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.

Survival after colorectal cancer diagnosis is associated with colorectal cancer family history.

BACKGROUND: Colorectal cancer (CRC) family history is a known risk factor for CRC development; however, effects of CRC family history on survival after CRC diagnosis are less well-defined. Our population-based analysis investigates whether familial CRC cases exhibit improved survival compared with sporadic CRC cases. METHODS: Cases enrolled in the University of California Irvine Gene-Environment Study of Familial Colorectal Cancer from 1994 to 1996 were analyzed, with follow-up through December 2006. Cases were categorized as familial or sporadic based on self-reported CRC family history in a first-degree relative. Univariate and multivariate survival analyses with Cox proportional hazards ratios were done for overall survival (OS) and CRC-SS (CRC-SS). RESULTS: One thousand one hundred fifty-four CRC cases were analyzed, including 781 colon cancer and 373 rectal cancer cases. Nineteen percent of colon cases had family history of CRC in a first-degree relative, compared with 16% of rectal cancer cases. No statistically significant differences between familial and sporadic colon or rectal cancer cases were detected for age, gender, ethnicity, stage, tumor location, histology, tumor grade, or stage-specific treatment rendered. Among colon cancer cases, family history of CRC (versus no family history as a reference group) was associated with improved OS (adjusted hazard ratio, 0.760; 95% confidence interval, 0.580-0.997), but not with CRC-SS (hazard ratio, 0.880; 95% confidence interval, 0.621-1.246). No OS or CRC-SS differences were detected for rectal cancer cases. CONCLUSIONS: CRC cases with family history of the disease have improved overall survival compared with sporadic CRC cases, a finding that is independent of other relevant clinical factors.

A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A.

Vitamin A has diverse biological functions. It is transported in the blood as a complex with retinol binding protein (RBP), but the molecular mechanism by which vitamin A is absorbed by cells from the vitamin A-RBP complex is not clearly understood. We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex. It is widely expressed in embryonic development and in adult organ systems. The RBP receptor represents a major physiological mediator of cellular vitamin A uptake.