title: An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer.
abstract: Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type; 30-40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α-E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Majewski
authors.forename: Irma
authors.initials: I
authors.lastname: Kluijt
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scerri
authors.forename: Daphne
authors.initials: D
authors.lastname: de Jong
authors.forename: Roelof J C
authors.initials: RJ
authors.lastname: Kluin
authors.forename: Samantha
authors.initials: S
authors.lastname: Hansford
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Astrid J
authors.initials: AJ
authors.lastname: Bosma
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hofland
authors.forename: Marcel
authors.initials: M
authors.lastname: Winter
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D015723:Gene Library; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051178:alpha Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495273:CTNNA1 protein, human; D015820:Cadherins; D004273:DNA, Neoplasm; D051178:alpha Catenin