title: Genetic susceptibility on CagA-interacting molecules and gene-environment interaction with phytoestrogens: a putative risk factor for gastric cancer.
abstract: OBJECTIVE
  To 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.
  
  
  METHODS
  In 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).
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jae Jeong
authors.initials: JJ
authors.lastname: Yang
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Cho
authors.forename: Kwang-Pil
authors.initials: KP
authors.lastname: Ko
authors.forename: Aesun
authors.initials: A
authors.lastname: Shin
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Ma
authors.forename: Bo Youl
authors.initials: BY
authors.lastname: Choi
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Han
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Song
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Bok Ghee
authors.initials: BG
authors.lastname: Han
authors.forename: Soung-Hoon
authors.initials: SH
authors.lastname: Chang
authors.forename: Hai-Rim
authors.initials: HR
authors.lastname: Shin
authors.forename: Daehee
authors.initials: D
authors.lastname: Kang
authors.forename: Keun-Young
authors.initials: KY
authors.lastname: Yoo
authors.forename: Sue K
authors.initials: SK
authors.lastname: Park
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007118:Immunoassay / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D008957:Models, Genetic; D016017:Odds Ratio; D048789:Phytoestrogens / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012306:Risk; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000382:microbiology; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C485285:CRK protein, human; D048789:Phytoestrogens; D050737:Proto-Oncogene Proteins c-crk; C080866:cagA protein, Helicobacter pylori; D019859:Proto-Oncogene Proteins c-met; D019061:src-Family Kinases