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

Media type: E-Article
Title: Pathway analysis of genetic variants in folate‐mediated one‐carbon metabolism‐related genes and survival in a prospectively followed cohort of colorectal cancer patients
Contributor: Ose, Jennifer; Botma, Akke; Balavarca, Yesilda; Buck, Katharina; Scherer, Dominique; Habermann, Nina; Beyerle, Jolantha; Pfütze, Katrin; Seibold, Petra; Kap, Elisabeth J.; Benner, Axel; Jansen, Lina; Butterbach, Katja; Hoffmeister, Michael; Brenner, Hermann; Ulrich, Alexis; Schneider, Martin; Chang‐Claude, Jenny; Burwinkel, Barbara; Ulrich, Cornelia M.
imprint: Wiley, 2018
Published in: Cancer Medicine
Language: English
DOI: 10.1002/cam4.1407
ISSN: 2045-7634
Keywords: Cancer Research ; Radiology, Nuclear Medicine and imaging ; Oncology
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:p>Folate‐mediated one‐carbon metabolism (<jats:styled-content style="fixed-case">FOCM</jats:styled-content>) is a key pathway essential for nucleotide synthesis, <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐<jats:styled-content style="fixed-case">FU</jats:styled-content>), which is predominantly used for colorectal cancer (<jats:styled-content style="fixed-case">CRC</jats:styled-content>) treatment. A comprehensive assessment of polymorphisms in <jats:styled-content style="fixed-case">FOCM</jats:styled-content>‐related genes and their association with prognosis has not yet been performed. Within 1,739 <jats:styled-content style="fixed-case">CRC</jats:styled-content> cases aged ≥30 years diagnosed from 2003 to 2007 (<jats:styled-content style="fixed-case">DACHS</jats:styled-content> study), we investigated 397 single nucleotide polymorphisms (<jats:styled-content style="fixed-case">SNP</jats:styled-content>s) and 50 candidates in 48 <jats:styled-content style="fixed-case">FOCM</jats:styled-content>‐related genes for associations with overall‐ (<jats:styled-content style="fixed-case">OS</jats:styled-content>) and disease‐free survival (<jats:styled-content style="fixed-case">DFS</jats:styled-content>) using multiple Cox regression (adjusted for age, sex, stage, grade, <jats:styled-content style="fixed-case">BMI</jats:styled-content>, and alcohol). We investigated effect modification by 5‐<jats:styled-content style="fixed-case">FU</jats:styled-content>‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (<jats:styled-content style="fixed-case">FDR</jats:styled-content>). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate <jats:styled-content style="fixed-case">SNP</jats:styled-content> in <jats:italic><jats:styled-content style="fixed-case">MTHFR</jats:styled-content></jats:italic> and two in <jats:italic><jats:styled-content style="fixed-case">TYMS</jats:styled-content>,</jats:italic> we observed significant inverse associations with <jats:styled-content style="fixed-case">OS</jats:styled-content> (<jats:italic><jats:styled-content style="fixed-case">MTHFR</jats:styled-content></jats:italic>: rs1801133, C677T: <jats:styled-content style="fixed-case">HR</jats:styled-content><jats:sub>het</jats:sub> = 0.81, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 0.67–0.97; <jats:italic><jats:styled-content style="fixed-case">TYMS</jats:styled-content></jats:italic>: rs1001761: <jats:styled-content style="fixed-case">HR</jats:styled-content><jats:sub>het</jats:sub> = 0.82, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 0.68–0.99 and rs2847149: <jats:styled-content style="fixed-case">HR</jats:styled-content><jats:sub>het</jats:sub> = 0.82, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 0.68–0.99). After <jats:styled-content style="fixed-case">FDR</jats:styled-content> correction, one polymorphism in paraoxonase 1 (<jats:italic><jats:styled-content style="fixed-case">PON</jats:styled-content>1</jats:italic>; rs3917538) was significantly associated with <jats:styled-content style="fixed-case">OS</jats:styled-content> (<jats:styled-content style="fixed-case">HR</jats:styled-content><jats:sub>het</jats:sub> = 1.28, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 1.07–1.53; <jats:styled-content style="fixed-case">HR</jats:styled-content><jats:sub>hzv</jats:sub> = 2.02, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>:1.46–2.80; <jats:styled-content style="fixed-case">HR</jats:styled-content><jats:sub>logAdd</jats:sub> = 1.31, <jats:styled-content style="fixed-case">p<jats:sub>FDR</jats:sub></jats:styled-content> = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (<jats:italic>P </jats:italic>= 0.04) and fluorouracil drug metabolism (<jats:italic>P</jats:italic> < 0.01) with significant gene–chemotherapy interactions, including <jats:italic><jats:styled-content style="fixed-case">PON</jats:styled-content>1</jats:italic> rs3917538. This study supports the concept that <jats:styled-content style="fixed-case">FOCM</jats:styled-content>‐related genes could be associated with <jats:styled-content style="fixed-case">CRC</jats:styled-content> survival and may modify effects of 5‐<jats:styled-content style="fixed-case">FU</jats:styled-content>‐based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in <jats:styled-content style="fixed-case">CRC</jats:styled-content>. These results require confirmation in additional clinical studies.</jats:p>
Access State: Open Access

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