Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer

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Abstract
We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumor-specific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken. Loss of gene expression in association with aberrant accumulation of 5-methylcytosine in gene promoter CpG islands is a common feature of human cancer. Here, we describe a method to discover these genes that permits identification of hundreds of novel candidate cancer genes in any cancer cell line. We now estimate that as much as 5% of colon cancer genes may harbor aberrant gene hypermethylation and we term these the cancer “promoter CpG island DNA hypermethylome.” Multiple mutated genes recently identified via cancer resequencing efforts are shown to be within this hypermethylome and to be more likely to undergo epigenetic inactivation than genetic alteration. Our approach allows derivation of new potential tumor biomarkers and potential pathways for therapeutic intervention. Importantly, our findings illustrate that efforts aimed at complete identification of the human cancer genome should include analyses of epigenetic, as well as genetic, changes.