Associations of a Polymorphism in the Ornithine Decarboxylase Gene with Colorectal Cancer Survival

Abstract

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

Association between the ornithine decarboxylase G316A polymorphism and breast cancer survival

“…In cultured cells, the E-box activator c-MYC and repressor MXI1 were found to preferentially bind to ODC minor A alleles, rather than major G alleles. Consistent with the results of the present study, Zell et al (16) reported that c-MYC, MAD1 and MAD4 preferred binding to ODC minor A-alleles, rather than major G-alleles, in vitro.…”

“…Furthermore, in colorectal cancer, the ODC polymorphism appeared to act as a genetic marker for predicting colon cancer recurrence. Furthermore, the ODC G316A genotype was found to be a prognostic factor in colorectal adenoma recurrence and survival (15,16).…”

“…The ODC A allele has been reported to be associated with poor survival in colorectal cancer (16). Martinez et al (30) reported that MAD1 (as well as MXI1) selectively suppressed the activity of the ODC promoter containing the A allele, as opposed to the G allele, in the HT29 human colon cancer-derived cell line.…”

“…Furthermore, the transcription of the ODC gene can be altered by this SNP (14). Previous studies have demonstrated that the ODC G316A polymorphism exhibits prognostic efficacy in colorectal adenoma recurrence and is associated with the survival of patients with colorectal cancer (15,16). However, the effects of this SNP on the clinical outcomes in breast cancer remain unclear.…”

Pharmacological and dietary agents for colorectal cancer chemoprevention: Effects on polyamine metabolism (Review)

“…SNP has been investigated as a marker for colorectal adenoma (43). In this connection, it has been observed that aspirin is able to decrease the risk of CRA recurrence especially in individuals homozygous for the ODC1 minor A allele compared with those with the major G allele (44).…”