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.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…However, in this case, the underlying family predisposing gene was CTNNA1 and not CDH1 [39], and somatic mutations at LMTK3, MCTP2, MED12, PIK3CA, and ARID1A genes have been demonstrated, as well as mutations in other genes recently shown to be part of the molecular signatures of sporadic GC [54][55][56][57][58][59]. Similar studies in a series of HDGC caused either by CDH1 or CTNNA1 germline mutations, and in different progression stages, would undoubtedly help to disclose the somatic mutation landscape of this disease.…”

“…-E-catenin inhibition has been shown to destabilize adherens junctions, weakening the interaction between cells [38]. Currently, three families have been described with CTNNA1 germline mutations [35,39]. Loss of -E-catenin expression with preservation of E-cadherin has been observed in GC identified in CTNNA1 mutation carriers.…”

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing

“…Germline mutations of CTNNA1 (ref. 28) or CDH1 (ref. 29) genes have been reported in hereditary diffuseGCs, and frequent PIK3CA mutations were observed in diffuse-type sporadic GCs 7 .…”

MicroRNAs in hereditary diffuse gastric cancer

“…Thus, investigations are continuing to identify genes that are associated with HDGC. The presence of mutations has been observed in diverse genes, listed as follows: Mutations reported in RHOA (10,11) are associated with the initial stages of cancer and its progression to metastasis; CTNNA1 mutated in HDGC acts as a tumor-suppressor gene (12) and changes in MAP3K6 generate an alteration in inflammation pathways and apoptosis. In addition, it has been found that these are predisposed to develop GC (13) and that changes in the INSR gene (14) exert an effect on the insulin signaling pathway, giving rise to changes in the pattern of glycosylation of the E-cadherin protein, destabilization of cellular membranes and the appearance of a mesenchymal phenotype.…”