Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

TitleUnraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.
Publication TypeJournal Article
Year of Publication2017
AuthorsVogelaar, IP, van der Post, RS, J van Krieken, HJm, Spruijt, L, van Zelst-Stams, WAg, C Kets, M, Lubinski, J, Jakubowska, A, Teodorczyk, U, Aalfs, CM, van Hest, LP, Pinheiro, H, Oliveira, C, Jhangiani, SN, Muzny, DM, Gibbs, RA, Lupski, JR, de Ligt, J, Vissers, LELM, Hoischen, A, Gilissen, C, van de Vorst, M, Goeman, JJ, Schackert, HK, Ranzani, GN, Molinaro, V, García, EBGómez, Hes, FJ, Holinski-Feder, E, Genuardi, M, Ausems, MGEM, Sijmons, RH, Wagner, A, van der Kolk, LE, Bjørnevoll, I, Høberg-Vetti, H, van Kessel, AGeurts, Kuiper, RP, Ligtenberg, MJL, Hoogerbrugge, N
JournalEur J Hum Genet
Date Published2017 Nov
KeywordsAdult, Aged, Antigens, CD, Cadherins, Early Detection of Cancer, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Male, Middle Aged, Sequence Analysis, DNA, Stomach Neoplasms

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Alternate JournalEur J Hum Genet
PubMed ID28875981
PubMed Central IDPMC5643972
Grant ListR01 NS058529 / NS / NINDS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States

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