Abstract 2831: Ornithine decarboxylase polymorphisms and risk of colorectal adenoma

Abstract

Abstract Introduction: In a recent randomized trial the combination of difluoromethylornithine (DFMO) and the NSAID sulindac was remarkably effective in reducing the risk of colorectal adenoma recurrence. DFMO is a specific inhibitor of ornithine decarboxylase (ODC), which catalyzes the first step in polyamine synthesis. ODC and polyamines, which regulate cell growth and survival, have long been associated with colon carcinogenesis. In previous studies a SNP in the ODC promoter region was associated with risk of adenoma and response to aspirin treatment. The objective of this research was to perform a more comprehensive investigation of the association of adenoma risk with common genetic variation across the entire ODC gene, including potential upstream and downstream regulatory regions. Methods: We investigated the association between genetic variation in the ODC gene and risk of adenoma recurrence among a cohort of 920 participants in the Aspirin/Folate Polyp Prevention Study. Using the Sequenom platform, we genotyped 29 SNPs within a 23kb region. Generalized linear regression was used to compute relative risks (RRs) and 95% confidence intervals (95% CIs) adjusted for age and gender. Interactions terms were used to test whether ODC genotype modified the protective effect of aspirin treatment. Results: As gene frequencies for 26 of the 29 SNPs varied significantly by race/ethnicity, analyses were limited to whites only (86%). There were 7 SNPs associated with increased risk and 3 with decreased risk of adenoma recurrence (see table). In addition, at least three SNPs without any main effect modified the effect of aspirin treatment: rs1405948 (P for interaction=0.048), rs28362422 (P=0.043), and rs4669584 (P=0.050). Conclusion: Our findings suggest that common genetic variation throughout the ODC gene and adjacent regulatory regions influence risk of adenoma recurrence as well as efficacy of aspirin treatment.Association of ODC polymorphisms with adenoma riskSNPRR95% CIP-valueModelMAFLocationrs23575511.231.06-1.440.008dominant0.345′ flankingrs23026141.371.08-1.740.009dominant0.04exon 2rs37526611.351.06-1.720.017dominant0.04intron 5rs10495001.381.08-1.750.009dominant0.04exon 12rs8181620.700.52-0.940.019recessive0.303′ flankingrs109296691.251.06-1.480.009dominant0.113′ flankingrs24634630.760.62-0.930.009recessive0.443′ flankingrs24304201.251.08-1.460.004dominant0.323′ flankingrs116949111.341.13-1.590.001dominant0.113′ flankingrs130009160.770.63-0.040.009recessive0.453′ flanking Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2831.