Prediction of tumor recurrence by tumor location in stage II and III colon cancer patients through common germ-line variants of genes involved in wnt signaling pathway.

Abstract

e14714 Background: Wnt signaling is essential for embryonic development, stem cells and tissue regeneration. The Wnt signaling pathway was found to be deregulated in 93% of colorectal cancer (CRC). Tumor recurrence after curative resection is still a major problem in the management of adjuvant CRC, with recurrence rate approximately 30-40%. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. In this study, our group tested whether gene polymorphisms [TCF7L2 rs7903146, AXIN2 (rs2240308, rs3923087) and P300 (rs7286979, rs220551 and rs5782022)] involved in Wnt signaling pathway could predict the risk of tumor recurrence in stage II and III CRC patients. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 years (range 22–78 years)) with stage II (105 patients) or III (129 patients) colon cancer at the University of Southern California/Norris Comprehensive Cancer Center. The median follow-up was 4.4 years. TCF7L2, AXIN2 and p300 SNPs were determined by PCR-RFLP or PCR-based direct sequence. The primary endpoint of the study was time to tumor recurrence (TTR). Results: In univariate analysis, patients with TCF7L2 rs7903146 TT genotype had significantly longer TTR (median=10.7 months, 95%CI 4.9,10.7 +) compared with those harboring CT (median=3.9months, 95% CI 2.4, 10.7) or CC genotype (median=5.9months, 95% CI 2.8, 11.4+) patients (p=0.042, log-rank test). In multivariate analysis, left-side tumor patients with p300 rs7286979 AA genotype had highest risk of TTR (HR=2.85, 95% CI 1.03,7.89) compared to those carring GA (HR=0.81, 95% CI 0.35,1.84) or AA genotype (p=0.048, Wald test). Conclusions: Our results show that germline polymorphisms profiling of Wnt signaling pathway TCF7L2 rs7903146, p300 rs7286979 may predict tumor recurrence risk in adjuvant colon cancer patients, and may dependent on tumor location. Our exploratory data warrants further validation.