusions.[181]
• Evidence of NF-κB pathway activation at the protein and RNA level.[181]
• Gain of chromosome 1q, in approximately one-quarter of cases, with an indeterminate effect on survival.[166]
• The concordance was high between immunohistochemistry for nuclear p65-RelA, fluorescence in situ hybridization for ZFTA and RELA, and DNA methylation-based classification for defining ST-EPN-ZFTA.[183]
• Homozygous deletion of CDKN2A has been associated with a poor prognosis in patients with ZFTA fusion–positive ependymoma.[184][Level of evidence B4] CDKN2A deletion has also been reported as a secondary event in recurrent ependymoma.[185]

Supratentorial ependymomas with YAP1 fusions (ST-EPN-YAP1)

ST-EPN-YAP1 is the second, less common subset of supratentorial ependymomas and has fusions involving YAP1 on chromosome 11. ST-EPN-YAP1 is characterized by the following:

• Median age at diagnosis of 1.4 years.[166]
• Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[166,181]
• A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[166]

Tumors mimicking supratentorial ependymomas

Supratentorial ependymomas without ZFTA or YAP1 fusions (on chromosome 11) are an undefined entity, and it is unclear what these samples represent. By DNA methylation analysis, these samples often cluster with other entities such as high-grade gliomas and embryonal tumors. As one example, a retrospective methylation analysis of supratentorial brain tumors identified a group of tumors distinct from supratentorial ependymoma that harbor recurrent PLAGL1 fusions.[186] The histological lineage of these PLAGL1-altered tumors is not yet clear. Nineteen of the 32 tumors (59%) had previously been reported as ependymomas. Caution should be taken when diagnosing a supratentorial ependymoma that does not harbor a fusion involving chromosome 11.[28,170,187]

Spinal ependymoma with MYCN amplification (SP-EPN-MYCN)

SP-EPN-MYCN is rare, with only 27 cases reported.[188-191]

• Median age at presentation was 31 years (range, 12–56 years).
• High level of MYCN amplification was present at diagnosis and relapse.
• SP-EPN-MYCN has a unique methylation profile compared with other spinal cord ependymomas, MYCN-amplified pediatric-type glioblastoma, and neuroblastoma.

For information about the treatment of childhood ependymoma, see Childhood Ependymoma Treatment.

