title: Prognostic impact of the c-MET polymorphism on the clinical outcome in locoregional gastric cancer patients.
abstract: OBJECTIVE
  Dysregulation of the c-MET signaling pathway results from various molecular mechanisms including mutation, amplification, and overexpression. Overexpression and amplification of c-MET have been correlated with poor clinical outcome in gastric cancer, whereas the associations between c-MET polymorphisms and prognosis have not been well defined. We examined the prognostic impact of functional polymorphisms of the MET gene on clinical outcome in gastric cancer.
  
  
  METHODS
  Candidate polymorphisms of the MET gene were analyzed by PCR-based direct sequencing for the associations with clinical outcome across three independent cohorts, including 161 Japanese, 101 US, and 63 Austrian patients, with locoregional gastric cancer, treated with surgery.
  
  
  RESULTS
  The univariable analysis showed that patients with any G (A/G or G/G genotype) allele of MET rs40239 had significantly longer disease-free survival and overall survival compared with those with the AA genotype in the Japanese cohort [hazard ratio (HR): 0.43, P=0.001, and HR: 0.47, P=0.006, respectively]; this remained significant upon multivariable analysis adjusted for age, sex, stage, and type of adjuvant therapy (HR: 0.48; P=0.009, HR: 0.50; P=0.017, respectively). However, there was no significant association of the polymorphism with clinical outcome in the US and Austrian cohorts. When stratified by sex in the Japanese cohort, male individuals, but not female individuals, with the G allele maintained a clinical outcome benefit in both univariable and multivariable analyses.
  
  
  CONCLUSIONS
  MET rs40239 may serve as a prognostic biomarker in locoregional gastric cancer. These data also suggest that genetic variants of c-MET may show sex-related differences in the impact on clinical outcome.
authors.affiliation: aSharon A. Carpenter Laboratory, Division of Medical Oncology bDepartment of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA cDepartment of Internal Medicine, Division of Clinical Oncology, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria Departments of dGastroenterology eSurgery, School of Medicine, Kitasato University, Sagamihara, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.forename: Stefan
authors.initials: S
authors.lastname: Stremitzer
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamauchi
authors.forename: Ana
authors.initials: A
authors.lastname: Sebio
authors.forename: Rita
authors.initials: R
authors.lastname: El-khoueiry
authors.forename: Syma
authors.initials: S
authors.lastname: Iqbal
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Barzi
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.forename: Michael
authors.initials: M
authors.lastname: Stotz
authors.forename: Mizutomo
authors.initials: M
authors.lastname: Azuma
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001317:Austria; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012737:Sex Factors; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D014481:United States
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met