DDX41-Associated Myeloid Malignancies (PDQ®)–Health Professional Version

[Note: A concerted effort is being made within the genetics community to use the term, variant rather than the term, mutation to describe genetic differences in the germline. These variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term, pathogenic variant to describe a disease-causing mutation. In this summary, the term, somatic mutations will be used to describe acquired genetic changes that arise in the hematopoietic system (blood stem cells and blood progenitor cells). For more information about variant classification, see the Cancer Genetics Overview summary.]

Germline pathogenic variants in the RNA helicase, DDX41, are associated with an autosomal dominant predisposition to myeloid malignancies and other cancers. The prevalence of DDX41 germline pathogenic variants is not clearly defined. However, these variants are thought to underlie 1% to 1.5% of all acute myeloid leukemia (AML) diagnoses,[1] making it one of the most commonly inherited predispositions to adult-onset myeloid malignancies.[2] Individuals who inherit DDX41 pathogenic variants have an increased lifetime risk to develop myelodysplastic syndrome (MDS) and AML. However, lymphoid malignancies such as non-Hodgkin lymphoma and myeloproliferative neoplasm (MPN) have also been reported in individuals with DDX41 pathogenic variants.[3-5]

DDX41 germline pathogenic variants are associated with a later median age of MDS/AML diagnosis than other inherited hematologic predisposition syndromes.[6] For DDX41 carriers, the age of MDS/AML diagnosis can range from 61 to 69 years. This age range is similar to the typical age of diagnosis in patients with sporadic MDS/AML in the general population. The myeloid malignancies that occur in individuals with DDX41 germline pathogenic variants are almost always diploid and harbor lower somatic mutational burdens than those seen in individuals without DDX41 germline pathogenic variants.[4,6] The penetrance of DDX41 pathogenic variants is incomplete and variable. DDX41 pathogenic variants are associated with a mild to moderate predisposition to hematologic malignancies (lifetime risk of hematologic malignancies ranges from 20% to 30% in DDX41 carriers). Nearly half of reported DDX41 carriers develop long-standing asymptomatic cytopenias (most commonly leukopenia) prior to malignancy development. However, some DDX41 carriers will only ever develop stable cytopenias that never progress to become hematologic malignancies. In these cases, individuals are typically transfusion-independent.[2]

Since DDX41 pathogenic variants have low penetrance and DDX41-related hematologic malignancies are often diagnosed at later ages, DDX41 carriers can be difficult to identify using the typical age– or family history–related screening criteria.

References

1. Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27 (5): 658-70, 2015. [PUBMED Abstract]
2. Sébert M, Passet M, Raimbault A, et al.: Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood 134 (17): 1441-1444, 2019. [PUBMED Abstract]
3. Lewinsohn M, Brown AL, Weinel LM, et al.: Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127 (8): 1017-23, 2016. [PUBMED Abstract]
4. Li P, Brown S, Williams M, et al.: The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood 140 (7): 716-755, 2022. [PUBMED Abstract]
5. Goyal T, Tu ZJ, Wang Z, et al.: Clinical and Pathologic Spectrum of DDX41-Mutated Hematolymphoid Neoplasms. Am J Clin Pathol 156 (5): 829-838, 2021. [PUBMED Abstract]
6. Quesada AE, Routbort MJ, DiNardo CD, et al.: DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol 94 (7): 757-766, 2019. [PUBMED Abstract]

DDX41 somatic mutations occur in myeloid and lymphoid malignancies and are increasingly included as part of somatic next-generation sequencing (NGS) panels. Studies have shown that molecular profiling is a useful and feasible tool to screen patients with hematologic malignancies for germline DDX41 pathogenic variants.[1,2] Two common Northern European founder pathogenic variants, p.Asp140Glyfs*2 and p.Met1Ile, account for most DDX41 germline pathogenic variants identified in individuals with European ancestry. As genetic testing becomes more routine, testing in additional populations indicates that missense variants, like DDX41 p.Val152Gly (p.V152G) and DDX41 p.Tyr259Cys (p.Y259C), may be more common in non-European populations.[3] When these missense and founder variants are found on somatic testing, they are present in the germline nearly 100% of the time. However, multiple nonsense and frameshift germline variants have been reported throughout the DDX41 gene. Therefore, full DDX41 gene sequencing is indicated when evaluating for a germline pathogenic variant.

In nearly 80% of cases, a second, somatically-acquired mutation (often the DDX41 p.Arg525His [p.R525H] variant), is acquired on the other DDX41 allele. This second hit is associated with progression to hematologic malignancy.[4,5] Likewise, if the DDX41 p.Arg525His variant is detected on somatic testing, even in absence of an additional DDX41 variant (presumably on the other allele), germline testing is warranted. Germline pathogenic variants on the other DDX41 allele could be present, especially when full somatic sequencing of the gene is not performed.

References

1. Sébert M, Passet M, Raimbault A, et al.: Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood 134 (17): 1441-1444, 2019. [PUBMED Abstract]
2. Bannon SA, Routbort MJ, Montalban-Bravo G, et al.: Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations. Front Oncol 10: 582213, 2020. [PUBMED Abstract]
3. Choi EJ, Cho YU, Hur EH, et al.: Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia. Haematologica 107 (2): 510-518, 2022. [PUBMED Abstract]
4. Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27 (5): 658-70, 2015. [PUBMED Abstract]
5. Duployez N, Largeaud L, Duchmann M, et al.: Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood 140 (7): 756-768, 2022. [PUBMED Abstract]

Emerging data suggest that DDX41 carriers who develop acute myeloid leukemia (AML) have higher complete remission rates and longer mean overall survival rates than individuals who do not carry a DDX41 pathogenic variant.[1-3] In addition, individuals with DDX41 germline pathogenic variants who develop myelodysplastic syndrome (MDS)/AML may show responses to treatment with lenalidomide.[3-6]

At least two cases of donor-derived leukemias have occurred in DDX41 carriers post–hematopoietic stem cell transplant (HSCT) from a matched-related donor carrying the same germline DDX41 pathogenic variant.[7,8] This highlights the need for systematic screening of germline DDX41 pathogenic variants in MDS/AML patients prior to HSCT. This will allow for appropriate donor selection and donor screening.

References

1. Li P, Brown S, Williams M, et al.: The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood 140 (7): 716-755, 2022. [PUBMED Abstract]
2. Duployez N, Largeaud L, Duchmann M, et al.: Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study. Blood 140 (7): 756-768, 2022. [PUBMED Abstract]
3. Alkhateeb HB, Nanaa A, Viswanatha D, et al.: Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms. Blood Adv 6 (2): 528-532, 2022. [PUBMED Abstract]
4. Polprasert C, Schulze I, Sekeres MA, et al.: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27 (5): 658-70, 2015. [PUBMED Abstract]
5. Abou Dalle I, Kantarjian H, Bannon SA, et al.: Successful lenalidomide treatment in high risk myelodysplastic syndrome with germline DDX41 mutation. Am J Hematol 95 (2): 227-229, 2020. [PUBMED Abstract]
6. Negoro E, Radivoyevitch T, Polprasert C, et al.: Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia 30 (12): 2405-2409, 2016. [PUBMED Abstract]
7. Kobayashi S, Kobayashi A, Osawa Y, et al.: Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation. Leukemia 31 (4): 1020-1022, 2017. [PUBMED Abstract]
8. Berger G, van den Berg E, Sikkema-Raddatz B, et al.: Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia 31 (2): 520-522, 2017. [PUBMED Abstract]

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