Testicular Neoplasms study with WXS data on dbGaP (327 participants)

phs003107 — Testicular Cancer Consortium WES

We have leveraged our previous collaborative research to better understand the genetic underpinnings of testicular germ cell tumor (TGCT), and have completed whole exome sequencing on the DNA of patients at high risk for TGCT. Specifically, we conducted a study of high-risk individuals using data from Penn Medicine and the NCI. We collected germline DNA from blood or saliva samples from men with bilateral TGCT, and a family history consisting of at least one first to third degree relative diagnosed with the disease. The goal of the study was to identify coding genomic variation associated with predisposition to TGCT. Whole exome sequencing and gene burden analyses were performed on 293 men with a family history of TGCT or bilateral disease. 228 unique families were represented in this sample. Our results found a missense variant in the hinge domain of proto-oncogene <a href="https://www.ncbi.nlm.nih.gov/gene/5292">PIM1</a>. Several more candidates were identified via gene burden association, including loss-of-function variants in <a href="https://www.ncbi.nlm.nih.gov/gene/51199">NIN</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/55278">QRSL1</a>. We also identified an association with variants in <a href="https://www.ncbi.nlm.nih.gov/gene/1080">CFTR</a> using gene-specific analysis. There was no association with sex and germ cell development pathways or regions identified by GWAS previously. We identified associations with three major pathways including, mitosis/cell cycle, co-translational protein targeting, and sex differentiation. Our results showed associations with variants in several genes, which suggests a multigenic heritability. We also found potential association with CFTR, co-translational protein targeting, and chromosomal segregation in sex determination. Our results suggest potential drug targets for TGCT prevention or treatment, e.g., PIM1, and the co-translational targeting pathway. To our knowledge, our study is the largest to date of men with high risk TGCT.