TARGET’s Studies of Childhood Kidney Tumors
About Kidney Tumors
Though kidney tumors are generally curable in children, subsets of patients afflicted with these diseases do not respond to treatment or eventually relapse. These children usually have poorer clinical outcomes than the majority of children diagnosed with kidney tumors. Furthermore, all patients undergo therapy regimens that can be detrimental later in life. Learn more about pediatric kidney cancers and current treatment strategies.
Therapeutically Applicable Research to Generate Effective Treatments (TARGET) investigators performed comprehensive molecular characterization of several high-risk or hard-to-treat kidney tumor types in order to determine the genetic changes that drive the initiation and progression of these diseases. Future research may identify treatments tailored to these alterations to improve outcomes for children afflicted with these kidney tumors.
The specific kidney tumor types studied include relapsed favorable histology Wilms tumor, anaplastic Wilms tumor (WT), clear cell sarcoma of the kidney (CSSK), and rhabdoid tumor (RT). The tissues used in this study were collected from patients enrolled in the National Wilms Tumor Study (mostly NWTS-5) clinical trial that was completed by the Children's Oncology Group (COG).
TARGET’s Wilms Tumor (WT) Project
WT is the most common type of childhood kidney cancer and usually occurs before the age of six. Most cases present with a favorable histology and respond well to standard treatment, however there are patients who relapse unexpectedly. A subset of WT patients are diagnosed with anaplasia, an unfavorable histology that does not respond to current therapies. TARGET investigators analyzed tumors from patients with anaplasia at diagnosis and patients who relapsed and for whom standard therapies were ineffective.
The TARGET WT project has produced comprehensive genomic profiles of nearly 130 poor outcome, clinically annotated patient cases that make up the discovery data set. This cohort includes around 80 favorable histology Wilms tumors (FHWT) that relapsed and approximately 50 anaplastic WT cases. Each fully characterized TARGET WT case includes data from nucleic acid samples extracted from tumor and normal tissues as follows:
- primary tumor sample collected at diagnosis
- normal tissue sample from peripheral blood and/or tumor adjacent normal kidney (case-matched)
- relapsed tumor sample (case-matched) when available; some cases have third sample (those cases are considered a “trio”)
- additional cases with partial molecular characterization and/or sequencing data are available to the research community
Tissues and clinical data used for the TARGET WT project were obtained from patients enrolled in the National Wilms Tumor Study (mostly NWTS-5) clinical trial that is now run through COG. Patient samples with full characterization were chosen based on the following criteria:
- tumor cellularity of >80% in tumor specimens and tumor necrosis of <20%
- high-quality nucleic acids in amounts adequate to complete comprehensive genomic profiling
- unfavorable histology (anaplasia) or relapse event in FHWT cases
The TARGET WT project team relied on a variety of platforms to obtain a fully characterized dataset of nearly 130 hard-to-cure WT cases. The COG renal tumors Statistics and Data Center provided clinical annotations and outcome data for all cases.
Some sequence mutations identified in the poor outcome discovery cohort, along with some previously published variants, were further analyzed in a validation cohort containing an additional 550-plus cases. Targeted capture sequencing was used to look at the presence and frequency of alterations in 400 gene variants. This validation effort was performed in an unbiased cohort that was randomly selected from patients enrolled on a single COG protocol, which allowed for determination of the frequency of these changes across a broader spectrum of WT subtypes.
TARGET’s Clear Cell Sarcoma of the Kidney (CCSK) Project
Clear cell sarcoma of the kidney (CCSK) is a rare kidney tumor that usually occurs in children ages 3 or younger. Although treatment outcomes are generally favorable, patients undergo highly toxic therapies, which can lead to complications later in life (e.g., additional cancers or infertility). As CCSK is uncommon, the lack of tumor tissues for research makes studying the underlying biology of the disease difficult. The TARGET Kidney Tumors (KT) project team analyzed tumors from pediatric CCSK patients using a comprehensive, integrated genomic approach to identify new therapeutic approaches or biomarkers that correlate with poor clinical outcome.
TARGET has produced comprehensive genomic profiles of 13 clinically annotated patient cases. Each fully characterized TARGET CCSK case consists of data generated from nucleic acid samples extracted from case-matched tumor and normal tissues as follows:
• primary tumor sample collected at diagnosis
• normal tissue sample from peripheral blood or tumor adjacent normal kidney (case-matched)
Tissues and clinical data used for the TARGET CCSK project were obtained from patients enrolled in the National Wilms Tumor Study (mostly NWTS-5) clinical trial that is now run through COG. Patient samples with full characterization were chosen based on the following criteria:
• tumor cellularity of >80% in tumor specimens and tumor necrosis of <20%
• high-quality nucleic acids in amounts adequate to complete comprehensive genomic profiling
• relapse event (~50 patient cases studied)
The TARGET KT project team analyzed a validation cohort of 9 additional CCSK cases to confirm the presence and frequency of candidate variants found in the discovery dataset. This validation effort was performed in an unbiased cohort that was selected based on availability of tissue from patients enrolled on a single protocol (NWTS-5, like the discovery cohort; cases were chosen without regard for relapse).
TARGET’s Rhabdoid Tumor (RT) Project
Rhabdoid tumors (RT) are rare and very aggressive kidney tumors found mostly in young children. These patients typically have poor prognoses. Malignant rhabdoid tumors (MRT) are also rare, highly lethal tumors that most commonly present in the kidney of infants. MRT may present within the brain, and these are classified as atypical teratoid/rhabdoid tumors. Very rarely, MRT may develop in the soft tissue.
The TARGET team has produced comprehensive genomic profiles of 40 clinically annotated patient cases. Each fully characterized TARGET RT case consists of data generated from nucleic acid samples extracted from case-matched tumor and normal tissues as follows:
- primary tumor sample collected at diagnosis
- normal tissue sample from peripheral blood or tumor adjacent normal kidney (case-matched)
Tissues and clinical data used for the TARGET RT project were obtained from patients enrolled in renal tumor protocols run through COG. Patient samples with full characterization were chosen based on the following criteria:
- tumor cellularity of >80% in tumor specimens and tumor necrosis of <20%
- high-quality nucleic acids in amounts adequate to complete comprehensive genomic, transcriptomic, and epigenomic profiling
The TARGET project team analyzed a validation cohort containing 29 additional RT cases to confirm the presence and frequency of candidate variants found in the discovery dataset. This validation effort was performed in an unbiased cohort that was selected based on availability of tissue from patients enrolled on COG renal tumor protocols (AREN03B2 or NWTS-5, like the discovery cohort).
Cell line and xenograft data were also generated as part of the TARGET RT project and can be accessed along with other cell line and xenograft data at the TARGET-MDLS study. These are the samples used in RT manuscripts with data at MDLS: TARGET-00-NAAEMA, TARGET-00-NAAEMC, TARGET-52-NAAELY, TARGET-00-NAAEMB, TARGET-52-NAAELV, and TARGET-52-NAAELZ.