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 - Garcia, Encarna B. Gomez
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 - Bjornevoll, Inga
AU - Hoogerbrugge, Nicoline
AU - Ligtenberg, Marjolijn J. L.
PY - 2018/10/1
Y1 - 2018/10/1
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 - heritability
KW - ctnna1-map3k6-myd88
KW - next generation sequencing
KW - MOLECULAR INVERSION PROBES
KW - MUTATIONS
KW - CDH1
KW - GUIDELINES
KW - CARCINOMAS
KW - ACCURACY
U2 - 10.1136/jmedgenet-2017-104962
DO - 10.1136/jmedgenet-2017-104962
M3 - Article
C2 - 29330337
SN - 0022-2593
VL - 55
SP - 669
EP - 674
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 10
ER -