Background: Pancreatic cancer is a rapidly fatal disease with few well-established risk factors. Genome-wide association studies (GWAS) have identified four genes associated with pancreatic cancer risk, but the low statistical significance thresholds in GWAS preclude identification of many associations and genetic risk for disease may not be fully explained by single genes or single nucleotide polymorphisms (SNPs). Collections of genes grouped into pathways may have a collective effect not detected in GWAS or candidate gene approaches. Also, biologic plausibility can be taken into consideration in pathway-based analyses. Laboratory and animal studies suggest a role for vitamin D in inhibiting tumor cell differentiation and angiogenesis, while stimulating apoptosis. Additionally, ecologic studies suggest lower pancreatic cancer incidence with higher UV exposure. However, epidemiologic studies on the association between vitamin D status and pancreatic cancer risk provide conflicting evidence with some studies suggesting positive associations. Vitamin D-related genetic pathways have not been examined in relation to pancreatic cancer risk.

Methods: Using biochemical knowledge of vitamin D metabolism and signaling to select vitamin-D related genes, we identified seven pathways (encompassing 119 unique genes) describing broader vitamin D involvement in pathways hypothesized to relate to pancreatic cancer risk. We used PanScan-I and PanScan-II genotyping data from the database of Genotypes and Phenotypes (dbGAP) to examine these pathways, genes, and SNPs with risk of pancreatic cancer. We included 1,510 pancreatic cancer cases and 1,561 controls from the PanScan-I cohorts and 2,136 cases and 2,186 controls from PanScan-II case-control studies. First, we examined associations among the cohort studies, and then we confirmed associations in the case-control studies and in analyses of the combined population. To test associations between the pathways and pancreatic cancer risk we used the adaptive rank truncated product statistic. For analyses at the gene and SNP levels (n=1631 SNPs in cohort studies, n=2231 SNPs in case-control studies) we used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals with pancreatic cancer risk.

Results: The seven identified pathways were not associated with risk of pancreatic cancer. Within the cohort studies, when we tested individual genes within the pathways we observed suggestive associations for PRKCA (p-value=0.0273), MAPK1 (p-value=0.0355), BCL2 (p-value=0.0321) and ABCD3 (p-value=0.0284). The significant associated allelic ORs ranged from 1.4 to 1.7 for markers near the PRKCA gene and 0.83 for a marker near the BCL2 gene, while individual SNPs were not significant at a p<0.001 level for MAPK1 or ABCD3. These gene and SNP-level associations were not replicated in the case-control studies, but in combined analyses of the cohort and case-controls studies PRKCA was associated with an increased risk of pancreatic cancer (p-value=0.0043).

Conclusions: The joint effects of the seven pathways including vitamin D-related genes were not related to pancreatic cancer risk in this study population. PRKCA, which was associated with risk in the cohort studies, may regulate cell proliferation, apoptosis, and differentiation, among other functions. Calcium can activate the PRKCA gene and there is some evidence for 1,25(OH)2D3 (the active form of vitamin D) playing a role in activation of PRKCA as well. Our study indicates that SNPs located near this gene may be involved in pancreatic cancer tumorigenesis. Future studies may consider the role of PRKCA in pancreatic cancer.

Citation Format: Hannah Arem, Dennis Maeder, Kai Yu, Bill Wheeler, Emily Steplowski, Neal Freedman, Susan T. Mayne, Harvey Risch, Joshua Sampson, Rachael Z. Stolzenberg-Solomon. Genetic pathways related to vitamin D and risk of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 61.