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Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism

Authors' Affiliations: ¹ Molecular Pathology Research and Development Laboratory, Department of Pathology, Peter MacCallum Cancer Centre, Melbourne and ² Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

Requests for reprints: Alexander Dobrovic, Peter MaCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria 3002, Australia. Phone: 61-3-9656-1807; Fax: 61-3-9656-1460; E-mail: alexander.dobrovic{at}petermac.org.

Methylation of the CpG island in the MGMT promoter region is a frequent event in several cancer types including colorectal cancer, lung cancer, lymphoma, and glioblastoma. A correlation between methylation and the T allele of the rs16906252 single nucleotide polymorphism (SNP) in colorectal carcinomas has previously been reported. As aberrant MGMT methylation can be an early event in tumor development, we tested the hypothesis that normal individuals possessing the T allele may be predisposed to somatic methylation at the MGMT promoter. Peripheral blood monononuclear cell DNA from 89 normal, healthy individuals was genotyped at rs1690625 and assessed for the methylation status of the MGMT promoter region using independent quantitative methodologies capable of detecting low-level methylation: MethyLight and Sensitive Melting Analysis after Real-time Methylation-Specific PCR (SMART-MSP). There was a strong association between presence of the T allele and detectable methylation (P = 0.00005) in the peripheral blood DNA. Furthermore, when a MSP assay flanking the SNP was used to amplify methylated sequences in heterozygotes, only the T allele was methylated. Thus, detectable somatic methylation of the MGMT promoter in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter SNP.

Key Words: DNA methylation • high resolution melting • SNP • predisposition