Open Access Highly Accessed Research article

Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

Pei Woon Ang12, Marie Loh12, Natalia Liem3, Pei Li Lim3, Fabienne Grieu1, Aparna Vaithilingam2, Cameron Platell14, Wei Peng Yong3, Barry Iacopetta1 and Richie Soong2*

Author Affiliations

1 School of Surgery, University of Western Australia, Perth, Australia

2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

3 Department of Haematology and Oncology, National University Hospital, Singapore, Singapore

4 Department of Surgery, St John of God Hospital, Subiaco, Australia

For all author emails, please log on.

BMC Cancer 2010, 10:227  doi:10.1186/1471-2407-10-227

Published: 21 May 2010

Abstract

Background

Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups.

Methods

DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate® methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS.

Results

A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P < 0.001).

Conclusions

Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups.