Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients

Cancer Medicine
Jennifer OseCornelia M Ulrich

Abstract

Folate-mediated one-carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5-fluorouracil (5-FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM-related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM-related genes for associations with overall- (OS) and disease-free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5-FU-based chemotherapy and assessed pathway-specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow-up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet  = 0.81, 95% CI: 0.67-0.97; TYMS: rs1001761: HRhet  = 0.82, 95% CI: 0.68-0.99 and rs2847149: HRhet  = 0.82, 95% CI: 0.68-0.99). After F...Continue Reading

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Citations

Sep 11, 2019·Genetic Epidemiology·Jun WangDavid V Conti
Dec 15, 2020·Drug Discovery Today·Chengcan YangLiang Ouyang
Apr 4, 2021·International Journal of Molecular Sciences·Aleksandra ZeljkovicBratislav Trifunovic
Jul 3, 2021·Journal of Personalized Medicine·Young-Joo JeonNam-Keun Kim

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Methods Mentioned

BETA
genotyping

Software Mentioned

SAS
R Foundation for Statistical Computing
R

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