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85. Johann PD, Hovestadt V, Thomas C, et al.: Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome. Brain Pathol 27 (4): 411-418, 2017. [PUBMED Abstract]
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87. Federico A, Thomas C, Miskiewicz K, et al.: ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance. Acta Neuropathol 143 (6): 697-711, 2022. [PUBMED Abstract]
88. Wilson BG, Wang X, Shen X, et al.: Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18 (4): 316-28, 2010. [PUBMED Abstract]
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90. Kurmasheva RT, Sammons M, Favours E, et al.: Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 64 (3): , 2017. [PUBMED Abstract]
91. Italiano A, Soria JC, Toulmonde M, et al.: Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol 19 (5): 649-659, 2018. [PUBMED Abstract]
92. Onvani S, Etame AB, Smith CA, et al.: Genetics of medulloblastoma: clues for novel therapies. Expert Rev Neurother 10 (5): 811-23, 2010. [PUBMED Abstract]
93. Dubuc AM, Northcott PA, Mack S, et al.: The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10 (3): 215-23, 2010. [PUBMED Abstract]
94. Thompson MC, Fuller C, Hogg TL, et al.: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24 (12): 1924-31, 2006. [PUBMED Abstract]
95. Kool M, Koster J, Bunt J, et al.: Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3 (8): e3088, 2008. [PUBMED Abstract]
96. Tabori U, Baskin B, Shago M, et al.: Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28 (8): 1345-50, 2010. [PUBMED Abstract]
97. Pfister S, Remke M, Benner A, et al.: Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27 (10): 1627-36, 2009. [PUBMED Abstract]
98. Ellison DW, Onilude OE, Lindsey JC, et al.: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23 (31): 7951-7, 2005. [PUBMED Abstract]
99. Polkinghorn WR, Tarbell NJ: Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4 (5): 295-304, 2007. [PUBMED Abstract]
100. Giangaspero F, Wellek S, Masuoka J, et al.: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112 (1): 5-12, 2006. [PUBMED Abstract]
101. Northcott PA, Korshunov A, Witt H, et al.: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29 (11): 1408-14, 2011. [PUBMED Abstract]
102. Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002. [PUBMED Abstract]
103. Jones DT, Jäger N, Kool M, et al.: Dissecting the genomic complexity underlying medulloblastoma. Nature 488 (7409): 100-5, 2012. [PUBMED Abstract]
104. Peyrl A, Chocholous M, Kieran MW, et al.: Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59 (3): 511-7, 2012. [PUBMED Abstract]
105. Taylor MD, Northcott PA, Korshunov A, et al.: Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123 (4): 465-72, 2012. [PUBMED Abstract]
106. Kool M, Korshunov A, Remke M, et al.: Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 123 (4): 473-84, 2012. [PUBMED Abstract]
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110. Morrissy AS, Cavalli FMG, Remke M, et al.: Spatial heterogeneity in medulloblastoma. Nat Genet 49 (5): 780-788, 2017. [PUBMED Abstract]
111. Wang X, Dubuc AM, Ramaswamy V, et al.: Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol 129 (3): 449-57, 2015. [PUBMED Abstract]
112. Cavalli FMG, Remke M, Rampasek L, et al.: Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell 31 (6): 737-754.e6, 2017. [PUBMED Abstract]
113. Northcott PA, Buchhalter I, Morrissy AS, et al.: The whole-genome landscape of medulloblastoma subtypes. Nature 547 (7663): 311-317, 2017. [PUBMED Abstract]
114. Schwalbe EC, Lindsey JC, Nakjang S, et al.: Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol 18 (7): 958-971, 2017. [PUBMED Abstract]
115. Hicks D, Rafiee G, Schwalbe EC, et al.: The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes. Neuropathol Appl Neurobiol 47 (2): 236-250, 2021. [PUBMED Abstract]
116. Northcott PA, Jones DT, Kool M, et al.: Medulloblastomics: the end of the beginning. Nat Rev Cancer 12 (12): 818-34, 2012. [PUBMED Abstract]
117. Korshunov A, Sahm F, Zheludkova O, et al.: DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas. Neuro Oncol 21 (2): 214-221, 2019. [PUBMED Abstract]
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119. Ellison DW, Dalton J, Kocak M, et al.: Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121 (3): 381-96, 2011. [PUBMED Abstract]
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121. Michalski JM, Janss AJ, Vezina LG, et al.: Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma. J Clin Oncol 39 (24): 2685-2697, 2021. [PUBMED Abstract]
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124. Begemann M, Waszak SM, Robinson GW, et al.: Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma. J Clin Oncol 38 (1): 43-50, 2020. [PUBMED Abstract]
125. Shuai S, Suzuki H, Diaz-Navarro A, et al.: The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature 574 (7780): 712-716, 2019. [PUBMED Abstract]
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127. Kool M, Jones DT, Jäger N, et al.: Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25 (3): 393-405, 2014. [PUBMED Abstract]
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131. Leary SE, Zhou T, Holmes E, et al.: Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Cancer 117 (14): 3262-7, 2011. [PUBMED Abstract]
132. Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999. [PUBMED Abstract]
133. Rutkowski S, von Hoff K, Emser A, et al.: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28 (33): 4961-8, 2010. [PUBMED Abstract]
134. Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome--a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009. [PUBMED Abstract]
135. von Bueren AO, von Hoff K, Pietsch T, et al.: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 13 (6): 669-79, 2011. [PUBMED Abstract]
136. Shih DJ, Northcott PA, Remke M, et al.: Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32 (9): 886-96, 2014. [PUBMED Abstract]
137. Schwalbe EC, Williamson D, Lindsey JC, et al.: DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol 125 (3): 359-71, 2013. [PUBMED Abstract]
138. Zhukova N, Ramaswamy V, Remke M, et al.: Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 31 (23): 2927-35, 2013. [PUBMED Abstract]
139. Gajjar A, Robinson GW, Smith KS, et al.: Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03). J Clin Oncol 39 (7): 822-835, 2021. [PUBMED Abstract]
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141. Gottardo NG, Hansford JR, McGlade JP, et al.: Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol 127 (2): 189-201, 2014. [PUBMED Abstract]
142. Louis DN, Perry A, Burger P, et al.: International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 24 (5): 429-35, 2014. [PUBMED Abstract]
143. Sharma T, Schwalbe EC, Williamson D, et al.: Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes. Acta Neuropathol 138 (2): 309-326, 2019. [PUBMED Abstract]
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146. Picard D, Miller S, Hawkins CE, et al.: Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 13 (8): 838-48, 2012. [PUBMED Abstract]
147. Spence T, Sin-Chan P, Picard D, et al.: CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol 128 (2): 291-303, 2014. [PUBMED Abstract]
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151. Li M, Lee KF, Lu Y, et al.: Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 16 (6): 533-46, 2009. [PUBMED Abstract]
152. Korshunov A, Okonechnikov K, Schmitt-Hoffner F, et al.: Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation. Acta Neuropathol Commun 9 (1): 20, 2021. [PUBMED Abstract]
153. Ueno-Yokohata H, Okita H, Nakasato K, et al.: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47 (8): 861-3, 2015. [PUBMED Abstract]
154. Roy A, Kumar V, Zorman B, et al.: Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat Commun 6: 8891, 2015. [PUBMED Abstract]
155. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007. [PUBMED Abstract]
156. Sharma MC, Mahapatra AK, Gaikwad S, et al.: Pigmented medulloepithelioma: report of a case and review of the literature. Childs Nerv Syst 14 (1-2): 74-8, 1998 Jan-Feb. [PUBMED Abstract]
157. Jakobiec FA, Kool M, Stagner AM, et al.: Intraocular Medulloepitheliomas and Embryonal Tumors With Multilayered Rosettes of the Brain: Comparative Roles of LIN28A and C19MC. Am J Ophthalmol 159 (6): 1065-1074.e1, 2015. [PUBMED Abstract]
158. Korshunov A, Jakobiec FA, Eberhart CG, et al.: Comparative integrated molecular analysis of intraocular medulloepitheliomas and central nervous system embryonal tumors with multilayered rosettes confirms that they are distinct nosologic entities. Neuropathology 35 (6): 538-44, 2015. [PUBMED Abstract]
159. Keck MK, Sill M, Wittmann A, et al.: Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. Acta Neuropathol 145 (1): 49-69, 2023. [PUBMED Abstract]
160. de Jong MC, Kors WA, de Graaf P, et al.: Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 15 (10): 1157-67, 2014. [PUBMED Abstract]
161. Ramasubramanian A, Kytasty C, Meadows AT, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (4): 825-9, 2013. [PUBMED Abstract]
162. Abramson DH, Dunkel IJ, Marr BP, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (6): 1319-20, 2013. [PUBMED Abstract]
163. Turaka K, Shields CL, Meadows AT, et al.: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer 59 (1): 121-5, 2012. [PUBMED Abstract]
164. Liu APY, Li BK, Pfaff E, et al.: Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study. Acta Neuropathol 141 (5): 771-785, 2021. [PUBMED Abstract]
165. de Kock L, Sabbaghian N, Druker H, et al.: Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 128 (4): 583-95, 2014. [PUBMED Abstract]
166. Pajtler KW, Witt H, Sill M, et al.: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27 (5): 728-43, 2015. [PUBMED Abstract]
167. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011. [PUBMED Abstract]
168. Mack SC, Witt H, Piro RM, et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 (7489): 445-50, 2014. [PUBMED Abstract]
169. Pajtler KW, Mack SC, Ramaswamy V, et al.: The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 133 (1): 5-12, 2017. [PUBMED Abstract]
170. Zschernack V, Jünger ST, Mynarek M, et al.: Supratentorial ependymoma in childhood: more than just RELA or YAP. Acta Neuropathol 141 (3): 455-466, 2021. [PUBMED Abstract]
171. Ramaswamy V, Hielscher T, Mack SC, et al.: Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34 (21): 2468-77, 2016. [PUBMED Abstract]
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173. Merchant TE, Bendel AE, Sabin ND, et al.: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma. J Clin Oncol 37 (12): 974-983, 2019. [PUBMED Abstract]
174. Baroni LV, Sundaresan L, Heled A, et al.: Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol 23 (8): 1360-1370, 2021. [PUBMED Abstract]
175. Panwalkar P, Clark J, Ramaswamy V, et al.: Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol 134 (5): 705-714, 2017. [PUBMED Abstract]
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180. Cavalli FMG, Hübner JM, Sharma T, et al.: Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol 136 (2): 227-237, 2018. [PUBMED Abstract]
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182. Pietsch T, Wohlers I, Goschzik T, et al.: Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. Acta Neuropathol 127 (4): 609-11, 2014. [PUBMED Abstract]
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189. Swanson AA, Raghunathan A, Jenkins RB, et al.: Spinal Cord Ependymomas With MYCN Amplification Show Aggressive Clinical Behavior. J Neuropathol Exp Neurol 78 (9): 791-797, 2019. [PUBMED Abstract]
190. Scheil S, Brüderlein S, Eicker M, et al.: Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol 11 (2): 133-43, 2001. [PUBMED Abstract]
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For information about the treatment of childhood liver cancer, see Childhood Liver Cancer Treatment.

