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

BMC Research Notes

Kokichi Sugano¹  Yoshikazu Yasuda²  Alan T Lefor²  Makiko Tahara¹  Yasuyuki Miyakura¹ 

[1] Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, 4-9-13, Yohnan, Utsunomiya, Tochigi 320-0834, Japan;Department of Surgery, Jichi Medical University, 3311-1, Shimotsuke, Tochigi 329-0498, Japan

关键词: Haplotype;    Colorectal cancer;    Methylation;    MLH1;    SNP;    MSI;   

Others  :  1118272
DOI  :  10.1186/1756-0500-7-835

 received in 2013-07-11, accepted in 2014-11-07,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Miyakura et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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