title: MLH1-93G > A is a risk factor for MSI colorectal cancer.
abstract: The -93G > A (rs1800734) polymorphism within the core promoter region of the MutL homolog 1 (MLH1) gene has recently been proposed as a low penetrance variant for colorectal cancer (CRC). We evaluated the significance of rs1800734 on CRC risk by genotyping 10 409 CRC cases and 6965 controls. The per allele odds ratio (OR) for all CRC-associated MLH1-93G > A was 1.06 (P = 0.037). Using a subset of 3132 cases with known microsatellite instability (MSI) status, the risk was shown to be confined to microsatellite instability-high (MSI-H) CRC; OR = 1.39 (P = 1.45 × 10(-4)). A meta-analysis of our study and four smaller published studies (totalling 801 cases, 10 890 controls) provided for increased evidence of relationship between MLH1-93G > A and MSI-H CRC risk (P = 3.43 × 10(-12)). The impact of MLH1-93G > A on CRC risk was shown to be independent of the 14 low penetrance loci for CRC identified by recent genome-wide association studies. These data provide further evidence that MLH1-93G > A is a low-penetrance variant for CRC and support the proposition that MLH1-93G > A acts as marker for a somatic event defining a specific CRC subtype.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Whiffin
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lubbe
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.forename: Steven
authors.initials: S
authors.lastname: Penegar
authors.forename: Ian
authors.initials: I
authors.lastname: Chandler
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1