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| 024 | 7 | _ | |a 10.1002/cam4.1407 |2 doi |
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| 041 | _ | _ | |a eng |
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| 100 | 1 | _ | |a Ose, Jennifer |b 0 |
| 245 | _ | _ | |a Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients. |
| 260 | _ | _ | |a Hoboken, NJ |c 2018 |b Wiley |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1668598842_29164 |2 PUB:(DE-HGF) |
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| 520 | _ | _ | |a 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 FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07-1.53; HRhzv = 2.02, 95% CI:1.46-2.80; HRlogAdd = 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. |
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| 700 | 1 | _ | |a Ulrich, Cornelia M |b 19 |
| 773 | _ | _ | |a 10.1002/cam4.1407 |g Vol. 7, no. 7, p. 2797 - 2807 |0 PERI:(DE-600)2659751-2 |n 7 |p 2797 - 2807 |t Cancer medicine |v 7 |y 2018 |x 2045-7634 |
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