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Genomics of LCH

BRAF, NRAS, and ARAF variants

The genomic basis of LCH was advanced by a 2010 report of an activating variant of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%).[1] Multiple subsequent reports have confirmed the presence of BRAF V600E variants in 50% or more of LCH cases in children.[2-4] Other BRAF variants that result in signal activation have been described.[3,5] ARAF variants are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.[6]

The presence of the BRAF V600E variant in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E variant by a sensitive quantitative polymerase chain reaction technique.[2] Circulating cells with the BRAF V600E variant could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The BRAF V600E allele was detected in circulating cell-free DNA in 100% of patients with risk-organ–positive multisystem LCH, 42% of patients with risk-organ–negative LCH, and 14% of patients with single-system LCH.[7]

The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the variant in the bone marrow of high-risk patients. In those with low-risk disease, the variant was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic variant occurs is critical in defining the extent of disease in LCH.

Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases,[8] while a later study of BRAF variants showed that 25% to 50% of adult patients with lung LCH had evidence of BRAF V600E variants.[8,9] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E variants and 40% had NRAS variants.[10] Approximately the same number of variants are polyclonal as are monoclonal. It has not been determined whether clonality and BRAF pathway variants are concordant in the same patients, which might suggest a reactive rather than a neoplastic condition in smoker's lung LCH and a clonal neoplasm in other types of LCH.

In a study of 117 patients with LCH, 83 adult patients with pulmonary LCH underwent molecular analysis. Nearly 90% of these patients had variants in the MAPK pathway.[11][Level of evidence C3] Of the 69 patients who had their biopsy samples further analyzed using a next-generation sequencing panel of 74 genes, 36% had BRAF V600E variants, 29% had BRAF N486-P490 deletions, 15% had MAP2K1 variants or deletions, and 4% had NRAS variants. Only one patient had a KRAS variant. Additionally, 11 patients had their biopsy samples analyzed using whole-exome sequencing. An average of 14 variants were found per patient, which is markedly higher than the average of one variant found per pediatric patient.[12] There were no clinical correlates, including presence of a BRAF V600E variant and smoking status. Of the 117 patients with LCH, 60% experienced a relapse.

Enlarge

The RAS-MAPK signaling pathway (see Figure 8) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then the extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E variant of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[1,13]

In a mouse model of LCH, the BRAF V600E variant was shown to inhibit a chemokine receptor (CCR7)–mediated migration of dendritic cells, forcing them to accumulate in the LCH lesion.[14] This variant also causes an increased expression of BCL2L1, which results in resistance to apoptosis. This process leads to the cells being less responsive to chemotherapy. The BRAF V600E variant also causes growth arrest of hematopoietic progenitor cells and a senescence-associated secretory phenotype that further promotes accumulation of the pathological cells.[15]

Another mouse model with the BRAF V600E variant under control of Scl or Map17 gene promoters added additional insights into the biology of neurodegenerative LCH.[16] These studies confirmed the hematopoietic origin of CD11a-positive macrophages with BRAF V600E variants. This process disrupts the blood-brain barrier and causes loss of Purkinje cells and progressive neurodegeneration by resistance to apoptosis and production of senescent associated secretory proteins, which include inflammatory cytokines IL-1, IL-6, and matrix metalloproteinases. Treatment with a MAP kinase inhibitor and a senolytic agent (navitoclax) decreased the pathogenic cell numbers and led to clinical improvement in the mice.

