Imaging, Diagnosis, Prognosis Associations of a Polymorphism in the Ornithine Decarboxylase Gene with Colorectal Cancer Survival

Purpose: Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer–specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells. Experimental Design: The study included 400 incident stage I-III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer–specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1. Results: Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer–specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A-alleles, compared with major G-alleles, in cultured cells. Conclusions: These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis. (Clin Cancer Res 2009;15(19):6208–16) Polyamines are small ubiquitous molecules involved in various processes, including transcription, RNA stabilization, ion channel gating, and others (1). Ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is essential for normal development and tissue repair in mammals but is downregulated in most adult tissues (2). Multiple abnormalities in the control of polyamine metabolism and transport result in increased polyamine levels that can promote tumorigenesis in several tissues (3). Polyamine metabolism is upregulated in the intestinal epithelial tissues of humans with familial Authors' Affiliations: Department of Epidemiology, Genetic Epidemiology Research Institute, and Chao Family Comprehensive Cancer Center, Department of Medicine, University of California, Irvine, California; Department of Cell Biology and Anatomy, College of Medicine, Gastrointestinal Cancer Program, Arizona Cancer Center, and Graduate Program in Biochemistry and Molecular Biology, The University of Arizona, and Cancer Prevention Pharmaceuticals, Tucson, Arizona Received 3/10/09; revised 6/8/09; accepted 7/1/09; published OnlineFirst 9/29/09. Grant support: NIH K23 CA133142 (J.A. Zell), L30 CA130160 (J.A. Zell), CA72008 (E.W. Gerner), CA78134 (H. Anton-Culver), CA78285 (H. AntonCulver), and CA95060 (E.W. Gerner). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Disclaimer: “The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N01-PC-54404 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement 1U58DP00807-01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and endorsement by the State of California, Department of Public Health the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred.” Requests for reprints: Jason A. Zell, Department of Epidemiology, 224 Irvine Hall, University of California, Irvine; Irvine, CA 92697. Phone: 1-949824-7401; Fax: 1-949-824-1343; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0592 6208 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Research. on August 28, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 29, 2009; DOI: 10.1158/1078-0432.CCR-09-0592