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Genetic Variation in Calcium-Sensing Receptor and Risk for Colon Cancer

Background: Experimental and epidemiologic studies have suggested that high calcium intake is associated with decreased colon cancer risk, yet very limited data are available for candidate genes in the calcium–vitamin D pathway and colon cancer risk. To address this, we evaluated whether calcium-sensing receptor (CASR) single-nucleotide polymorphisms are associated with colon cancer risk. We also examined interactions among CASR, calcium, and vitamin D intake and previously genotyped vitamin D–related genes. Methods: We conducted a large multicenter population-based case-control study of 1,600 cases and 1,949 controls. Seventeen tagging single-nucleotide polymorphisms for CASR were selected from common single-nucleotide polymorphisms (minor allele frequency, ≥5%) based on resequencing data. Haplotypes were estimated and evaluated using HaploStats. Results: We did not observe an association between any CASR genotypes or haplotypes and colon cancer risk overall. However, when stratified by anatomic site, statistically significant associations were seen with risk for proximal colon cancer [rs10934578 TT: odds ratio, 1.35; 95% confidence interval (95% CI), 1.01-1.81; rs12485716 AG/AA: odds ratio, 0.84; 95% CI, 0.71-1.00; rs4678174 CT/CC: odds ratio, 0.83; 95% CI, 0.70-0.98; rs2270916 CC: odds ratio, 0.43; 95% CI, 0.19-0.97]. Concordantly, we observed a suggested association for a CASR haplotype (rs4678174, rs2270916) with risk for proximal colon cancer (global P = 0.08). We did not observe any meaningful gene-environment (calcium and vitamin D) or gene-gene (CYP24A1, CYP27B1, and VDR) interactions with CASR genotypes and colon cancer risk. Conclusion: Our study does not provide evidence for an overall association between CASR single-nucleotide polymorphisms and colon cancer; however, results suggest a possible role of CASR on proximal colon cancer, and subsite differences are consistent with known calcium biology. Nonetheless, these findings require confirmation. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2755–65)