Cancer Stem Cell SNPs Have Opposite Prognostic Outcome in Patients with Gastric Cancer Among Asian and Western Countries Melissa J. LaBonte 1, Takeru Wakatsuki 1, Wu Zhang 1, Dongyun Yang 2, Mizutomo Azuma 3, Armin Gerger 5, Michael Stotz 5, Yan Ning 1, Nico Volz 1, Sebastian Stintzing 1, Joseph E Li 1, Rita El-Khoueiry 1, Peter M Wilson 1, Wasaburo Koizumi 3, Masahiko Watanabe 4, Martin Maus 1, Afsaneh Barzi 1, Syma Iqbal 1, Anthony El-Khoueiry 1, and Heinz-Josef Lenz 1,2 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 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 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 < 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 rs 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. Abstract ID: Results Conclusions Introduction Methods 4110 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: ], 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: ], 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: ], 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: ], p=0.073) in the USA cohort (Figure 2). 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. 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). References Figure 1: CD44 rs187116Figure 2: CD166 rs1157 Figure 3: Table 1: Patient characteristics Gene expression analysis of CD44 and CD166 AA vs. AG/GG; P=0.061 AA/AG vs. GG; P= ) Takaishi S, et al; Stem Cells. 27, ) Ishigami S, et al; J Surgical Oncol. 103, ) Winder T, et al; Int J Cancer. 129, ) Gerger A, et al; Clin Cancer Res. 17, 2011 JapaneseAustrianUSC Total number(%)Total number(%)Total number(%) Ethnicity Japanese169100Caucasian63100Caucasian6346 Hispanic others Median Age, yrs Median Age All68 (31-88)All66 (37-86)All64 (26-85) Gender Male Male3250.8Male Female6035.5Female3149.2Female Stage Ib2816.6Ib1219.4Ib128.8 II5331.4II2540.3II III6035.5III2540.3III IV2816.6IV T category N category ECOG PS NA NA NA Tumor Site Stomach Stomach4877.4Stomach GEJ31.8GEJ1422.6GEJ Tumor differentiation well/mode6840.2moderate711.1well/mode3727 poor poor5079.4poor Undifferentiated69.5 Lauren class. Diffuse Diffuse2760.0Diffuse Intestinal6840.2Intestinal1124.4Intestinal Mixed Mixed Type of chemo. S-1 based FU or cape. based FU/LV UFT169.5Taxan based23.25-FU/Oxali others63.6others34.85-FU, Cis, CPT none6035.5none4977.8none Radiation yes yes no169100no6095.2no4835 A B A B A B