Abstract
ObjectivesTo evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk.MethodsIn the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay.Results SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05–7.65], 1.24 [95% CI = 1.01–1.53], 1.19 [95% CI = 1.01–1.41], and 1.37 [95% CI = 1.15–1.62], respectively; meta OR = 4.59 [95% CI 2.74–7.70], 1.36 [95% CI = 1.09–1.70], 1.20 [95% CI = 1.00–1.44], and 1.32 [95% CI = 1.10–1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05).ConclusionsOur findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.
Highlights
Helicobacter pylori (H. pylori), a group I human gastric carcinogen by the International Agency for Research on Cancer (IARC) [1], is the strongest risk factor in the gastric cancer development, and persistent H. pylori infection is the first step towards gastric carcinogenesis [1,2,3]
Tyrosine phosphorylated Cytotoxin-associated gene A (CagA) by SRC family kinases interacts with SHP2 tyrosine phosphatase, CRK, CRKL and c-Src tyrosine kinase (CSK) and induces cell scattering, dissociation and mortality connected to cancer development [8,12,13,14,15]
There was no significant difference between cases and controls according to sex, H. pylori infection, CagA/VacA seropositivity, smoking/drinking status and gastric ulcer history in the discovery and extension phases (p.0.05)
Summary
Helicobacter pylori (H. pylori), a group I human gastric carcinogen by the International Agency for Research on Cancer (IARC) [1], is the strongest risk factor in the gastric cancer development, and persistent H. pylori infection is the first step towards gastric carcinogenesis [1,2,3]. In spite of numerous evidence that H. pylori plays a crucial role in gastric carcinogenesis, only a small portion of infected people develop gastric cancer. This implies that other factors involved in the pathogenic mechanism of H. pylori can modify individual susceptibility for gastric cancer. Non-phosphorylated CagA interacts with c-MET and GRB2 which promotes oncogenic response including cell proliferation and morphological changes such as hummingbird formation [8,16,17,18,19] This CagA translocation and its cellular interaction with those proteins can be a crucial initiating step in gastric carcinogenesis [9,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
