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

Abstract

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. (REV INVEST CLIN. [AHEAD OF PRINT])

Low expression of E-Cadherin and <i>Cdh1</i> variants associated with diffuse gastric cancer

“…The rs16260 variant was previously associated to risk of DGC in our population, with an OR of 1.98 (95% CI 1.01-3.98) for heterozygotes and 6.5 (95% CI 2.1-19.6) for homozygotes 57 , and the others are reported as having uncertain significance (c.531 + 4G > A and c.2331C > G) or have not been reported (c. −273G > A, c.388-83G > A,C, and c.388-48A > G), all of which were included in the predictive analysis. We reported in a previous study that allele A of variant c. −273G > A could modify the binding sites of the transcription factors IRF3 and SP2 58 . Prediction for the intronic variants c.388-83G > A,C and c.388-48A > G with the NNSplice and NetGene2 programs showed that splicing would not be affected.…”

Associations between CDH1 gene polymorphisms and the risk of gastric cancer: A meta-analysis based on 44 studies

“…[23] Therefore, loss of E-cadherin function during tumor progression could be partially attributable to SNPs of putative susceptibility alleles. [24] Numerous studies have proved the associations between CDH1 polymorphisms and the risk of GC in humans. [25][26][27] The most widely studied sites are CDH1 rs16260 (−160C > A) and rs5030625 (−347G > GA) in the promoter region, which can decrease the transcription efficiency of the gene.…”

“…[ 23 ] Therefore, loss of E-cadherin function during tumor progression could be partially attributable to SNPs of putative susceptibility alleles. [ 24 ]…”