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Prognostic impact of the c-MET polymorphism on the clinical outcome in locoregional gastric cancer patients

Sunakawa, Yu; Wakatsuki, Takeru; Yang, Dongyun; Zhang, Wu; Ning, Yan; Stintzing, Sebastian; Stremitzer, Stefan; Yamauchi, Shinichi; Sebio, Ana; El-khoueiry, Rita; Iqbal, Syma; Barzi, Afsaneh; Gerger, Armin; Stotz, Michael; Azuma, Mizutomo; Watanabe, Masahiko; Koizumi, Wasaburo; Lenz, Heinz-Josef

doi: 10.1097/FPC.0000000000000091
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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.

Conclusion 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.

Supplemental Digital Content is available in the text.

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

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.pharmacogeneticsandgenomics.com).

Correspondence to Heinz-Josef Lenz, MD, Sharon A. Carpenter Laboratory, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Ave, Suite 3456, Los Angeles, CA 90033, USA Tel: +1 323 865 3967; fax: +1 323 865 0061; e-mail: lenz@usc.edu

Received May 22, 2014

Accepted August 8, 2014

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