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000136779 1001_ $$aOse, Jennifer$$b0
000136779 245__ $$aPathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients.
000136779 260__ $$aHoboken, NJ$$bWiley$$c2018
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000136779 520__ $$aFolate-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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000136779 7001_ $$0P:(DE-He78)5444d70823957b5081dfd421dbfed155$$aBotma, Akke$$b1$$udkfz
000136779 7001_ $$0P:(DE-HGF)0$$aBalavarca, Yesilda$$b2
000136779 7001_ $$0P:(DE-HGF)0$$aBuck, Katharina$$b3
000136779 7001_ $$aScherer, Dominique$$b4
000136779 7001_ $$0P:(DE-HGF)0$$aHabermann, Nina$$b5
000136779 7001_ $$0P:(DE-He78)a286621712d6d390c909e519145368d0$$aBeyerle, Jolantha$$b6$$udkfz
000136779 7001_ $$0P:(DE-He78)83906db1355a576371363a4b9f107d3d$$aPfütze, Katrin$$b7$$udkfz
000136779 7001_ $$0P:(DE-He78)fd17a8dbf8d08ea5bb656dfef7398215$$aSeibold, Petra$$b8$$udkfz
000136779 7001_ $$0P:(DE-He78)560b51721f3767b514947799cf29820a$$aKap, Elisabeth Johanna$$b9$$udkfz
000136779 7001_ $$0P:(DE-He78)e15dfa1260625c69d6690a197392a994$$aBenner, Axel$$b10$$udkfz
000136779 7001_ $$0P:(DE-He78)bbfe0ebad1e3b608bca2b49d4f86bd09$$aJansen, Lina$$b11$$udkfz
000136779 7001_ $$0P:(DE-He78)7ca7eafba864e5c3ebb7598149380452$$aButterbach, Katja$$b12$$udkfz
000136779 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b13$$udkfz
000136779 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b14$$udkfz
000136779 7001_ $$aUlrich, Alexis$$b15
000136779 7001_ $$aSchneider, Martin$$b16
000136779 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b17$$udkfz
000136779 7001_ $$0P:(DE-He78)15b7fd2bc02d5ef47a2fe2dd0140d2bf$$aBurwinkel, Barbara$$b18$$udkfz
000136779 7001_ $$aUlrich, Cornelia M$$b19
000136779 773__ $$0PERI:(DE-600)2659751-2$$a10.1002/cam4.1407$$gVol. 7, no. 7, p. 2797 - 2807$$n7$$p2797 - 2807$$tCancer medicine$$v7$$x2045-7634$$y2018
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