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Background  Methylation of the  MLH1  promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the  MLH1  promoter region ( MLH1 -93G/A; rs1800734) has been proposed to be associated with  MLH1  promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of  MLH1 -93G/A and six other SNPs surrounding  MLH1 -93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients.    Methods  Methylation of the  MLH1  promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the  MLH1 -93G/A SNP were examined by SSCP analysis.    Results  Methylation of the  MLH1  promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of  MLH1 -93G/A genotypes A/A, A/G and G/G were 26% (n = 54), 51% (n = 108) and 23% (n = 48), respectively, and they were significantly associated with the methylation status (p = 0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of  MLH1 -93G/A was more common in cases with methylation than the G-allele (p = 0.0094), especially in females (p = 0.0067). In logistic regression, the A/A genotype of the  MLH1 -93G/A SNP was shown to be the most significant risk factor for methylation of the  MLH1  promoter region (odds ratio 2.82, p = 0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the  MLH1 -93G/A SNP and the A-allele of  MLH1 -93G/A SNP was significantly associated with  MLH1  promoter methylation.    Conclusions  These results indicate that individuals, and particularly females, carrying the A-allele at the  MLH1 -93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the  MLH1  promoter region.    Electronic supplementary material  The online version of this article (doi:10.1186/1756-0500-7-835) contains supplementary material, which is available to authorized users.

Haplotype defined by the MLH1-93G/A polymorphism is associated with MLH1 promoter hypermethylation in sporadic colorectal cancers