Abstract PL01-04: ODC genotype as prognostic and predictive factors in colorectal carcinogenesis and prevention (2010)

Abstract Polyamines are increased in many intraepithelial neoplasia, which are risk factors for cancer in humans (1). Ornithine decarboxylase (ODC1), the first enzyme in polyamine synthesis, is regulated in part by Ebox transcription factors including MYC and MAD family members. The ODC1 gene contains several single nucleotide polymorphisms (SNPs) which are associated with risk of colorectal neoplasia. A SNP located 316 nucleotides from the start of transcription (rs2302615) has functional consequences for Ebox transcription factor binding and promoter activity. Both the transcription activator MYC and transcriptional repressors in the MAD family preferentially bind the ODC promoter element containing the minor A allele, which is flanked by two canonical E-boxes, resulting in allele-specific expression (2, 3). This SNP is associated with both risk of metachronous colorectal adenoma (CRA), in several independent studies (2, 4), and survival of patients with stages I-III colon cancer (3). The ODC1 SNP was also found to be predictive of reduced risk of CRA in association with aspirin use by three independent groups (2, 4, 5). The mechanism underlying the relationship between the ODC1 SNP and aspirin appears to involve the action of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on polyamine catabolism and export. NSAIDs, including aspirin and sulindac, and celecoxib transcriptionally activate SAT1, a spermidine/spermine acetyltransferase, by unique mechanisms (6-8). Acetylation targets these polyamines for export by an SLC3A2-dependent arginine antiporter (9). Thus, NSAIDs and celecoxib, by activating polyamine export, complement ODC1 inhibitors, which suppress polyamine synthesis, to reduce tissue polyamine contents. In a prospective, randomized, placebo-controlled clinical trial of difluoromethylornithine (DFMO), a selective ODC1 inhibitor, and the NSAID sulindac for three years, combination treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple CRAs, in patients with prior colon polyps (10). The 30% rate of non-advanced CRA development in the treatment arm was strongly associated with both the ODC1 SNP and dietary polyamines (11). Consideration of homeostatic regulatory processes, supported by measurements of tissue polyamine contents in participants in this trial, support the interpretation that decreased ODC transcription, resulting from the ODC1 SNP, is associated with altered polyamine transport. Treatment-associated toxicities were rare and associated with pretreatment clinical and genetic risk factors. The ODC1 SNP was predictive of ototoxicity in this trial (11). These studies identify genetic variability in ODC1, a MYC target gene, as a prognostic factor for colorectal carcinogenesis and as a predictive factor for treatments targeting this pathway. The role(s) of other ODC1 SNPs in colorectal or other cancers remains to be established. References: 1. Gerner EW, Meyskens FL, Jr. Polyamines and cancer: old molecules, new understanding. Nature Reviews Cancer 2004;4(10):781-92. 2. Martinez ME, O'Brien TG, Fultz KE, et al. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc Natl Acad Sci U S A 2003;100(13):7859-64. 3. Zell JA, Ziogas A, Ignatenko N, et al. Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival. Clin Cancer Res 2009;15(19):6208-16. 4. Hubner RA, Muir KR, Liu JF, Logan RF, Grainge MJ, Houlston RS. Ornithine decarboxylase G316A genotype is prognostic for colorectal adenoma recurrence and predicts efficacy of aspirin chemoprevention. Clin Cancer Res 2008;14(8):2303-9. 5. Barry EL, Baron JA, Bhat S, et al. Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention. Journal of the National Cancer Institute 2006;98(20):1494-500. 6. Babbar N, Ignatenko NA, Casero RA, Jr., Gerner EW. Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. J Biol Chem 2003;278(48):47762-75. 7. Babbar N, Gerner EW, Casero RA, Jr. Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells. Biochemical Journal 2006;394(Pt 1):317-24. 8. Ignatenko NA, Besselsen DG, Stringer DE, Blohm-Mangone KA, Cui H, Gerner EW. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr Cancer 2008;60 Suppl 1:30-5. 9. Uemura T, Yerushalmi HF, Tsaprailis G, et al. Identification and characterization of a diamine exporter in colon epithelial cells. J Biol Chem 2008;283(39):26428-35. 10. Meyskens FL, Jr., McLaren CE, Pelot D, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila Pa) 2008;1(1):32-8. 11. Zell JA, McLaren CE, Chen WP, Thompson PA, Gerner EW, Meyskens FL. Ornithine Decarboxylase-1 Polymorphism, Chemoprevention With Eflornithine and Sulindac, and Outcomes Among Colorectal Adenoma Patients. J Natl Cancer Inst 2010; epub ahead of print. Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL01-04.