Comparing the DNA Hypermethylome with Gene Mutations in Human Colorectal Cancer

Kornel E Schuebel ,Minoru Toyota,Wayne Yu,Kamwing Jair,Leander Van Neste,Leslie Cope,Hiromu Suzuki,Wim Van Criekinge,Nita Ahuja,Manon Van Engeland,Sandra Van Den Bosch,Kohzoh Imai,Wei Chen,Sabine C Glöckner ,Joo Mi Yi ,Angela H Ting ,James G Herman ,Timothy A Chan ,Stephen B Baylin

doi:10.1371/journal.pgen.0030157

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.

Highlights

It is well established that loss of proper gene function in human cancer can occur through both genetic and epigenetic mechanisms [1,2]
Loss of gene expression in association with aberrant accumulation of 5-methylcytosine in gene promoter CpG islands is a common feature of human cancer
We 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

Summary

Introduction

It is well established that loss of proper gene function in human cancer can occur through both genetic and epigenetic mechanisms [1,2]. The number of genes mutated in human tumor samples is being clarified. The best-defined epigenetic alteration of cancer genes involves DNA hypermethylation of clustered CpG dinucleotides, or CpG islands, in promoter regions associated with the transcriptional inactivation of the affected genes [2]. These promoters are located proximal to nearly half of all genes [4] and are thought to remain primarily methylation free in normal somatic tissues. Given the large number of potential target promoters present in the genome, we hypothesized that many more hypermethylated genes await discovery

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