Weren RDA, van der Post RS, Vogelaar IP, van Krieken JH, Spruijt L, Lubinski J, Jakubowska A, Teodorczyk U, Aalfs CM, van Hest LP, Oliveira C, Kamping EJ, Schackert HK, Ranzani GN, Gómez García EB, Hes FJ, Holinski-Feder E, Genuardi M, Ausems MGEM, Sijmons RH, Wagner A, van der Kolk LE, Cats A, Bjørnevoll I, Hoogerbrugge N, and Ligtenberg MJL
Background: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1 , MAP3K6 or MYD88 ., Methods: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1 germline mutation for germline variants affecting CTNNA1 , MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes., Results: Predicted deleterious germline variants were not encountered in MYD88 , but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1 , deleterious variants in MAP3K6 also occur frequently in the general population., Conclusions: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)