• Azaria García-Ruvalcaba, Lourdes Del C Rizo de la Torre, María T Magaña-Torres, Ernesto Prado-Montes-de-Oca, Andrea V Ruiz-Ramírez, Héctor Rangel-Villalobos, José A Aguilar-Velázquez, Andrea M García-Muro, and Josefina Y Sánchez-López.
• Genetics Division, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jal.; Doctorate Program in Human Genetics, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jal.; Mexico.
• Rev Invest Clin. 2021 Jan 19.

BackgroundEarly-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.ObjectiveThe objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population.MethodsWe 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.ResultsWe 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.ConclusionsClassical 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.

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