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Updated: Jul 26, 2026
Transgenic Rodent Assay for Quantifying Male Germ Cell Mutant Frequency
Published on: August 6, 2014
Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation
Louise C Pyle1, Jung Kim2, Jonathan Bradfield3
1Rare 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.
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.
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