1. Transcription Factor 7-like 2 (TCF7L2) Polymorphism Was Associated with Worse Survival in Three Independent Cohorts from the USA, Austria, and Japan Rita El-Khoueiry 1, Takeru Wakatsuki 1, Yan Ning 1, Wu Zhang 1, Dongyun Yang 2, Mizutomo Azuma 3, Armin Gerger 5, Michael Stotz 5, Melissa J. LaBonte 1, Nico Volz 1, Sebastian Stintzing 1, Joseph E Li 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 2010. D2 lymphadenectomy based surgery were conducted in Japan and Austria, while D1 lymphadenectomy based surgery were conducted in the USA. Adjuvant fluoropyrimidine based chemotherapy was conducted in ~60% of 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. The primary endpoint of this study was time to recurrence (TTR) in the USA cohort and disease-free survival (DFS) in the Japanese and Austrian cohorts. The secondary endpoint was overall survival (OS). To evaluate prognostic value of this polymorphism, endpoints were estimated using Kaplan-Meier method and compared by log-rank test. The level of significance was set to p < 0.05. The Wnt/β-catenin signaling pathway controls cell proliferation, differentiation, and stem cell maintenance. Disruption of this pathway has been shown in the majority of colorectal (CRC) and gastric cancers (GC) (1-3). The TCF7L2 complex plays a critical role in this pathway. Interaction of TCF7L2 and β-catenin results in translocation to the nucleus and leads to up-regulation of target genes, including c-myc and cyclin D1. Previous reports have shown that the TCF7L2 polymorphism, rs7903146 C/T, is associated with risk of CRC and breast cancer (4, 5); however, so far, no data has been provided for the prognostic role of this polymorphism in GC. Therefore, we tested the hypothesis of whether this polymorphism could predict outcome in GC using three independent cohorts (USA, Austria and Japan) that were ethnically and etiologically different. Abstract ID: Results Conclusions Introduction Methods 4088 Patients characteristics in this study are shown in Table 1. In the USA cohort, TCF7L2 polymorphism (rs7903146) TT/CT showed a shorter TTR than CC (1.7 vs. 4.4 years, HR: 2.09 95%CI: 1.21- 3.59, p=0.0053) (Figure 1). A similar trend was shown in the Austrian cohort, TT/CT showed a shorter DFS than CC (2.08 vs. 5.42 years, HR: 1.79 [95%CI: 0.90-3.55], p=0.092) (Figure 2). Moreover, in the Japanese cohort, TT showed a shorter DFS than CT/CC (0.15 vs. 4.82 years, HR: 10.5 [95%CI: 2.46-45.5], p=0.001) (Figure 3). These results were confirmed in the OS in the US and Japanese cohorts. TT/CT showed a shorter OS (3.3 vs. 5.5 years, HR: 2.41 95%CI: 1.28-4.53, p=0.0043) in the USA cohort. TT showed a shorter OS than CT/CC (0.22 vs. 5.76 years, HR: 15.2 [95%CI: 3.50-66.7], p<0.001) in the Japanese cohort. The TCF7L2 polymorphism was associated with worse prognosis in terms of recurrence in patients with GC in three independent global cohorts. This polymorphism may be negative prognostic factor in GC regardless of ethnicity and etiology, suggesting the important role of Wnt/β-Catenin signaling in GC. References Figure 1: USA CohortFigure 2: Austrian Cohort Figure 3: Japanese Cohort Table 1:Patients characteristics of 3 cohorts JapaneseAustrianUSC Total number(%)Total number(%)Total number(%) 16963 137 Ethnicity Japanese169100Caucasian63100Caucasian6346 Hispanic4532.8 others2921.2 Median Age, yrs Median Age All68 (31-88)All66 (37-86)All64 (26-85) Gender Male10964.5Male3250.8Male8360.6 Female6035.5Female3149.2Female5439.4 Stage Ib2816.6Ib1219.4Ib128.8 II5331.4II2540.3II3626.3 III6035.5III2540.3III7151.8 IV2816.6IV0 1813.1 T category 1127.1111.6142.9 26639.123758.724432.1 38852.132438.137957.7 431.8411.64107.3 N category 03621.301930.202719.7 18550.313149.216446.7 23319.521320.623122.6 3158.930 31510.9 ECOG PS 015792.90NA 06245.3 1127.11NA 16547.4 2002NA 2107.3 Tumor Site Stomach16698.2Stomach4877.4Stomach8869.8 GEJ31.8GEJ1422.6GEJ3830.2 Tumor differentiation well/mode6840.2moderate711.1well/mode3727 poor10159.8poor5079.4poor9770.8 Undifferentiated69.5 Lauren class. 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