Relevance of DNA repair gene polymorphisms to gastric cancer risk and phenotype.

Patricia Carrera‐Lasfuentes ,Rafael Campo,Mark Strunk,Manuel Zaballa,Rafael Benito,Federico Sopeña,Elena Piazuelo,Elizabeth Hijona,María Asunción García-González,Llúcia Titó,Marisa Manzano,Enrique Quintero,Luis Barranco,Fernando Geijo,Santos Santolaria,Jesús Espinel,María Pellisé ,Jorge Espinós ,Ángel Lanas ,Luís Bujanda ,Concepción Thomson ,Ángeles Pérez‐Aísa ,Ferran González‐Huix ,Mauro D’amato ,David Nicolás–Pérez

doi:10.18632/oncotarget.16261

Abstract

Variations in DNA repair genes have been reported as key factors in gastric cancer (GC) susceptibility but results among studies are inconsistent. We aimed to assess the relevance of DNA repair gene polymorphisms and environmental factors to GC risk and phenotype in a Caucasian population in Spain. Genomic DNA from 603 patients with primary GC and 603 healthy controls was typed for 123 single nucleotide polymorphisms in DNA repair genes using the Illumina platform. Helicobacter pylori infection with CagA strains (odds ratio (OR): 1.99; 95% confidence interval (CI): 1.55–2.54), tobacco smoking (OR: 1.77; 95% CI: 1.22–2.57), and family history of GC (OR: 2.87; 95% CI: 1.85–4.45) were identified as independent risk factors for GC. By contrast, the TP53 rs9894946A (OR: 0.73; 95% CI: 0.56–0.96), TP53 rs1042522C (OR: 0.76; 95% CI: 0.56–0.96), and BRIP1 rs4986764T (OR: 0.55; 95% CI: 0.38–0.78) variants were associated with lower GC risk. Significant associations with specific anatomopathological GC subtypes were also observed, most notably in the ERCC4 gene with the rs1799801C, rs2238463G, and rs3136038T variants being inversely associated with cardia GC risk. Moreover, the XRCC3 rs861528 allele A was significantly increased in the patient subgroup with diffuse GC (OR: 1.75; 95% CI: 1.30–2.37). Our data show that specific TP53, BRIP1, ERCC4, and XRCC3 polymorphisms are relevant in susceptibility to GC risk and specific subtypes in Caucasians.

Highlights

Gastric cancer (GC) represents the fifth most common neoplasia and the third leading cause of cancer– related death worldwide [1]
Over the last few years, numerous studies concerning the association between DNA repair gene polymorphisms and GC risk have been conducted in different geographic areas and ethnic groups
To assess the relevance of DNA repair gene polymorphisms to GC susceptibility and phenotype, we analyzed a total of 123 single nucleotide polymorphisms (SNPs) located in 52 genes involved in different DNA repair pathways

Summary

Introduction

Gastric cancer (GC) represents the fifth most common neoplasia and the third leading cause of cancer– related death worldwide [1]. GC is a heterogeneous disease that shows distinct clinical, epidemiological, and molecular features among tumors arising from the proximal (cardia) or distal (non–cardia) stomach, and among intestinal and diffuse histological subtypes [2, 3]. These differences in phenotype seem to be determined by complex interactions between environmental and host genetic factors. Helicobacter pylori (H. pylori) infection has been identified as the single most common cause of GC [4] This organism, which colonizes over half of the world’s population, first induces a chronic superficial gastritis in virtually all infected people, initiating a process that in certain individuals may lead to GC [5]. Why only a minority (< 1%) of infected individuals develops gastric malignancy remains a matter of speculation, suggesting that factors other than bacterial infection alone are involved in the carcinogenesis process

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