Vitamin D, calcium, dairy products and genes involved in their metabolic pathways in colorectal cancer risk and survival

Abstract

Background Vitamin D, calcium, and dairy products are inversely associated with colorectal cancer incidence. These inverse associations may be mediated by the vitamin D binding protein, the vitamin D receptor (VDR), and the calcium sensing receptor (CASR). The purpose of the thesis was to investigate prediagnostic consumption of vitamin D, calcium, and dairy products and genetic variations in genes involved in their metabolic pathways (GC, VDR, and CASR) for their relevance to colorectal cancer risk and survival in the Newfoundland and Labrador population. Methods A population-based case-control study identified over 700 incident colorectal cancer cases (including 531 patients with follow-up data on mortality end-points) and 489 matched controls. Data on diet and lifestyle factors were gathered via epidemiological questionnaires. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom® myDesign™ Array in controls. Multivariable logistic regression examined the associations of these nutrients and genetic variants with colorectal cancer risk. Kaplan-Meier curves and Cox models assessed the relationship with overall survival (all-cause mortality, OS) and disease-free survival (DFS) among colorectal cancer patients. Results Results from this study are presented in three related, yet standalone manuscripts: 1) The GC rs2282679 polymorphism was not associated with colorectal cancer risk overall but was correlated with the DFS of colorectal cancer patients (per C allele HR, 1.36; 95% CI, 1.05- 1.77). The association of this SNP on DFS was limited to BRAF wild-type tumors. 2) VDR and CASR genes were associated with DFS and OS of colorectal cancer, respectively, at the gene level. Haplotype analysis within linkage blocks of CASR revealed the G-G-G-G-G-A- C haplotype (rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757) to be associated with a decreased OS of colon cancer (HR, 3.15; 95% CI, 1.66-5.96). 3) Prediagnostic calcium intake from foods, but not total calcium intake, was negatively associated with all-cause mortality (HR for Q2 vs. Q1, 0.44; 95% CI, 0.26-0.75). An inverse relationship was also seen in a dose-response fashion for prediagnostic cheese intake (P trend=0.029). No evidence for modification by factors known to be associated with colorectal cancer survival was observed. Conclusions Our results indicate that genetic variations in GC, VDR and CASR genes are associated with survival after colorectal cancer diagnosis. These findings also suggest a protective role of prediagnostic intakes of cheese and calcium from foods against colorectal cancer progression.