In summary, LCH is now considered a myeloid neoplasm primarily driven by activating variants of the MAPK pathway. Fifty percent to 60% of the activating variants are caused by BRAF V600E variants, which are enriched in patients with multisystem risk organ–positive LCH and in patients with neurodegenerative-disease LCH.[17] Ongoing studies are assessing whether low-level variant detection in peripheral blood can be used as a minimal residual disease marker to assist in therapeutic decisions.

Other RAS-MAPK pathway alterations

Because RAS-MAPK pathway activation (elevated phosphor-ERK) can be detected in all LCH cases, including those without BRAF variants, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:

• MAP2K1 variants. Whole-exome sequencing on biopsy samples of BRAF-altered versus BRAF–wild-type LCH tissue revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 variants, while no BRAF-altered specimens had MAP2K1 variants.[13] The variants in MAP2K1 (which codes for MEK1) were activating, as indicated by their induction of ERK phosphorylation.[13]

  Another study showed MAP2K1 variants exclusively in 11 of 22 BRAF–wild-type cases.[18] One study showed that MAP2K1 and other variants associated with pediatric and adult LCH were mutually exclusive of BRAF variants.[19] The authors found a variety of variants in other pathways (e.g., JNK, RAS-ERK, and JAK-STAT) in pediatric and adult patients with BRAF V600E or MAP2K1 variants. Another study evaluated the kinase alterations and myeloid-associated variants in 73 adult patients with LCH.[20] They reported a median of two variants per adult patient, as opposed to children who usually have only one variant. BRAF V600E was found in 31%, BRAF indel in 29%, and MAP2K1 in 19% of patients with LCH. A variety of other protein kinase and related pathways were found in 89% of adult patients with LCH. MAP2K1 variants were exclusive of BRAF variants.

• In-frame BRAF deletions and FAM73A::BRAF gene fusions. In-frame BRAF deletions and in-frame FAM73A::BRAF gene fusions have occurred in the group of BRAF V600E and MAP2K1 variant–negative cases.[12]

In summary, studies support the universal activation of ERK in LCH. ERK activation in most cases of LCH is explained by BRAF and MAP2K1 alterations.[1,12,13] Altogether, these variants in the MAP kinase pathway account for nearly 80% of the causes of the universal activation of ERK in LCH.[1,12,13] The remaining cases have a range of variants that include small deletions in BRAF, BRAF gene fusions (discussed above), as well as variants in ARAF, MAP3K1, NRAS, ERBB3, PI3CA, CSF1R, and other rare targets.[19,17][Level of evidence C1]

Clinical implications

Clinical implications of the described genomic findings include the following:

• LCH is included in a group of other pediatric tumors with activating BRAF variants, such as select nonmalignant conditions (e.g., benign nevi) [21] and low-grade malignancies (e.g., pilocytic astrocytoma).[22,23] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[21,24]
• In some pediatric studies, BRAF V600E variants have been associated with more severe multisystem disease, treatment failure, increased reactivations, and an increased risk of neurodegeneration (see below).[25] These clinical correlates were recently investigated for non-BRAF V600E variants in an international study. Similar to the BRAF V600E cohort, all patients with multisystem risk organ–positive LCH had detectable variants in peripheral blood mononuclear cells. Of seven patients with multisystem risk organ–negative LCH, four had detectable variants. No patients with single-system disease had detectable variants in peripheral blood mononuclear cells. The authors concluded that other MAPK pathway variants are associated with risk status, similar to BRAF V600E variants.[17]

  BRAF V600E variants can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of melanoma in adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcomes compared with treatment using a BRAF inhibitor alone.[26,27]

  Several case reports and two case series have also demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[28-33] However, the long-term role of this therapy is complicated because most patients will relapse when the inhibitors are discontinued. For more information, see the sections on Treatment of recurrent, refractory, or progressive high-risk disease: multisystem LCH and Targeted therapies for the treatment of single-system and multisystem disease.

• Circulating BRAF V600E–altered cells have been found in 59% of patients who developed neurodegenerative-disease LCH, compared with 15% of patients who did not develop neurodegenerative-disease LCH. Detectable altered circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–altered cells.[34]
• With additional research, the observation of the BRAF V600E variant (or potentially MAP2K1 variants) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease.[2] Additionally, for patients who have a somatic variant, persistence of circulating cells with the variant may be useful as a marker of residual disease.[2]

For information about the treatment of childhood LCH, see Langerhans Cell Histiocytosis Treatment.

