An α‐E‐catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. Issue 4 (15th February 2013)

• Record Type: Journal Article
• Authors: Majewski, Ian J; Kluijt, Irma; Cats, Annemieke; Scerri, Thomas S; de, Daphne; Kluin, Roelof JC; Hansford, Samantha; Hogervorst, Frans BL; Bosma, Astrid J; Hofland, Ingrid; Winter, Marcel; Huntsman, David; Jonkers, Jos; Bahlo, Melanie; Bernards, René
• Is Part Of: Journal of pathology. Volume 229:Issue 4(2013)
• Page Start: 621
• Page End: 629
• Publication Date: 2013-02-15
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4152
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p> <bold>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 <italic>E‐cadherin</italic> (<italic>CDH1</italic>), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in <italic>CDH1</italic>, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of <italic>α</italic>‐E‐catenin (<italic>CTNNA1</italic>) 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 <italic>CTNNA1</italic> 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 <italic>α</italic>‐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 <italic>PIK3CA</italic>, <italic>ARID1A</italic>, <italic>MED12</italic> and <italic>MED23</italic>.</bold> </p> </abstract>