| Summary: | Testicular germ cell tumors (TGCTs) represent the most frequent malignancy in young adult men and have one the highest heritability rates among all cancers. A recent multicenter case–control study identified <i>CHEK2</i> as the first moderate-penetrance TGCT predisposition gene. Here, we analyzed <i>CHEK2</i> in 129 TGCT cases unselected for age of onset, histology, clinical outcome, and family history of any cancer, and the frequency of identified variants was compared to findings in 27,173 ancestry-matched cancer-free men. We identified four TGCT cases harboring a P/LP variant in <i>CHEK2</i> (4/129, 3.10%), which reached statistical significance (<i>p</i> = 0.0191; odds ratio (OR), 4.06; 95% CI, 1.59–10.54) as compared to the control group. Cases with P/LP variants in <i>CHEK2</i> developed TGCT almost 6 years earlier than individuals with <i>CHEK2</i> wild-type alleles (5.67 years; 29.5 vs. 35.17). No association was found between <i>CHEK2</i> status and further clinical and histopathological characteristics, including histological subtypes, the occurrence of aggressive TGCT, family history of TGCT, and family history of any cancer. In addition, we found significant enrichment for the low-penetrance <i>CHEK2</i> variant p.Ile157Thr (<i>p</i> = 0.0259; odds ratio (OR), 3.69; 95% CI, 1.45–9.55). Thus, we provide further independent evidence of <i>CHEK2</i> being a moderate-penetrance TGCT predisposition gene.
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