Abstract 4585: Folate-mediated one-carbon metabolism polymorphisms associated with risk and survival of colorectal cancer

Introduction Folate-mediated one-carbon metabolism (FOCM) is a key pathway necessary for nucleotide synthesis, DNA methylation, replication and repair. Genetic variants in FOCM genes, especially the MTHFR-C677T polymorphism, have been associated with colorectal neoplasia. Moreover, FOCM is an important target for chemotherapeutic drugs for the treatment of colorectal cancer (CRC), such as 5-fluorouracil (5-FU). We performed a comprehensive assessment of FOCM-related genetic variation in relation to CRC risk and survival in an unfortified population. Methods Associations of 457 tagging and candidate SNPs in 47 FOCM-related genes with CRC risk and survival were investigated within a German population-based case-control study (the DACHS- study). Using multivariate adjusted logistic (n = 1754 incident cases and 1781 matched controls) and Cox regression (5 years follow-up of CRC cases only; 585 deceased), we evaluated co-dominant, dominant, and log-additive modes of inheritance. SNPs were genotyped using the Illumina GoldenGate Assay. Correction for multiple testing was performed using false discovery rates (FDR). Results Individuals having both variant alleles of a candidate SNP in the ADH1C gene (rs1693482) had a significantly decreased risk of developing CRC (ORhet = 0.94 [95% CI = 0.81-1.10]; ORhzv = 0.74 [95% CI = 0.59-0.92]; p-trend = 0.013). Before correction for multiple testing, 19 nominally significant genetic main effects on CRC risk were observed. None of the studied tagging SNPs was significantly associated with risk after multiple test correction. One polymorphism in the PON1 gene (rs3917538) was significantly associated with overall survival (HRhet = 1.22 [95% CI = 1.03-1.45]; HRhzv = 2.00 [95% CI = 1.48-2.71]; p-trend = 0.01), after correction for multiple testing. Effect modification by 5-FU chemotherapy was observed between two polymorphisms (MTHFR-rs4846047 [Int-pFDR = 0.02] and TK1-rs1811086 [Int-pFDR = 0.02]) for the endpoint overall survival. Cases with variant alleles of these SNPs had a reduced effect of 5-FU on overall survival. Conclusion Genetic variation in FOCM appears to be associated with CRC risk and survival. Furthermore, 5-FU might interact with FOCM polymorphisms. Further large investigations are required to replicate our findings. Citation Format: Akke Botma, Katharina Buck, Yesilda Balavarca, Dominique Scherer, Nina Habermann, Reka Toth, Lina Jansen, Michael Hoffmeister, Hermann Brenner, Elisabeth J. Kap, Petra Seibold, Axel