References

1. Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010. [PUBMED Abstract]
2. Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014. [PUBMED Abstract]
3. Satoh T, Smith A, Sarde A, et al.: B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 7 (4): e33891, 2012. [PUBMED Abstract]
4. Sahm F, Capper D, Preusser M, et al.: BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 120 (12): e28-34, 2012. [PUBMED Abstract]
5. Héritier S, Hélias-Rodzewicz Z, Chakraborty R, et al.: New somatic BRAF splicing mutation in Langerhans cell histiocytosis. Mol Cancer 16 (1): 115, 2017. [PUBMED Abstract]
6. Nelson DS, Quispel W, Badalian-Very G, et al.: Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 123 (20): 3152-5, 2014. [PUBMED Abstract]
7. Héritier S, Hélias-Rodzewicz Z, Lapillonne H, et al.: Circulating cell-free BRAF(V600E) as a biomarker in children with Langerhans cell histiocytosis. Br J Haematol 178 (3): 457-467, 2017. [PUBMED Abstract]
8. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003. [PUBMED Abstract]
9. Roden AC, Hu X, Kip S, et al.: BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 38 (4): 548-51, 2014. [PUBMED Abstract]
10. Mourah S, How-Kit A, Meignin V, et al.: Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis. Eur Respir J 47 (6): 1785-96, 2016. [PUBMED Abstract]
11. Jouenne F, Chevret S, Bugnet E, et al.: Genetic landscape of adult Langerhans cell histiocytosis with lung involvement. Eur Respir J 55 (2): , 2020. [PUBMED Abstract]
12. Chakraborty R, Burke TM, Hampton OA, et al.: Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood 128 (21): 2533-2537, 2016. [PUBMED Abstract]
13. Chakraborty R, Hampton OA, Shen X, et al.: Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124 (19): 3007-15, 2014. [PUBMED Abstract]
14. Hogstad B, Berres ML, Chakraborty R, et al.: RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med 215 (1): 319-336, 2018. [PUBMED Abstract]
15. Bigenwald C, Le Berichel J, Wilk CM, et al.: BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology. Nat Med 27 (5): 851-861, 2021. [PUBMED Abstract]
16. Wilk CM, Cathomas F, Török O, et al.: Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders. Immunity 56 (12): 2790-2802.e6, 2023. [PUBMED Abstract]
17. Milne P, Abhyankar H, Scull B, et al.: Cellular distribution of mutations and association with disease risk in Langerhans cell histiocytosis without BRAFV600E. Blood Adv 6 (16): 4901-4904, 2022. [PUBMED Abstract]
18. Brown NA, Furtado LV, Betz BL, et al.: High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 124 (10): 1655-8, 2014. [PUBMED Abstract]
19. Durham BH, Lopez Rodrigo E, Picarsic J, et al.: Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med 25 (12): 1839-1842, 2019. [PUBMED Abstract]
20. Chen J, Zhao AL, Duan MH, et al.: Diverse kinase alterations and myeloid-associated mutations in adult histiocytosis. Leukemia 36 (2): 573-576, 2022. [PUBMED Abstract]
21. Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436 (7051): 720-4, 2005. [PUBMED Abstract]
22. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008. [PUBMED Abstract]
23. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008. [PUBMED Abstract]
24. Jacob K, Quang-Khuong DA, Jones DT, et al.: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17 (14): 4650-60, 2011. [PUBMED Abstract]
25. Héritier S, Emile JF, Barkaoui MA, et al.: BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol 34 (25): 3023-30, 2016. [PUBMED Abstract]
26. Larkin J, Ascierto PA, Dréno B, et al.: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371 (20): 1867-76, 2014. [PUBMED Abstract]
27. Long GV, Stroyakovskiy D, Gogas H, et al.: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386 (9992): 444-51, 2015. [PUBMED Abstract]
28. Eckstein OS, Visser J, Rodriguez-Galindo C, et al.: Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition. Blood 133 (15): 1691-1694, 2019. [PUBMED Abstract]
29. Donadieu J, Larabi IA, Tardieu M, et al.: Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol 37 (31): 2857-2865, 2019. [PUBMED Abstract]
30. Kolenová A, Schwentner R, Jug G, et al.: Targeted inhibition of the MAPK pathway: emerging salvage option for progressive life-threatening multisystem LCH. Blood Adv 1 (6): 352-356, 2017. [PUBMED Abstract]
31. Lee LH, Gasilina A, Roychoudhury J, et al.: Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. JCI Insight 2 (3): e89473, 2017. [PUBMED Abstract]
32. Héritier S, Jehanne M, Leverger G, et al.: Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis. JAMA Oncol 1 (6): 836-8, 2015. [PUBMED Abstract]
33. Váradi Z, Bánusz R, Csomor J, et al.: Effective BRAF inhibitor vemurafenib therapy in a 2-year-old patient with sequentially diagnosed Langerhans cell histiocytosis and Erdheim-Chester disease. Onco Targets Ther 10: 521-526, 2017. [PUBMED Abstract]
34. McClain KL, Picarsic J, Chakraborty R, et al.: CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer 124 (12): 2607-2620, 2018. [PUBMED Abstract]

Molecular features of neuroblastoma

Children with neuroblastoma can be divided into subsets with different predicted risks of relapse on the basis of clinical factors and biological markers at the time of diagnosis.

• Low-risk or intermediate-risk neuroblastoma patients. Patients classified as low risk or intermediate risk have a favorable prognosis, with survival rates exceeding 95%. Low-risk and intermediate-risk neuroblastoma usually occur in children younger than 18 months. These tumors commonly have gains of whole chromosomes and are hyperdiploid when examined by flow cytometry.[1,2]
• High-risk neuroblastoma patients. The prognosis is more guarded for patients with high-risk neuroblastoma, with a long-term survival rate of less than 50%. High-risk neuroblastoma generally occurs in children older than 18 months and is often metastatic to bone and bone marrow. Segmental chromosome abnormalities (gains or losses) and/or MYCN gene amplification are usually detected in these tumors. They are near diploid or near tetraploid by flow cytometric measurement.[1-7] High-risk tumors may rarely harbor exonic variants, but most high-risk tumors lack such gene variants. For more information, see the Exonic Variants in Neuroblastoma section.

Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:

• Segmental chromosomal aberrations.
• MYCN gene amplifications.
• FOXR2 activation.
• Low rates of exonic variants, with activating variants in ALK being the most common recurring alteration.
• Genomic alterations that promote telomere maintenance.

Segmental chromosomal aberrations

Segmental chromosomal aberrations, found most frequently in 1p, 2p, 1q, 3p, 11q, 14q, and 17p, are best detected by comparative genomic hybridization. These aberrations are seen in most high-risk and/or stage 4 neuroblastoma tumors.[3,4,6-8] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of segmental chromosome aberrations) correlated with the following:[3-7][Level of evidence C2]

• Advanced age at diagnosis.
• Advanced stage of disease.
• Higher risk of relapse.
• Poorer outcome.

