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Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival.


ABSTRACT: 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.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.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.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.

SUBMITTER: Zell JA 

PROVIDER: S-EPMC2769500 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival.

Zell Jason A JA   Ziogas Argyrios A   Ignatenko Natalia N   Honda Jane J   Qu Ning N   Bobbs Alexander S AS   Neuhausen Susan L SL   Gerner Eugene W EW   Anton-Culver Hoda H  

Clinical cancer research : an official journal of the American Association for Cancer Research 20090929 19


<h4>Purpose</h4>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.<h4>Experimental design</h4>The study included 400 incident stage I-III colorectal ca  ...[more]

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