The ERBB2 gene polymorphisms rs2643194, rs2934971, and rs1058808 are associated with increased risk of gastric cancer

Abstract

Gastric cancer (GC) is the third most lethal type of cancer worldwide. Single nucleotide polymorphisms (SNPs) in regulatory sites or coding regions can modify the expression of genes involved in gastric carcinogenesis, as ERBB2 , which encodes for the tyrosine-kinase receptor HER-2. The aim of this work was to analyze the association of the polymorphisms: rs2643194, rs2517951, rs2643195, rs2934971, and rs1058808 with GC, as they have not yet been analyzed in GC patients, as well as to report their frequency in the general Mexican population (GMP). We studied genomic DNA from subjects with GC (n=74), gastric inflammatory diseases (GID, n=76 control subjects), and GMP (n=102). Genotypes were obtained by means of real-time PCR and DNA-sequencing. The risks for GC were estimated through odds ratio (OR) using the Cochran-Armitage trend test and multinomial logistic regression. Increased risk for GC was observed under the dominant inheritance model for the rs2643194 TT or CT genotypes with an OR of 2.75 (95%CI 1.12−6.75, P=0.023); the rs2934971 TT or GT genotypes with an OR of 2.41 (95%CI 1.01−5.76, P=0.043), and the rs1058808 GG or CG genotypes with an OR of 2.21 (95%CI 1.00−4.87, P=0.046). The SNPs rs2643194, rs2934971, and rs1058808 of the ERBB2 gene were associated with increased risk for GC.

Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine

“… 40 Moreover, MAPK1 (c.857–3854A > C and c.119 + 21641G > A), RAF1 (c.1669-36C > T) and HRAS (c.-1115T > C) intronic variants increased GA susceptibility on the Chilean population, 45 even when they were initially reported as variables of uncertain significance in ClinVar. Similar disparities between studies were found in Mexican population, where an increased GA susceptibility was associated with the EGFR promotor region variants c.-216G > T, c.-191C > A 49 (related to augmented expression of EGFR protein), the ERBB2 intronic variants c.-18 + 1614C > T, c.-18 + 3073G > T and the missense variant c.3418C > G, 50 classified as variables of uncertain significance in ClinVar. Also, a decreased susceptibility was associated with the TGF-β promoter variant c.-509C > T which is associated with higher TGF-β plasmatic concentration.…”

The ERBB2 Exonic Variant Pro1170Ala Modulates Mitogen-Activated Protein Kinase Signaling Cascades and Associates with Allergic Asthma

“…The minor allele “G” of the exonic SNP rs1058808 causes a non-synonymous Pro1170Ala mutation to the amino acid sequence of the ErbB2 protein. Based on the information from UniProt [33], the Pro1170Ala mutation is located in the disordered region of the cytoplasmic domain of ErbB2 and was predicted to be a damaging variant with potential effects on its protein structure and function [41]. In our work, the Pro1170Ala mutation results in a marked decrease in the phosphorylation level of tyrosine residues in the ErbB2 protein, at the same time also correlates with reduced asthma risk in our study population.…”