In an analysis of localized, resectable, non-MYCN amplified neuroblastoma, cases from two consecutive European studies and a North American cohort (including INSS stages 1, 2A, and 2B) were analyzed for segmental chromosome aberrations (namely gain of 1q, 2p, and 17q and loss of 1p, 3p, 4p, and 11q). The study revealed a different prognostic impact of tumor genomics depending on patient age (<18 months or >18 months). Patients were treated with surgery alone regardless of a tumor residuum.[9][Level of evidence C1]

• The presence of segmental chromosome aberrations, especially 11q loss, significantly reduced survival in patients older than 18 months with stage 2 neuroblastoma but not in the cohort of patients younger than 18 months.
• Chromosome 1p loss is a risk factor for relapse but not for diminished overall survival (OS) in patients younger than 18 months. The 5-year event-free survival (EFS) rate was 62% for patients with 1p loss and 87% for patients with no 1p loss (P = .019). The 5-year OS rate was 92% for patients with 1p loss and 97% for patients with no 1p loss.
• Segmental chromosome aberrations (especially 11q loss) are risk factors for reduced EFS and OS in patients older than 18 months. In patients younger than 18 months, only segmental chromosome aberrations led to relapse and death, with 11q loss as the strongest marker (11q loss: 5-year EFS rate, 48%; no 11q loss: 5-year EFS rate, 85%; P = .033; 11q loss: 5-year OS rate, 46%; no 11q loss: 5-year OS rate, 92%; P = .038).

In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, segmental chromosomal aberrations were found in most patients. Older children were more likely to have them and to have more of them per tumor cell. In children aged 12 to 18 months, the presence of segmental chromosomal aberrations had a significant effect on EFS but not on OS. However, in children older than 18 months, there was a significant difference in OS between children with segmental chromosomal aberrations (67%) and children without segmental chromosomal aberrations (100%), regardless of tumor histology.[7]

Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[1,2] An analysis of 133 patients (aged ≥18 months) with INSS stage 3 tumors without MYCN amplification demonstrated that segmental chromosomal aberrations were associated with inferior EFS, and 11q loss was independently associated with worse OS.[10]

In an analysis of intermediate-risk patients in a Children's Oncology Group (COG) study, 11q loss, but not 1p loss, was associated with reduced EFS but not OS (11q loss and no 11q loss: 3-year EFS rates, 68% and 85%, respectively; P = .022; 3-year OS rates, 88% and 94%, respectively; P = .09).[11][Level of evidence B4]

In a multivariable analysis of 407 patients from four consecutive COG high-risk trials, 11q loss of heterozygosity was shown to be a significant predictor of progressive disease, and lack of 11q loss of heterozygosity was associated with both higher rates of end-induction complete response and end-induction partial response.[12][Level of evidence C1]

An international collaboration studied 556 patients with high-risk neuroblastoma and identified two types of segmental copy number aberrations that were associated with extremely poor outcome. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%. Amplifications of regions not encompassing the MYCN locus, in addition to MYCN amplification, were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[13]

MYCN gene amplification

MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[14] Among patients with high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[15]

In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis, in both time to tumor progression and OS, in almost all multivariate regression analyses of prognostic factors.[1,2] In the ANBL00B1 (NCT00904241) study of 4,832 newly diagnosed patients enrolled between 2007 to 2017, the 5-year EFS and OS rates were 77% and 87%, respectively, for patients whose tumors were MYCN nonamplified (n = 3,647; 81%). In comparison, the 5-year EFS and OS rates were 51% and 57%, respectively, for patients whose tumors were MYCN amplified (n = 827; 19%).[8]

Within the localized-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than do patients with diploid tumors.[16] However, patients with hyperdiploid tumors with MYCN amplification or any segmental chromosomal aberrations do relatively poorly, compared with patients with hyperdiploid tumors without MYCN amplification.[3]

Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification. In a multivariable logistic regression analysis of 7,102 patients in the International Neuroblastoma Risk Group (INRG) study, pooled segmental chromosomal aberrations and gains of 17q were poor prognostic features, even when not associated with MYCN amplification. However, another poor prognostic feature, segmental chromosomal aberrations at 11q, are almost entirely mutually exclusive of MYCN amplification.[17,18]

In a cohort of 6,223 patients from the INRG database with known MYCN status, the OS hazard ratio (HR) associated with MYCN amplification was 6.3 (95% confidence interval [CI], 5.7–7.0; P < .001). The greatest adverse prognostic impact of MYCN amplification for OS was in the youngest patients (aged <18 months: HR, 19.6; aged ≥18 months: HR, 3.0). Patients whose outcome was most impacted by MYCN status were those with otherwise favorable features, including age younger than 18 months, high mitosis-karyorrhexis index, and low ferritin.[19][Level of evidence C1]

Intratumoral heterogeneous MYCN amplification (hetMNA) refers to the coexistence of MYCN-amplified cells as a cluster or as single scattered cells and non-MYCN–amplified tumor cells. HetMNA has been reported infrequently. It can occur spatially within the tumor as well as between the tumor and the metastasis at the same time or temporally during the disease course. The International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) biology group investigated the prognostic significance of this neuroblastoma subtype. Tumor tissue from 99 patients identified as having hetMNA and diagnosed between 1991 and 2015 was analyzed to elucidate the prognostic significance of MYCN-amplified clones in otherwise non-MYCN–amplified neuroblastomas. Patients younger than 18 months showed a better outcome in all stages compared with older patients. The genomic background correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. This study suggests that hetMNA tumors be evaluated in the context of the genomic tumor background in combination with the clinical pattern, including the patient's age and disease stage. Future studies are needed in patients younger than 18 months who have localized disease with hetMNA.[20]

FOXR2 activation

FOXR2 gene expression is observed in approximately 8% of neuroblastoma cases. FOXR2 gene expression is normally absent postnatally, with the exception of male reproductive tissues.[21] FOXR2 expression is also observed in a subset of central nervous system (CNS) primitive neuroectodermal tumors, termed CNS NB-FOXR2.[22] FOXR2 overexpression was virtually mutually exclusive in neuroblastoma tumors with both elevated MYC and MYCN expression. Although MYCN gene expression was not elevated in neuroblastoma with FOXR2 activation, the gene expression profile for the FOXR2 expressing cases closely resembled that of MYCN-amplified neuroblastoma. FOXR2 binds MYCN and appears to stabilize the MYCN protein, leading to high levels of MYCN protein in neuroblastoma with FOXR2 activation. This finding provides an explanation for the similar gene expression profiles for neuroblastoma with FOXR2 activation and neuroblastoma with MYCN amplification.

