Cancer Stem Cell SNPs Have Opposite Prognostic Outcome in Patients with Gastric Cancer

1. Cancer Stem Cell SNPs Have Opposite Prognostic Outcome in Patients with Gastric Cancer Among Asian and Western Countries Melissa J. LaBonte1, Takeru Wakatsuki1, Wu Zhang1, DongyunYang2, Mizutomo Azuma3, Armin Gerger5, Michael Stotz5, Yan Ning1, Nico Volz1, Sebastian Stintzing1, Joseph E Li1, Rita El-Khoueiry1, Peter M Wilson1, Wasaburo Koizumi3, Masahiko Watanabe4, Martin Maus1, Afsaneh Barzi1, SymaIqbal1, Anthony El-Khoueiry1, and Heinz-Josef Lenz1,2 1. Department of Medical Oncology, 2. Department of Preventive Medicine; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 3. Department of Gastroenterology, 4 Department of Surgery; Kitasato University East Hospital 5. Division of Clinical Oncology, Medical University of Graz Abstract ID: 4110 Introduction Results The clinical significance of cancer stem cells (CSC) has been well established; however, their prognostic role remains controversial. CD44 is recognized as a CSC marker in gastric cancer (GC) (1) and, recently, the clinical impact of CD166 in GC was reported (2). Our group previously reported SNPs in CD44 rs187116 G>A and CD166 rs1157 G>A are associated with outcome in USA patients with adjuvant GC and colorectal cancer, respectively (3, 4); however these results have not been validated in an independent cohort to date. Since GC has regional differences in epidemiology and clinicopathology, we tested the hypothesis that ethnicity and regional differences in GC could influence the prognostic role of CD44 and CD166 in GC. Patients characteristics of 3 cohorts are shown in Table 1. In CD44 rs187116, AA showed a shorter OS than AG/GG (2.0 years vs. not reached, HR: 2.87 [95%CI: 1.61-5.13], p<0.001) in the Japanese cohort, while AA showed a longer OS than AG/GG (7.3 vs. 4.1 years, HR: 2.0 [95%CI: 0.90-4.55], p=0.079) in the US cohort (Figure 1). In CD166 rs1157, AA/AG showed a shorter OS than GG (3.9 years vs. not reached, HR: 1.81 [95%CI: 1.05-3.12],p=0.033) in the Japanese cohort, while AA showed a longer OS that AG/GG (not reached vs. 4.7 years, HR: 5.00[95%CI: 0.70-35.95], p=0.073) in the USA cohort (Figure 2). In CD44 rs187116, AA was associated with lower gene expression level than AG/GG (p=0.061), while no significant difference was shown between AA/AG and GG in CD166 (Figure 3). Figure 3: Figure 1: CD44 rs187116 Figure 2: CD166 rs1157 Table 1: Patient characteristics A A Gene expression analysis of CD44 and CD166 A AA vs. AG/GG; P=0.061 Methods 369 patients with histopathologically-confirmed localized GC were enrolled (stage Ib-IV; TNM 6th), 169 patients from Japan, 137 patients from the USA, and 63 patients from Austria between 2002 and 2010. D2 lymphadenectomy based surgery were conducted in Japan and Austria, while D1 lymphadenectomy based surgery were conducted in USA. Adjuvant fluoropyrimidine based chemotherapy was conducted in ~60% patients. Genomic DNA was extracted from peripheral blood or formalin fixed paraffin embedded tumor tissue using the QIAmp kit. All samples were analyzed by means of PCR-based direct DNA- sequencing. Microdissection and gene expression analysis in the Japanese cohort were conducted in order to assess a correlation between genotypes and relative gene expression levels. The primary endpoint of this study was overall survival (OS). To evaluate prognostic value of these polymorphisms, endpoints were estimated using the Kaplan-Meier method and compared by log-rank test. The level of significance was set to p < 0.05. B B B AA/AG vs. GG; P=0.494 Conclusions References SNP profiles in CSC markers predicted opposite prognostic outcomes in patients with GC among Asian and Western countries. This is the first report suggesting that the prognostic role of CSC markers in GC may differ based on ethnic groups or etiology differences. 1) Takaishi S, et al; Stem Cells. 27, 2009 4 ) GergerA, et al; Clin Cancer Res. 17, 2011 2) Ishigami S, et al; J Surgical Oncol. 103, 2011 3) Winder T, et al; Int J Cancer. 129, 2011