Purpose: Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage II colon cancer who are more likely to benefit from adjuvant chemotherapy. Interleukin 1 beta (IL1B) and interleukin 1 receptor antagonist (IL1RN) have been shown to play a critical role in the early onset of tumor-associated angiogenesis. In this study, we tested whether eight functionally significant polymorphisms within six genes of the angiogenesis pathway [IL1B, IL1RN, vascular endothelial growth factor A (VEGFA), VEGF receptor 2, interleukin-8, cyclooxygenase-2] will predict the risk of tumor recurrence in stage II colon cancer patients treated with 5-fluorouracil based adjuvant chemotherapy.
Experimental design: Blood samples were obtained from 109 patients with stage II colon cancer at the University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism protocols.
Results: Patients harboring the IL1RN/IL1B 1-T-C (IL-1RN variable number tandem repeats (VNTR)/IL1B C+3954T/C-511T) haplotype were at greatest risk of developing tumor recurrence [relative risk (RR): 2.72, 95% confidence interval (CI): 1.22-6.08] (adjusted P=0.015). In addition, IL1B +3954 any T (RR: 2.78, 95% CI: 0.99-7.83) (adjusted P=0.043), IL1RN VNTR (RR: 6.09, 95% CI: 1.11-33.4) (adjusted P=0.038), and VEGFA -634 any C (RR: 2.91, 95% CI: 1.13-7.48) (adjusted P=0.026) were shown to be adverse prognostic markers, in both univariate and multivariable analyses.
Conclusion: Polymorphisms in IL1B, IL1RN, and VEGFA as well as IL1B/IL1RN haplotype analysis may serve as molecular markers for tumor recurrence in stage II colon cancer, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.