Neuroblastoma with FOXR2 activation is observed at comparable rates in high-risk and non–high-risk cases.[21] Among high-risk cases, outcomes for patients whose tumors showed FOXR2 activation were similar to those for cases with MYCN amplification. In a multivariable analysis, FOXR2 activation was significantly associated with inferior OS, along with INSS stage 4, age 18 months or older, and MYCN amplification.

Exonic variants in neuroblastoma (including ALK variants and amplification)

Compared with adult cancers, pediatric neuroblastoma tumors show a low number of variants per genome that affect protein sequence (10–20 per genome).[23] The most common gene variant is ALK, which is altered in approximately 10% of patients (see below). Other genes with even lower frequencies of variants include ATRX, PTPN11, ARID1A, and ARID1B.[24-30] As shown in Figure 9, most neuroblastoma cases lack variants in genes that are altered in a recurrent manner.

Enlarge

The ALK gene provides instructions for making a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. ALK is the exonic variant found most commonly in neuroblastoma. Germline variants in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic are also found as oncogenic drivers in neuroblastoma.[29]

Two large cohort studies examined the clinical correlates and prognostic significance of ALK alterations. One study from the COG examined ALK status in 1,596 diagnostic neuroblastoma samples across all risk groups.[29] Another study from SIOPEN evaluated 1,092 patients with high-risk neuroblastoma.[31]

• ALK tyrosine kinase domain variants occurred primarily at three hot spots (F1174, R1275, and F1245 positions), with 10% to 15% of variants occurring at other kinase domain positions.
• In the COG cohort, the frequency of ALK variants was 10% in the high-risk neuroblastoma group, 8% in the intermediate-risk neuroblastoma group, and 6% in the low-risk neuroblastoma group.
• In the SIOPEN high-risk population, ALK variants were divided into clonal (>20% variant allele frequency [VAF]) and subclonal (0.1%–20% VAF). Clonal ALK variants were detected in 10% of cases, and subclonal variants were found in 3.9% of patients. A total of 13.9% of the cases had an ALK variant.
• ALK variants were found at higher rates in patients with MYCN-amplified tumors compared with those without MYCN amplification: 10.9% versus 7.2%, respectively, for the COG cohort and 14% versus 6.5%, respectively, for the SIOPEN cohort (for clonal ALK variants).
• For patients with high-risk neuroblastoma, the ALK amplification was observed in approximately 4% of cases in both the COG and the SIOPEN cohorts. ALK amplification occurred almost exclusively in cases that also had MYCN amplification.
• ALK alterations were associated with inferior prognoses for high-risk neuroblastoma patients in both the COG and the SIOPEN studies:
  • In the SIOPEN cohort, a statistically significant difference in OS was observed between cases with ALK amplification (ALKa) or clonal ALK variant (ALKm) versus subclonal ALKm or no ALK alterations (5-year OS rate: ALKa, 26% [95% CI, 10%–47%]; clonal ALKm, 33% [95% CI, 21%–44%]; subclonal ALKm, 48% [95% CI, 26%–67%]; and no alteration, 51% [95% CI, 46%–55%], respectively; P = .001). In a multivariate model, ALK amplification (HR, 2.38; P = .004) and clonal ALK variant (HR, 1.77; P = .001) were independent predictors of poor outcome.
  • In the COG high-risk neuroblastoma population, inferior prognoses, similar to those seen in the SIOPEN cohort, were observed for cases with ALK variants and ALK amplifications.

In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK variants.[32]

Small-molecule ALK kinase inhibitors such as lorlatinib (added to conventional therapy) are being tested in patients with recurrent ALK-altered neuroblastoma (NCT03107988) and in patients with newly diagnosed high-risk neuroblastoma with activated ALK (COG ANBL1531).[29] For more information, see the sections on Treatment of High-Risk Neuroblastoma and Treatment of Recurrent Neuroblastoma in Neuroblastoma Treatment.

Genomic evolution of exonic variants

There are limited data regarding the genomic evolution of exonic variants from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[33] while a second study evaluated 16 paired diagnostic and relapsed specimens.[34] Both studies identified an increased number of variants in the relapsed samples compared with the samples at diagnosis. This has been confirmed in a study of neuroblastoma tumor samples sent for next-generation sequencing.[35]

• In the first study, an increased incidence of variants in genes associated with RAS-MAPK signaling was found in tumors at relapse compared with tumors from the same patient at diagnosis; 15 of 23 relapse samples contained somatic variants in genes involved in this pathway, and each variant was consistent with pathway activation.[33]

  In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 (78%) relapse samples. Aberrations were found in ALK (n = 10), NF1 (n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of variants presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.

