Transcription Factor 7-like 2 (TCF7L2) Polymorphism Was Associated with Worse Survivalin Three Independent Cohorts from the USA, Austria, and Japan

Rita El-Khoueiry1, Takeru Wakatsuki1, Yan Ning1, Wu Zhang1, Dongyun Yang2, Mizutomo Azuma3, Armin Gerger5, Michael Stotz5, Melissa J. LaBonte1, Nico Volz1, Sebastian Stintzing1, Joseph E Li1, Peter M Wilson1, Wasaburo Koizumi3, Masahiko Watanabe4, Martin Maus1, Afsaneh Barzi1, Syma Iqbal1, 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, CA3. 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.

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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 Cohort Figure 2: Austrian Cohort Figure 3: Japanese CohortTable 1: Patients characteristics of 3 cohortsJapanese Austrian USCTotal number (%) Total number (%) Total number (%)

169 63   137Ethnicity Ethnicity     EthnicityJapanese 169 100 Caucasian 63 100 Caucasian 63 46

    Hispanic 45 32.8    others 29 21.2

Median Age, yrs Median Age, yrs     Median AgeAll 68 (31-88) All 66 (37-86) All 64 (26-85)Gender Gender     GenderMale 109 64.5 Male 32 50.8 Male 83 60.6Female 60 35.5 Female 31 49.2 Female 54 39.4Stage Stage     StageIb 28 16.6 Ib 12 19.4 Ib 12 8.8II 53 31.4 II 25 40.3 II 36 26.3III 60 35.5 III 25 40.3 III 71 51.8IV 28 16.6 IV 0   IV 18 13.1T category T category     T category

1 12 7.1 1 1 1.6 1 4 2.92 66 39.1 2 37 58.7 2 44 32.13 88 52.1 3 24 38.1 3 79 57.74 3 1.8 4 1 1.6 4 10 7.3

N category N category     N category0 36 21.3 0 19 30.2 0 27 19.71 85 50.3 1 31 49.2 1 64 46.72 33 19.5 2 13 20.6 2 31 22.63 15 8.9 3 0   3 15 10.9

ECOG PS ECOG PS     ECOG PS

0 157 92.9 0 NA NA 0 62 45.3

1 12 7.1 1 NA NA 1 65 47.4

2 0 0 2 NA NA 2 10 7.3

Tumor Site     Tumor Site     Tumor Site    Stomach 166 98.2 Stomach 48 77.4 Stomach 88 69.8GEJ 3 1.8 GEJ 14 22.6 GEJ 38 30.2

Tumor differentiation Tumor differentiation Tumor differentiationwell/mode 68 40.2 moderate 7 11.1 well/mode 37 27poor 101 59.8 poor 50 79.4 poor 97 70.8      Undifferentiated 6 9.5      Lauren class. Lauren class.     Lauren class.Diffuse 101 59.8 Diffuse 27 60.0 Diffuse 40 29.2Intestinal 68 40.2 Intestinal 11 24.4 Intestinal 50 36.5Mixed 0 0 Mixed 7 15.6 Mixed 21 15.3Type of chemo. Type of chemo.     Type of chemo.

S-1 based 87 51.5 5-FU or cape. based 9 14.3 5-FU/LV 70 51.1

UFT 16 9.5 Taxan based 2 3.2 5-FU/Oxali. 19 13.9others 6 3.6 others 3 4.8 5-FU, Cis, CPT-11 25 18.2none 60 35.5 none 49 77.8 none 23 16.8Radiation Radiation     Radiationyes 0 0 yes 3 4.8 yes 88 64.2no 169 100 no 60 95.2 no 48 35

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