Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation and Protein-targeting Genes.
| Title: | Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation and Protein-targeting Genes. |
|---|---|
| Authors: | Pyle LC; Rare Disease Institute, Center for Genetic Medicine, Children's National Hospital, Washington, DC, USA; Department of Precision Medicine, George Washington University, Washington, DC, USA; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Kim J; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.; Bradfield J; Quantinuum Research LLC, Philadelphia, PA, USA.; Damrauer SM; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; D'Andrea K; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Einhorn LH; Simon Cancer Center, Indiana University, Indianapolis, IN, USA.; Godse R; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Hakonarson H; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Kanetsky PA; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.; Kember RL; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Jacobs LA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Maxwell KN; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Rader DJ; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Vaughn DJ; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Weathers B; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Wubbenhorst B; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Regeneron Genetics Center Research Team; Regeneron Genetics, Terrytown, NY, USA.; Cancer Genomics Research Laboratory; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.; Greene MH; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.; Nathanson KL; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Stewart DR; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. Electronic address: drstewart@mail.nih.gov. |
| Source: | European urology [Eur Urol] 2024 Apr; Vol. 85 (4), pp. 337-345. Date of Electronic Publication: 2023 May 26. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: Switzerland NLM ID: 7512719 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7560 (Electronic) Linking ISSN: 03022838 NLM ISO Abbreviation: Eur Urol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2002- : Amsterdam : Elsevier Science; Original Publication: Basel, New York, Karger. |
| MeSH Terms: | Testicular Neoplasms*/genetics ; Testicular Neoplasms*/pathology ; Neoplasms, Germ Cell and Embryonal*/genetics; Germ Cells/pathology ; Male ; Humans ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Exome Sequencing ; Case-Control Studies |
| Abstract: | Background: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk.; Objective: To identify coding genomic variants associated with predisposition to TGCT.; Design, Setting, and Participants: The study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls.; Outcome Measurements and Statistical Analysis: We carried out exome sequencing and gene burden analysis to identify associations with TGCT risk.; Results and Limitations: Gene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for truncating variants, p = 0.47 for all variants) or evidence of associations with the regions previously identified via genome-wide association studies (GWAS). When considering all significant coding variants together with genes associated with TGCT on GWAS, there were associations with three major pathways: mitosis/cell cycle (Gene Ontology identity GO:1903047: observed/expected variant ratio [O/E] 6.17, false discovery rate [FDR] 1.53 × 10-11), co-translational protein targeting (GO:0006613: O/E 18.62, FDR 1.35 × 10-10), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 × 10-4).; Conclusions: To the best of our knowledge, this study is the largest to date on men with HR-TGCT. As in previous studies, we identified associations with variants for several genes, suggesting multigenic heritability. We identified associations with co-translational protein targeting, and chromosomal segregation and sex determination, identified via GWAS. Our results suggest potentially druggable targets for TGCT prevention or treatment.; Patient Summary: We searched for gene variations that increase the risk of testicular cancer and found numerous new specific variants that contribute to this risk. Our results support the idea that many gene variants inherited together contribute to the risk of testicular cancer.; (Published by Elsevier B.V.) |
| Comments: | Comment in: Transl Androl Urol. 2024 Mar 31;13(3):476-478. doi: 10.21037/tau-23-560.. (PMID: 38590959); Comment in: Transl Androl Urol. 2024 Jul 31;13(7):1329-1332. doi: 10.21037/tau-24-85.. (PMID: 39100820) |
| Grant Information: | T32 GM008638 United States GM NIGMS NIH HHS; R01 CA114478 United States CA NCI NIH HHS; U01 CA164947 United States CA NCI NIH HHS; P30 ES013508 United States ES NIEHS NIH HHS; P30 CA016520 United States CA NCI NIH HHS; Z99 CA999999 United States ImNIH Intramural NIH HHS; K08 CA248704 United States CA NCI NIH HHS; ZIA CP010142 United States ImNIH Intramural NIH HHS; KL2 TR001879 United States TR NCATS NIH HHS |
| Contributed Indexing: | Keywords: Cancer; Exome; Genomics; Germ cell tumor; Predisposition; Testicular cancer |
| SCR Disease Name: | Testicular Germ Cell Tumor |
| Entry Date(s): | Date Created: 20230528 Date Completed: 20240318 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10676450 |
| DOI: | 10.1016/j.eururo.2023.05.008 |
| PMID: | 37246069 |
| Database: | MEDLINE |
Journal Article