• In the second study, ALK variants were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[34]
• A third retrospective variant-sequencing study used data from Foundation Medicine to compare tumor samples from patients with newly diagnosed neuroblastoma with tumor samples from patients with refractory and relapsed neuroblastoma. The study found a higher percentage of variants that were targetable with current drugs in the relapsed and refractory group.[35]
• A fourth study evaluated the frequency of ALK alterations at diagnosis and relapse. There were significantly higher rates of ALK variants at relapse than at diagnosis (17.7% at relapse vs. 10.5% at diagnosis). The rate of ALK amplifications did not differ between diagnosis and relapse.[36]

Given the widespread metastatic nature of high-risk and relapsed neuroblastoma, use of circulating tumor DNA (ctDNA) technologies may reveal additional genomic alterations not found in conventional tumor biopsies. Moreover, these approaches have demonstrated the ability to detect resistant variants in patients with neuroblastoma who were treated with ALK inhibitors.[37][Level of evidence C1] In one analysis of serial ctDNA samples from patients treated with lorlatinib, ALK variant allele frequency tracked with disease burden in most but not all patients.[38] In subsets of patients who progressed while taking lorlatinib, second compound variants in ALK or variants in other genes, including RAS pathway genes, were reported.

In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK variant hot spots, which revealed 4.8% clonal variants and an additional 5% subclonal variants. This finding suggests that subclonal ALK gene variants are common.[39] Thus, deep sequencing can reveal the presence of variants in tiny subsets of neuroblastoma tumor cells that may be able to survive during treatment and grow to constitute a relapse.

Genomic alterations promoting telomere maintenance

Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, eventually resulting in the cell’s inability to replicate. Patients whose tumors lack telomere maintenance mechanisms have an excellent prognosis, while patients whose tumors harbored telomere maintenance mechanisms have a substantially worse prognosis.[40] Low-risk neuroblastoma tumors, as defined by clinical/biological features, have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[24,25,40,41] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:

• Chromosomal rearrangements involving a chromosomal region at 5p15.33 proximal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and alternative lengthening of telomeres (ALT) activation.[24,25,41] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Children whose tumors have TERT rearrangements have a poor prognosis, which is comparable to the prognosis of children whose tumors have MYCN amplification.[41] Next-generation sequencing or fluorescence in situ hybridization (FISH) may be used to identify these alterations. One study identified TERT rearrangements by FISH in 6% of all patients with neuroblastic tumors regardless of risk group and in 12.4% of patients with high-risk neuroblastic tumors.[42]
• Another mechanism promoting TERT overexpression is MYCN amplification,[43] which is associated with approximately 40% to 50% of high-risk neuroblastoma cases.
• ALT is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. ALT activation is present in approximately 20% to 25% of newly diagnosed high-risk cases, compared with approximately 5% to 12% of low-risk and intermediate-risk cases.[41,44,45] Compared with newly diagnosed cases, the proportion of neuroblastoma cases with ALT-positive tumors was higher in a cohort of patients who relapsed (10% vs. 48%, respectively). This finding may reflect the relatively indolent course of tumors with ALT activation after relapse, compared with the clinical course of other tumors after relapse. Over time, the proportion of patients with relapsed ALT-positive neuroblastomas (out of patients with neuroblastoma) appears larger than that of patients with another tumor type who relapsed (out of patients diagnosed with that tumor).[44] Neuroblastoma cases with ALT activation have low TERT expression and can be identified by immunohistochemistry for the ALT-associated promyelocytic nuclear body, by FISH with a telomere probe to visualize telomere ultrabright spots, and by the C-circle assay.[44,45] Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[26,44,45] Cases lacking ATRX variants often show low ATRX protein expression.[44]

  ALT-positive tumors in pediatric populations rarely present before the age of 18 months and occur almost exclusively in older children (median age at diagnosis, approximately 8 years).[41,44] The proportion of neuroblastoma cases with ATRX variants increases with age into the adolescent and young adult populations.[26]

  The prognosis for high-risk patients with ALT activation is as poor as that for patients with MYCN amplification for EFS;[41,44] however, OS is more favorable for patients with ALT activation. The more favorable OS appears to result from a more protracted disease course after relapse, but with long-term survival at 10 to 15 years being as low as that for other high-risk neuroblastoma patients.[41,44] In one report, EFS and OS for low-risk and intermediate-risk patients with ALT activation were similar to those observed for ALT-positive patients with high-risk disease.[44]

Additional biological factors associated with prognosis

MYC and MYCN expression

Immunostaining for MYC and MYCN proteins on a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[46] Sixty-eight tumors (19%) highly expressed the MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors (10.9%) expressed MYC highly and were mutually exclusive of high MYCN expression. In the MYC-expressing tumors, MYC or MYCN gene amplification was not seen. Segmental chromosomal aberrations were not examined in this study.[46]

• Patients with favorable-histology tumors without high MYC/MYCN expression had favorable survival (3-year EFS rate, 89.7% ± 5.5%; 3-year OS rate, 97% ± 3.2%).
• Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% (± 13.6%) and a 3-year OS rate of 83.5% (± 9.4%).
• Three-year EFS rates in patients with MYCN amplification, high MYCN expression, and high MYC expression were 48.1% (± 11.5%), 46.2% (± 12%), and 43.4% (± 23.1%), respectively. OS rates were 65.8% (± 11.1%), 63.2% (± 12.1%), and 63.5% (± 19.2%), respectively.
• Additionally, when high expression of MYC and MYCN proteins underwent multivariate analysis with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.

Neurotrophin receptor kinases

Expression of neurotrophin receptor kinases and their ligands vary between high-risk and low-risk tumors. TrkA is found on low-risk tumors, and absence of its ligand NGF is postulated to lead to spontaneous tumor regression. In contrast, TrkB is found in high-risk tumors that also express its ligand, BDNF, which promotes neuroblastoma cell growth and survival.[47]

For information about the treatment of neuroblastoma, see Neuroblastoma Treatment.

References