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

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: HR het = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HR het = 0.82, 95% CI: 0.68–0.99 and rs2847149: HR het = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HR het = 1.28, 95% CI: 1.07–1.53; HR hzv = 2.02, 95% CI:1.46–2.80; HR logAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P < 0.01) with significant gene–chemotherapy interactions, including PON1 rs3917538. This study supports the concept that FOCM‐related genes could be associated with CRC survival and may modify effects of 5‐FU‐based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in CRC. These results require confirmation in additional clinical studies.

Improved diagnostic value by combining plasma PON1 level with tumor biomarkers in Colorectal Cancer patients

“…Its diagnostic value in endometrial cancer, colorectal cancer, etc. has also been reported [23,24]. In this study, we found that PON1 also has diagnostic value for CRC in the Chinese population which is consistent with previous research.…”

Which patients to sample in clinical cohort studies when the number of events is high and measurement of additional markers is constrained by limited resources

“…Further details on the study can be found elsewhere. [7][8][9] Basic patient and tumor characteristics such as age, gender, UICC stage, and adjuvant chemotherapy (yes/no) are available for all patients; in addition, various specific factors have been measured for a large proportion of patients in routinely stored tumor tissue. One of these factors is the so-called Microsatellite instability (MSI) that is defined as hypermutability of microsatellite sequences.…”

Genome‐wide association study of circulating folate one‐carbon metabolites

“…We further evaluated the 1,316 SNPs in 24 genes that are known to play important roles in FOCM according to prior studies (Cheng et al, ; Levine et al, ; Ose et al, ). Out of the 1,316 SNPs, 39 were mapped to coding exonic variants and the rest (1,277) were intronic or noncoding variants (Table S1).…”

“…Finally, as there are candidate genes known to play important roles in FOCM, we selected 24 genes (Table S1) involved in FOCM according to prior studies (Cheng et al, ; Figueiredo, Levine, Crott, Baurley, & Haile, ; Levine et al, ; Ose et al, ). We used the ANNOVAR software to characterize the SNPs with gene‐based annotation (K. Wang, Li, & Hakonarson, ) and included coding exonic, intronic, and noncoding variants (Table S1).…”