In a study reported in JAMA Oncology, AlDubayan et al found that inherited pathogenetic variants in the checkpoint kinase 2 gene (CHEK2), among inherited pathogenetic DNA-repair gene (DRG) alterations, were associated with susceptibility to testicular germ cell tumors.
The study involved screening for 48 DRGs in 205 unselected men with testicular germ cell tumors and 27,173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort as part of the discovery stage. Significant findings were evaluated in independent cohorts of 448 unselected men with testicular germ cell tumors and 442 population-matched controls, as well as in 231 high-risk men with testicular germ cell tumors and 3,090 ancestry-matched controls from the Penn Medicine Biobank.
Association With CHEK2 Variant
Among the 205 unselected men with testicular germ cell tumors (mean age = 33.04), 22 pathogenic germline DRG variants—one-third of which were in CHEK2—were found in 20 (9.8%) men. Unselected men with testicular germ cell tumors were significantly more likely (odds ratio [OR] = 3.87, P = .006) to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals in this discovery cohort.
In a cohort of 448 unselected Croatian men with testicular germ cell tumors (mean age = 31.98 years) vs 442 unselected Croatian men without testicular germ cell tumors (≥ 50 years at sample collection), the odds ratio was > 1.4 (P = .03). Among the 231 high-risk men with testicular germ cell tumors (mean age = 31.54 years) vs 3,090 ancestry-matched controls (all aged > 50 years), the odds ratio was 6.30 (P = .001).
The low-penetrance CHEK2 variant (p.Ile157Thr) was identified as a Croatian founder testicular germ cell tumor risk variant (OR = 3.93, P = .002). Men with the pathogenic CHEK2 loss-of-function variants developed testicular germ cell tumors at a significantly younger age than those with wild-type CHEK2 (5.95 years younger, P = .009).
The investigators concluded, “This multicenter case-control analysis of men with or without testicular germ cell tumors provides evidence for CHEK2 as a novel moderate-penetrance testicular germ cell tumor susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving testicular germ cell tumor susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.”
Eliezer M. Van Allen, MD, of the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was funded by the National Institutes of Health, ASCO’s Conquer Cancer Foundation, and others. The study authors' full disclosures can be found at jamanetwork.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.