Premium
The MLH1 −93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer
Author(s) -
Samowitz Wade S.,
Curtin Karen,
Wolff Roger K.,
Albertsen Hans,
Sweeney Carol,
Caan Bette J.,
Ulrich Cornelia M.,
Potter John D.,
Slattery Martha L.
Publication year - 2008
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20584
Subject(s) - mlh1 , microsatellite instability , biology , epigenetics , dna methylation , colorectal cancer , cdkn2a , genetics , methylation , cancer research , microsatellite , cancer , dna mismatch repair , allele , gene , gene expression
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. © 2008 Wiley‐Liss, Inc.