title: Contribution of the MLH1 -93G>a promoter polymorphism in modulating susceptibility risk in Malaysian colorectal cancer patients.
abstract: BACKGROUND
  Colorectal cancer (CRC) exists in a more common sporadic form and less common hereditary forms, associated with the Lynch syndrome, familial adenomatous polyposis (FAP) and other rare syndromes. Sporadic CRC is believed to arise as a result of close interaction between environmental factors, including dietary and lifestyle habits, and genetic predisposition factors. In contrast, hereditary forms such as those related to the Lynch syndrome result from inheritance of germline mutations of mismatch repair (MMR) genes. However, in certain cases, the influence of low penetrance alleles in familial colorectal cancer susceptibility is also undeniable.
  
  
  OBJECTIVE
  To investigate the genotype frequencies of MLH1 promoter polymorphism -93G>A and to determine whether it could play any role in modulating familial and sporadic CRC susceptibility risk.
  
  
  METHODS
  A case-control study comprising of 104 histopathologically confirmed CRC patients as cases (52 sporadic CRC and 52 Lynch syndrome patients) and 104 normal healthy individuals as controls was undertaken. DNA was extracted from peripheral blood and the polymorphism was genotyped employing PCR-RFLP methods. The genotypes were categorized into homozygous wild type, heterozygous and homozygous variants. The risk association between these polymorphisms and CRC susceptibility risk was calculated using binary logistic regression analysis and deriving odds ratios (ORs).
  
  
  RESULTS
  When risk association was investigated for all CRC patients as a single group, the heterozygous (G/A) genotype showed a significantly higher risk for CRC susceptibility with an OR of 2.273, (95%CI: 1.133-4.558 and p-value=0.021). When analyzed specifically for the 2 types of CRC, the heterozygous (G/A) genotype showed significantly higher risk for sporadic CRC susceptibility with and OR of 3.714, (95%CI: 1.416-9.740 and p-value=0.008). Despite high OR value was observed for Lynch syndrome (OR: 1.600, 95%CI: 0.715-3.581), the risk was not statistically significant (P=0.253).
  
  
  CONCLUSIONS
  Our results suggest an influence of MLH1 promoter polymorphism -93G>A in modulating susceptibility risk in Malaysian CRC patients, especially those with sporadic disease.
authors.affiliation: Human Genome Centre, USM, Kota Bharu, Malaysia. rankathil@hotmail.com
authors.forename: Zahary Mohd
authors.initials: ZM
authors.lastname: Nizam
authors.forename: Ahmad Aizat
authors.initials: AA
authors.lastname: Abdul Aziz
authors.forename: Gurjeet
authors.initials: G
authors.lastname: Kaur
authors.forename: Muhammad Radzi
authors.initials: MR
authors.lastname: Abu Hassan
authors.forename: Ahmad Shanwani
authors.initials: AS
authors.lastname: Mohd Sidek
authors.forename: Lee Yeong
authors.initials: LY
authors.lastname: Yeh
authors.forename: Maya
authors.initials: M
authors.lastname: Mazuwin
authors.forename: Ravindran
authors.initials: R
authors.lastname: Ankathil
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012306:Risk; D018570:Risk Assessment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1