Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation and Protein-targeting Genes

Louise C. Pyle, 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.
Jung Kim, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Jonathan Bradfield, Quantinuum Research LLC, Philadelphia, PA, USA.
Scott M. Damrauer, 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.
Kurt D'Andrea, Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Lawrence H. Einhorn, Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
Rama Godse, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Hakon Hakonarson, 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.
Peter A. Kanetsky, Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Rachel L. Kember, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Linda A. Jacobs, 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.
Kara N. Maxwell, 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.
Daniel J. Rader, 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.
David J. Vaughn, 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.
Benita Weathers, Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Bradley Wubbenhorst, 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.
Mark H. Greene, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Katherine L. Nathanson, 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.
Douglas R. Stewart, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. Electronic address: drstewart@mail.nih.gov.

Document Type

Journal Article

Publication Date

5-26-2023

Journal

European urology

DOI

10.1016/j.eururo.2023.05.008

Keywords

Cancer; Exome; Genomics; Germ cell tumor; Predisposition; Testicular cancer

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), co-translational protein targeting (GO:0006613: O/E 18.62, FDR 1.35 × 10), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 × 10). 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.

Department

Pediatrics

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