Small fraction of testicular cancer cases may be causatively related to CHEK2 inactivating germ-line mutations: evidence for somatic loss of the remaining CHEK2 allele in the tumor tissue.

A recent study suggested a role of CHEK2 loss-of-function germ-line pathogenic variants in the predisposition to testicular cancer (TC) (AlDubayan et al. JAMA Oncol 5:514-522, 2019). We attempted to validate this finding relying on the high population frequency of recurrent CHEK2 pathogenic variants in Slavic populations. CHEK2 pathogenic alleles (c.1100delC (p.Thr367Metfs); del5395 [del ex9-10]; IVS2 + 1G > A [c.444 + 1G > A]) were detected in 7/280 (2.5%) TC patients vs. 3/424 (0.7%) healthy men and 6/1007 (0.6%) healthy women [OR 4.0 (95% CI 1.5-11), p = 0.009 for pooled control groups]. Somatic CHEK2 loss-of-heterozygosity (LOH) was detected in 4 out of 6 tumors available for analysis; strikingly all these instances of LOH involved inactivation of the wild-type allele. The CHEK2 c.470T > C (p.Ile157Thr) variant was detected in 21/280 (7.5%) affected vs. 22/424 (5.2%) non-affected men [OR 1.5 (95% CI 0.8-2.7), p = 0.3]. Somatic CHEK2 LOH was revealed only in 6 out of 21 tumors obtained from CHEK2 c.470T > C (p.Ile157Thr) carriers, with the C-allele lost in two cases and T-allele deleted in four tumors. The results of comparison of allele frequencies in TC patients versus population controls coupled with the data on CHEK2 LOH status in tumor tissues support the association of CHEK2 pathogenic variants with TC risk.