medwireNews: Inherited pathogenic variants in the DNA repair gene CHEK2 are associated with an increased risk for developing testicular germ cell tumors (TGCTs), findings indicate.
“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,” say Eliezer Van Allen (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and co-investigators.
They screened for pathogenic, or likely pathogenic germline variants, in 48 DNA repair genes associated with predisposition to cancer in a cohort of 205 men with TGCT not specifically chosen for early-onset disease or family history of TGCTs and therefore described as “unselected,” and 27,173 ancestry-matched individuals without cancer from the Exome Aggregation Consortium cohort.
Twenty (9.8%) men with TGCT harbored pathogenic or likely pathogenic variants in 10 genes, most commonly in CHEK2, with either a loss-of-function (LOF) or p.Ile157Thr mutation seen in 3.9%.
TGCT patients were a significant 3.87 times more likely to test positive for CHEK2 LOF variants than the cancer-free controls. The CHEK2 p.Ile157Thr variant was also more common among individuals with TGCT than those without cancer, but this was not statistically significant.
The researchers replicated the findings in a cohort drawn from the Penn Medicine Biobank that comprised 231 high-risk TGCT patients, described as such because they had at least two family members with TGCTs or had bilateral tumors, and 3090 cancer-free individuals. The likelihood of harboring CHEK2 LOF variants was a significant 6.30-fold higher for the TGCT than control group, and again the enrichment of CHEK2 p.Ile157Thr among TGCT patients was nonsignificant.
In a third Croatian cohort – formed of 448 unselected men with TGCT and 442 controls – both CHEK2 LOF variants and the p.Ile157Thr mutation were significantly enriched among men with TGCT than cancer-free controls, with odds ratios of over 1.41 and of 3.93, respectively.
“To our knowledge, CHEK2 is the only Mendelian TGCT predisposition gene that has so far been identified, which carries both mechanistic and clinical importance,” the study authors write in JAMA Oncology.
“Mechanistically, our findings complement a growing body of evidence for CHEK2 as a master regulator of chromosomal segregation, DNA damage repair, and cell cycle regulation during germ cell development and maturation,” they say.
The team continues: “Beyond the potential for TGCT risk stratification, the identification of pathogenic germline CHEK2 variants in men with TGCTs could be informative for the clinical management of these individuals.”
And Van Allen et al conclude that “as several studies exploring the efficacy of targeted therapeutic interventions (such as CHEK1 and CHEK2 inhibitors) in DNA-repair–proficient and DNA-repair–deficient tumors are under way, our study identified potentially targetable DNA-repair defects that might be exploited in chemotherapy-resistant testicular cancers.”
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