Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility

• Published in: Journal of medical genetics Vol. 55; no. 10; pp. 669 - 674
• Main Authors: Weren, Robbert D A, van der Post, Rachel S, Vogelaar, Ingrid P, van Krieken, J Han, Spruijt, Liesbeth, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M, van Hest, Liselotte P, Oliveira, Carla, Kamping, Eveline J, Schackert, Hans K, Ranzani, Guglielmina N, Gómez García, Encarna B, Hes, Frederik J, Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H, Wagner, Anja, van der Kolk, Lizet E, Cats, Annemieke, Bjørnevoll, Inga, Hoogerbrugge, Nicoline, Ligtenberg, Marjolijn J L
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.10.2018; BMJ Publishing Group
• Series: Short report
• Subjects: Adult; Aged; alpha Catenin - genetics; Antigens, CD - genetics; Bioinformatics; Cadherins - genetics; Cancer Genetics; Cohort Studies; Consortia; Defects; Deoxyribonucleic acid; DNA; E-cadherin; Europe; Family medical history; Female; Gastric cancer; Genes; Genetic Predisposition to Disease; Genetic testing; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Male; MAP Kinase Kinase Kinases - genetics; Middle Aged; Mutation; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Patients; Proteins; Sequence Analysis, DNA; Stomach Neoplasms - genetics; Young Adult; Europe; Netherlands; cancer: gastric; ctnna1 – map3k6 – myd88; next generation sequencing; heritability
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2017-104962

BackgroundIn 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.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted 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.ConclusionsBased 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.