Project Funding Details

Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer death worldwide. Biological plausibility, extensive experimental evidence and strong supportive data from prospective observational studies point towards a protective effect of higher circulating vitamin D [25(OH)D] levels against CRC development. However, it is unclear whether or to what extent this association is modified by variation in genes involved in 25(OH)D metabolism and signalling. The existing data to date are inconsistent, but do suggest that some single nucleotide polymorphisms (SNPs), such as those in genes relating to vitamin D receptor binding sites do modulate CRC risk. However, it is now becoming better understood that a wide array of genes across the human genome are involved in vitamin D metabolism (e.g. absorption, endogenous synthesis, transport, activation, deactivation) and action (including transcriptional activity/post-transcriptional effects). Thus, it is plausible that variation in many genes may modulate the vitamin D-CRC risk association. Many of these genes are polymorphic, but few studies to date have comprehensively investigated their individual and collective potential to modulate circulating vitamin D levels or the association of vitamin D with CRC incidence. Thus, the main objective of this study was to examine the association between CRC risk and genetic variation in genes related to vitamin D metabolism. This nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of over 520,000 subjects from 10 Western European countries. In total, 1,420 first incident CRC cases, developed after enrolment into the cohort, were matched with a similar number of controls. In total, 1,176 tagging SNPs were measured using a custom Illumina Golden Gate assay. Incidence rate ratios (RR) and 95% confidence intervals (95%CI) were estimated from unconditional logistic regression models adjusting for age, sex, and centre. Serum 25(OH)D levels were measured by enzyme-immunoassay and adjusted for the week of blood collection using the residual method (CRC=1,139; colon=764). Adaptive rank-truncated product (ARTP) method implemented in R-package PIGE was used for pathway analysis. The results of this large observational study in Western European populations suggest, for the first time, that some genes involved in transcriptional activity of the 1,25(OH)2D-VDR-RXR complex may influence CRC risk independently and in combination with vitamin D levels. The findings also confirm previous observations for a role of SMAD3 and SMAD7 genes, and the C-MYC genetic region, with risk of CRC development.

Background: Colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men worldwide. Various lines of evidence suggest that it should be highly preventable by modifications of diet and lifestyle, yet to date the only clearly established dietary and dietary-lifestyle-related factors are high intake of red/processed meats and alcohol, low physical activity, higher adult attained height, and obesity. Compelling recent research indicates that higher body vitamin D level is also associated with CRC prevention and some potential mechanisms for its observed role have been put forward. The degree to which vitamin D protects against colorectal carcinogenesis may depend on a person’s genetic background. Variation in genes involved in vitamin D synthesis, transport, activation and deactivation may alter an individual’s vitamin D status and subsequently his/her CRC risk. Also, variation in genes responsive to vitamin D signalling may alter molecular pathways that play an important role in colorectal carcinogenesis. To date, only a few human studies have investigated variation within these genes or assessed biologically plausible interrelationships between genes. A novel aspect of this project was its use of vitamin D status biomarker and availability of detailed information on dietary/lifestyle/nutrient factors in relation to CRC risk. Using this data, the project undertook a genetic pathway analysis approach. Aims and objectives: The main aim of this project was to measure variation within the genes involved in vitamin D pathway and genes modulated by vitamin D and to explore potential interactions between genes, vitamin D biomarkers and environment in relation to risk of CRC development. How the study was carried out: This project was conducted using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a large cohort of over 520,000 participants from ten Western European countries. The cohort is an excellent resource because it has already collected dietary and lifestyle information along with blood samples for genetic analyses. This project focused on 1,139 CRC cases that have developed within the EPIC cohort over a period of 11 years since the start of the cohort. These cases were matched with an equal number of healthy participants on age, study centre, and other risk factors. Genetic variation in the genes related to vitamin D metabolism and action, and in the genes that are regulated by vitamin D was measured. Differences in variation in these genes were compared between the CRC cases and the matched healthy controls. To analyse the data, we used statistical methods to look into pathways of gene function and combine the genetic data with dietary, lifestyle and biomarker information. Key findings and conclusions: Our results, based on a large observational study in Western European populations suggest that a series of genes whose role is to control the activity of the vitamin D receptor complex may influence CRC risk independently and in combination with vitamin D levels. Our findings also confirm previous observations for a role of specific cell signalling mechanisms with risk of CRC development.