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Original Investigation
January 24, 2019

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors

Author Affiliations
  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 2Cancer Program, the Broad Institute of MIT and Harvard, Cambridge, Massachusetts
  • 3Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts
  • 4Department of Medicine, King Saud bin Abdul-Aziz University for Health Sciences, Riyadh, Saudi Arabia
  • 5Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 6Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 7Division of Medical Oncology, Urogenital Unit, Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
  • 8Department of Urology, University Hospital Center Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
  • 9Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 10Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 11Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 12Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 13Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 14Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 15Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
  • 16Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, Florida
JAMA Oncol. 2019;5(4):514-522. doi:10.1001/jamaoncol.2018.6477
Key Points

Question  Do inherited pathogenic variants in DNA repair genes confer higher susceptibility to testicular germ cell tumors?

Findings  In this multistage case-control study involving 884 men, carriers of germline pathogenic variants in CHEK2 were 4 to 6 times more likely to develop testicular germ cell tumors and, on average, had a 6-year earlier age of presentation than carriers of the wild-type CHEK2 alleles.

Meaning  Inherited CHEK2 mutations are high-risk drivers of susceptibility to testicular germ cell tumors and might be informative for the clinical cancer-risk management of mutation carriers and their at-risk family members.


Importance  Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.

Objective  To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.

Design, Setting, and Participants  A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018.

Main Outcomes and Measures  Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls.

Results  Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009).

Conclusions and Relevance  This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.