Genetics and epigenetics of pediatric germ cell tumors

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Scientific Abstract Malignant germ cell tumors (GCTs) in children and adults are hypothesized to occur as a result of events in utero. The high heritability of adult testicular GCT (TGCT) suggests a genetic etiology, and recent genomewide association studies support this through the discovery of multiple susceptibility loci. We recently confirmed a subset of these loci as susceptibility variants for pediatric GCT. While 5-year relative survival rates are very high overall for GCTs, mainly due to the effectiveness of cisplatin chemotherapy, approximately 20% of patients will display resistance to chemotherapy or relapse following treatment. Clinical risk stratification to identify patients with poor prognosis is still very crude and further molecular analysis, including analysis of tumor epigenetics, may help to tailor treatment. Our recently completed Children’s Oncology Group (COG) case- parent triad study of GCT was the first large study to collect germline DNA samples from pediatric and adolescent GCT cases, tumor specimens and outcomes data. The research proposed in this application will allow us to extend the scope of our ongoing study by evaluating tumor DNA methylation as a prognostic factor for GCT and by expanding our analyses of germline genetic variation to include the sex chromosomes. Our overarching goal for the proposed study is to evaluate the contribution of genetics and epigenetics in pediatric GCT risk and outcomes. Our hypothesis is that DNA methylation patterns will predict GCT cases who are likely to have poor outcomes. Further, we hypothesize that common and moderately rare variants on the sex chromosomes increase risk for GCT. To evaluate these hypotheses, we will combine data from our ongoing COG case-parent triad study of pediatric GCT (N=867 cases and 1,517 parent controls) with GCT cases and controls obtained from the state biobank programs in California, Michigan and Washington (N=1,601 cases and 1,601 controls). Our primary aims will be to: 1) Identify methylation patterns that predict poor outcomes, including disease relapse and death, and 2) Discover single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) on the sex chromosomes that contribute to GCT risk in children and adolescents. We will also evaluate the contribution of rare genetic variants in GCT through the use of aggregate burden tests in an exploratory aim. Methylation will be evaluated using the Illumina EPIC methylation array in 500 GCT tumor samples. Germline genetic analyses will be conducted using existing GWAS data generated on the Illumina Human CoreExome array. The contribution of rare variants will be assessed through analysis of whole exome sequencing data generated through the Gabriella Miller Kids First Pediatric Research Program (N=250 trios) and Exome content available for the entire dataset (N=2,468 cases). Little is known about the etiology of pediatric GCT; analysis of germline genetic variation will shed light on disease biology. Identification of methylation patterns associated with poor prognosis could improve the existing clinical risk stratification and suggest new avenues for treatment. Finally, this will be the first study of GCT susceptibility in any age group to include individuals of non-European ancestry.