BACKGROUND: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. METHODS: A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity. RESULTS: The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03). CONCLUSIONS: The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.
BACKGROUND: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. METHODS: A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity. RESULTS: The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1Ile219Val and Western diet (p value interaction: 0.03). CONCLUSIONS: The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.
Authors: Sun Ha Park; Ga Young Lee; Hyo-Sung Jeon; Su Jeong Lee; Kyung Mee Kim; Sang Soo Jang; Chang Ho Kim; Won Kee Lee; Sin Kam; Rang Woon Park; In-San Kim; Tae Hoon Jung; Jae Yong Park Journal: Int J Cancer Date: 2004-11-20 Impact factor: 7.396
Authors: K Liu; M Slattery; D Jacobs; G Cutter; A McDonald; L Van Horn; J E Hilner; B Caan; C Bragg; A Dyer Journal: Ethn Dis Date: 1994 Impact factor: 1.847
Authors: Molin Wang; Donna Spiegelman; Aya Kuchiba; Paul Lochhead; Sehee Kim; Andrew T Chan; Elizabeth M Poole; Rulla Tamimi; Shelley S Tworoger; Edward Giovannucci; Bernard Rosner; Shuji Ogino Journal: Stat Med Date: 2015-12-01 Impact factor: 2.373
Authors: Inês Teles Alves; Saskia Hiltemann; Thomas Hartjes; Peter van der Spek; Andrew Stubbs; Jan Trapman; Guido Jenster Journal: Hum Genet Date: 2013-04-25 Impact factor: 4.132
Authors: Miralem Mrkonjic; Nicole M Roslin; Celia M Greenwood; Stavroula Raptis; Aaron Pollett; Peter W Laird; Vaijayanti V Pethe; Theodore Chiang; Darshana Daftary; Elizabeth Dicks; Stephen N Thibodeau; Steven Gallinger; Patrick S Parfrey; H Banfield Younghusband; John D Potter; Thomas J Hudson; John R McLaughlin; Roger C Green; Brent W Zanke; Polly A Newcomb; Andrew D Paterson; Bharati Bapat Journal: PLoS One Date: 2010-10-13 Impact factor: 3.240