Contribution of the MLH1 -93G>A Promoter Polymorphismin Modulating Susceptibility Risk in Malaysian ColorectalCancer Patients


Background: Colorectal cancer (CRC) exists in a more common sporadic form and less common hereditaryforms, 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 dietaryand lifestyle habits, and genetic predisposition factors. In contrast, hereditary forms such as those related to theLynch syndrome result from inheritance of germline mutations of mismatch repair (MMR) genes. However, incertain cases, the influence of low penetrance alleles in familial colorectal cancer susceptibility is also undeniable.Aim: To investigate the genotype frequencies of MLH1 promoter polymorphism -93G>A and to determine whetherit could play any role in modulating familial and sporadic CRC susceptibility risk.
Methods: A case-controlstudy comprising of 104 histopathologically confirmed CRC patients as cases (52 sporadic CRC and 52 Lynchsyndrome patients) and 104 normal healthy individuals as controls was undertaken. DNA was extracted fromperipheral blood and the polymorphism was genotyped employing PCR-RFLP methods. The genotypes werecategorized into homozygous wild type, heterozygous and homozygous variants. The risk association betweenthese polymorphisms and CRC susceptibility risk was calculated using binary logistic regression analysis andderiving 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).
Conclusion: Our results suggest an influence ofMLH1 promoter polymorphism -93G>A in modulating susceptibility risk in Malaysian CRC patients, especiallythose with sporadic disease.