Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia.
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Genetic variants in the coding regions of the mismatch repair genes MLH1 (Ile-219Val) and MSH3 (Arg-940Glu and Thr-1036Ala) could contribute to an individual's susceptibility as modifiers in leukaemogenesis. To investigate this possibility, we conducted a case-control study on 287 children with ALL and 320 healthy controls both of French-Canadian origin. MLH1 and MSH3 variants, when taken independently, seemed to play little or no role in the aetiology of childhood ALL. However, when the MLH1 genotypes were combined with genotypes previously shown to influence ALL susceptibility, we found that the MLH1 variant Val-219 further increases the risk of GSTM1 null and CYP1A1*2A genotypes [combined odds ratio (OR) = 6.0, P = 0.002] as well as that of CYP2E1*5 (OR = 15.8, P = 0.001). No association was found with MSH3 variants. This study suggests an association of leukaemogenesis in children with both xenobiotic metabolism and DNA repair, and thus points to the effect of environmental exposure.
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D002170:Canada; D002352:Carrier Proteins; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002675:Child, Preschool; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004260:DNA Repair; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D012306:Risk; D015262:Xenobiotics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015262:Xenobiotics; C501486:MLH1 protein, human