Predicting Pathogenicity of CDH1 Gene Variants in Patients with Early-onset Diffuse Gastric Cancer from Western Mexico.

BACKGROUND: Early-onset diffuse gastric cancer (EODGC) occurs at or before 50 years of age. Pathogenic mutations and germline deletions in the CDH1 gene (E-cadherin) are well-documented genetic factors associated with the causes of EODGC. OBJECTIVE: The objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population. METHODS: We studied seven EODGC patients from a biomedical research center in western Mexico. Variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. The DeepSEA and SNPClinic v.1.0 software and the Ensembl (1000 Genomes Project, 1kGP) and ClinVar databases were used to predict functional single-nucleotide polymorphisms (SNPs). The genetic admixture of the Mexican patients was corroborated by 22 short tandem repeat loci genotyping and structure analysis. RESULTS: We found 12 germline CDH1 variants in all EODGC patients, and all of them are considered as polymorphisms: rs34561447, rs5030625, rs16260, rs1330727101, rs28372783, rs942269593, rs3743674, rs1801552, rs34939176, rs33964119, rs3556654, and rs1801026. The prediction of regulatory SNPs in the promoter suggests a role for a retrovirus in EODGC that induces the transcription of interferon-related genes through toll-like receptor-interferon response factor 3 signaling, as three SNPs in the CDH1 promoter alter three binding sites for this transcription factor. In addition, SNPs rs28372783 and rs1801026 could alter upstream stimulatory factors 1 (USF1)/USF2-mediated telomerase-dependent lymphocyte activation in EODGC. Other interesting result is a CTCF-dependent shorter CDH1 isoform lacking exon 14, probably due to exon-skipping mediated by rs33964119. CONCLUSIONS: Classical pathogenic germline mutations in the CDH1 gene were not found in these 7 EODGC patients. However, the in silico approaches revealed the possible involvement of a retrovirus and a shorter E-cadherin isoform in EODGC. Nevertheless, further in vitro and in vivo assays are needed to confirm these predictions.