title: The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer.
abstract: The MLH1 -93 G>A promoter polymorphism has been reported to be associated with an increased risk of microsatellite unstable colorectal cancer. Other than microsatellite instability, however, the genetic and most epigenetic changes of tumors associated with this polymorphism have not been studied. We evaluated associations between the -93 G>A polymorphism and CpG island methylator phenotype (CIMP), BRAF V600E mutations, and MLH1 methylation in tumors from a sample of 1,211 individuals with colon cancer and 1,968 controls from Utah, Northern California, and Minnesota. The -93 G>A polymorphism was determined by the five prime nuclease assay. CIMP was determined previously by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A (p16). The BRAF V600E mutation was determined by sequencing exon 15. The MLH1 -93 G>A promoter polymorphism was associated with CIMP (odds ratio (OR) 3.44, 95% confidence interval (CI) 1.85, 6.42), MLH1 methylation (OR 4.16, 95%CI 2.20, 7.86), BRAF mutations (OR 4.26, 95%CI 1.83, 9.91), and older age at diagnosis (OR 3.65, 95%CI 2.08, 6.39) in microsatellite unstable tumors. These associations were not observed in stable tumors. Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 -93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway.
authors.affiliation: Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA. wade.samowitz@aruplab.com
authors.forename: Wade S
authors.initials: WS
authors.lastname: Samowitz
authors.forename: Karen
authors.initials: K
authors.lastname: Curtin
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
authors.forename: Hans
authors.initials: H
authors.lastname: Albertsen
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1