A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: A case control study in an Italian population

We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using χ2-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis.We observed a significant (p < 0.0004) association of the CDH1 163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09–9.93) and 1.38 (95%CI = 0.75–2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and H. pylori infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied.The CDH1 163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.Gastric cancer is a major cause of cancer-related mortality and is usually classified into two histological types, the intestinal and the diffuse form (Lauren classification [1]). The general incidence rates for stomach cancer are in a steady decline, largely due to decreasing rates of the intestinal cancer-type. This falling frequency is believed to be the result of improved nutrition and sanitary conditions. In contrast, the incidence of diffuse gastric cancer (DGC) alone appears more stable over the past few decades [1,2]. Such a constant rate suggests a larger contribution of inherited genetic risk rather than environmental factors to the diffuse form of stomach cancer.Owing to its early development underneath the