Utility of DNA methylation markers for diagnosing cancer.

Abstract

DNA methylation occurs at the CpG residues and serves as a powerful epigenetic mechanism that negatively regulates gene expression. This process is catalyzed by DNA methyltransferases and occurs within CpG islands found in the promoter regions of \u3e70% of human genes. Given the important role of DNA methylation in regulating gene expression, un-programmed changes in methylation patterns are expected to either silence or activate transcription of tumor suppressor genes (via hypermethylation) or oncogenes (via demethylation), respectively, and by doing so promote a disease state. In light of the fact that a number of different cancers are frequently associated with hypermethylated tumor suppressor genes together with the observation that tumor derived genomic DNAs are present in various body fluids including serum/plasma, urine, sputum and bronchial lavage, methylated DNA has shown tremendous promise to serve as a robust biomarker for detecting cancer. Over the last several years protocols for capturing small amounts of DNA in circulation have been developed. Once captured, DNA methylation may be readily monitored by restriction enzyme digestion or bisulfite conversion followed by amplification of the desired genomic region with the polymerase chain reaction (PCR). New technologies which employ methyl-binding protein or antibodies that bind specifically to methylated-CpG residues have now enabled investigators to interrogate the status of entire DNA methyome of diseased tissue in an efficient and cost-effective manner. In this review, we describe the various tumor suppressor genes that are frequently hypermethylated in different cancers and how these and other methylated loci may be employed as clinically useful biomarkers for diagnosing cancer noninvasively using readily available body fluids