Identification and characterization of CDH1 germline variants in sporadic gastric cancer patients and in individuals at risk of gastric cancer

To screen and characterize germline variants for E-cadherin (CDH1) in non-hereditary gastric cancer (GC) patients and in subjects at risk of GC. 59 GCs, 59 first degree relatives (FDRs) of GC, 20 autoimmune metaplastic atrophic gastritis (AMAGs) and 52 blood donors (BDs) were analyzed for CDH1 by di...

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Published in:PloS one Vol. 8; no. 10; p. e77035
Main Authors: Garziera, Marica, Canzonieri, Vincenzo, Cannizzaro, Renato, Geremia, Silvano, Caggiari, Laura, De Zorzi, Mariangela, Maiero, Stefania, Orzes, Enrico, Perin, Tiziana, Zanussi, Stefania, De Paoli, Paolo, De Re, Valli
Format: Journal Article
Language:English
Published: United States Public Library of Science 2013
Public Library of Science (PLoS)
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Summary:To screen and characterize germline variants for E-cadherin (CDH1) in non-hereditary gastric cancer (GC) patients and in subjects at risk of GC. 59 GCs, 59 first degree relatives (FDRs) of GC, 20 autoimmune metaplastic atrophic gastritis (AMAGs) and 52 blood donors (BDs) were analyzed for CDH1 by direct sequencing, structural modelling and bioinformatics. Functional impact on splicing was assessed for intronic mutations. E-cadherin/β-catenin immunohistochemical staining and E-cadherin mRNA quantification using RT-PCR were performed. In GCs, 4 missense variants (p.G274S; p.A298T; p.T470I; p.A592T), 1 mutation in the 5'UTR (-71C>G) and 1 mutation in the intronic IVS12 (c.1937-13T>C) region were found. First pathogenic effect of p.A298T mutation was predicted by protein 3D modelling. The novel p.G274S mutation showed a no clear functional significance. Moreover, first, intronic IVS12 (c.1937-13T>C) mutation was demonstrated to lead to an aberrant CDH1 transcript with exon 11 deletion. This mutation was found in 2 GCs and in 1 BD. In FDRs, we identified 4 variants: the polymorphic (p.A592T) and 3 mutations in untranslated regions with unidentified functional role except for the 5'UTR (-54G>C) that had been found to decrease CDH1 transcription. In AMAGs, we detected 2 alterations: 1 missense (p.A592T) and 1 novel variant (IVS1 (c.48+7C>T)) without effect on CDH1 splicing. Several silent and polymorphic substitutions were found in all the groups studied. Overall our study improves upon the current characterization of CDH1 mutations and their functional role in GC and in individuals at risk of GC. Mutations found in untranslated regions and data on splicing effects deserve a particular attention like associated with a reduced E-cadherin amount. The utility of CDH1 screening, in addition to the identification of other risk factors, could be useful for the early detection of GC in subjects at risk (i.e. FDRs and AMAGs), and warrants further study.
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Competing Interests: Dr. Valli De Re declares that he is a co-author and Editorial Board member of PLOS ONE. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Conceived and designed the experiments: MG VC RC SG VD. Performed the experiments: MG VC RC SG LC MDZ VD. Analyzed the data: MG RC LC VD. Wrote the paper: MG VD. Tissue biobanking management: TP. Microbiological evaluation of samples: SZ. Data manager: EO. Enrolment and clinical evaluation of patients: SM. Support overall the study: VC RC PDP VD.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0077035