Small fraction of testicular cancer cases may be causatively related to CHEK2 inactivating germ-line mutations: evidence
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ORIGINAL ARTICLE
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 Valeriya I. Ni1 · Alexandr O. Ivantsov1,2 · Mariya A. Kotkova1 · Sofia V. Baskina1 · Elena V. Ponomareva3 · Rashida V. Orlova3 · Eldar E. Topuzov3 · Kirill K. Kryukov4 · Kseniya V. Shelekhova4 · Svetlana N. Aleksakhina1 · Anna P. Sokolenko1,2 · Evgeny N. Imyanitov1,2,4,5
© Springer Nature B.V. 2020
Abstract 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. Keywords CHEK2 mutation · Loss of heterozygosity · Testicular cancer
Introduction Testicular cancer (TC) is a relatively rare neoplasm with an annual incidence below 10 cases per 100,000 men. However, this is the most common oncological disease among young adult males. Multiple investigations suggest a significant role of genetic make-up in TC predisposition. Genome-wide * Evgeny N. Imyanitov [email protected] 1
N.N. Petrov Institute of Oncology, Leningradskaya, 68, Pesochny‑2, St.‑Petersburg, Russia 197758
2
St.-Petersburg Pediatric Medical University, St.‑Petersburg, Russia 194100
3
City Oncological Dispensary, St.‑Petersburg, Russia 198255
4
City Cancer Center, St.‑Petersburg, Russia 197758
5
I.I. Mechnikov North-Western Medical University, St.‑Petersburg, Russia 191015
association studies (GWAS) identified a few dozen low-penetrance variants; however, their actual medical significance remains unclear given that they have only marginal effect on the disease risk elevation [1–6]. Recent investigation utilized systematic analysis of DNA repair genes in TC patients and discovered the involvement of CHEK2 germ-line pathogenic variants in TC susceptibility [7]. There ar
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