TY - JOUR
T1 - Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility
AU - Weren, Robbert D.A.
AU - Van Der Post, Rachel S.
AU - Vogelaar, Ingrid P.
AU - Van Krieken, J. Han
AU - Spruijt, Liesbeth
AU - Lubinski, Jan
AU - Jakubowska, Anna
AU - Teodorczyk, Urszula
AU - Aalfs, Cora M.
AU - Van Hest, Liselotte P.
AU - Oliveira, Carla
AU - Kamping, Eveline J.
AU - Schackert, Hans K.
AU - Ranzani, Guglielmina N.
AU - Gómez García, Encarna B.
AU - Hes, Frederik J.
AU - Holinski-Feder, Elke
AU - Genuardi, Maurizio
AU - Ausems, Margreet G.E.M.
AU - Sijmons, Rolf H.
AU - Wagner, Anja
AU - Van Der Kolk, Lizet E.
AU - Cats, Annemieke
AU - Bjørnevoll, Inga
AU - Hoogerbrugge, Nicoline
AU - Ligtenberg, Marjolijn J.L.
N1 - Funding Information:
Funding this study was funded by KWF Kankerbestrijding (grant number KUN 2013-5876, rSvdp).
Publisher Copyright:
© 2018 Article author(s) (or their employer(s) unless otherwise stated in the text of the article). All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PY - 2018/10
Y1 - 2018/10
N2 - 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 CDH1germline 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.
AB - 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 CDH1germline 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.
KW - cancer: gastric
KW - ctnna1 - map3k6 - myd88
KW - heritability
KW - next generation sequencing
KW - alpha Catenin/genetics
KW - Genetic Predisposition to Disease
KW - Stomach Neoplasms/genetics
KW - Europe
KW - Humans
KW - Middle Aged
KW - Antigens, CD/genetics
KW - Male
KW - Myeloid Differentiation Factor 88/genetics
KW - Sequence Analysis, DNA
KW - MAP Kinase Kinase Kinases/genetics
KW - Young Adult
KW - Cadherins/genetics
KW - Germ-Line Mutation
KW - Adult
KW - Female
KW - Aged
KW - High-Throughput Nucleotide Sequencing
KW - Cohort Studies
UR - https://www.scopus.com/pages/publications/85049163281
U2 - 10.1136/jmedgenet-2017-104962
DO - 10.1136/jmedgenet-2017-104962
M3 - Article
C2 - 29330337
AN - SCOPUS:85049163281
SN - 0022-2593
VL - 55
SP - 669
EP - 674
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 10
ER -