Abstract 4294: One-carbon metabolism and colorectal cancer risk according to molecular subtypes: a Bayesian network learning approach
Authors: Myte Robin , Gylling Björn , Häggström Jenny , Schneede Jörn , Ueland Per Magne , Hallmans Göran , Johansson Ingegerd , Palmqvist Richard , Van Guelpen Bethany 
Published: July 2016

Abstract
Background: Colorectal cancer (CRC) is a heterogeneous disease caused by a number of distinct pathways defined by genetic and epigenetic events. These molecular subtypes differ in prognosis and treatment options, and recent studies also imply differences in etiology. One-carbon metabolism has been extensively studied in relation to incident CRC risk because of its involvement in nucleotide synthesis and methylation reactions, yet only a few studies have evaluated if associations differ over CRC subtypes. In this study, we investigated a targeted panel of circulating metabolites and a set of single nucleotide polymorphisms involved in one-carbon metabolism in relation to the risk of overall CRC and CRC subtypes approximated by mutations in the BRAF and KRAS oncogenes, microsatellite instability (MSI), or CpG island methylator phenotype (CIMP).
Methods: This was a prospective population-based nested case control study of 613 CRC cases and 1190 matched controls. The data included plasma concentrations of 14 one-carbon metabolites, 17 related single nucleotide polymorphisms, and other lifestyle-related information for all subjects, and clinical and molecular information for the tumors. In order to account for interactions and dependencies between variables, we applied multivariate Bayesian network learning in combination with more traditional univariate multinomial logistic regression to investigate independent relations to subtype specific CRC risk.
Results: Preliminary findings show that vitamin B6 (Pyridoxal 5-phosphate, PLP) and vitamin B2 (riboflavin) had the strongest independent relations to overall CRC risk in the multivariate analyses. Folate, glycine, vitamin B6, and the RFC1 80G&gt;A polymorphism displayed signs of independent relations to CRC subtypes. In univariate multinomial logistic regression models, plasma folate expressed the strongest etiologic heterogeneity, and was more clearly related to the risk of CIMP low/high tumors, tumors with MSI, or tumors without KRAS mutation, respectively.
Conclusions: This study investigated a large set of prediagnostic circulating metabolites and single nucleotide polymorphisms related to one-carbon metabolism using multivariate statistical learning. We found that some components showed signs of subtype specific relations, of which the association for folate was clearest. Our results suggest that the role of one-carbon metabolism in colorectal carcinogenesis may differ between specific molecular pathways.
Citation Format: Robin Myte, Björn Gylling, Jenny Häggström, Jörn Schneede, Per Magne Ueland, Göran Hallmans, Ingegerd Johansson, Richard Palmqvist, Bethany Van Guelpen. One-carbon metabolism and colorectal cancer risk according to molecular subtypes: a Bayesian network learning approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4294.