The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer
Received 25 May 2006; accepted 31 August 2006. published online 26 September 2006.
Background & Aims: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. Methods: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI−/LOH− subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16INK4α, p14ARF, and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARβ2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. Results: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI−/LOH− (P = .03) subgroups. MSI and MSI−/LOH− tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (ρ = −0.36; P < .0001). Conclusions: The associations between methylation frequencies at CIMP-related markers and MSI or MSI−/LOH− sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.
⁎Division of Gastroenterology, Department of Internal Medicine and the Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
‡University of Freiburg, Department of Internal Medicine, Division of Gastroenterology, Freiburg, Germany
§Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
∥Institute for Health Care Research and Improvement, Baylor University Medical Center, Dallas, Texas
¶CALGB Statistical Center, Duke University Medical Center, Durham, North Carolina
#Department of Pathology, McGill University, Montreal, Canada
⁎⁎Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts
‡‡University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
§§Brigham and Women’s Hospital, Boston, Massachusetts
Address requests for reprints to: Ajay Goel, PhD, Baylor University Medical Center, 3500 Gaston Avenue, Gastrointestinal Cancer Research Laboratory, Suite H-250, Dallas, Texas 75246. fax: (214) 818-9292
C. Richard Boland, MD, Baylor University Medical Center, 3500 Gaston Avenue, Gastrointestinal Cancer Research Laboratory, Suite H-250, Dallas, Texas 75246. fax: (214) 818-9292.
Supported by a grant from the NIH (RO1-CA 72851; to C.R.B.), an American Cancer Society-IRG award (to A.G), and a grant from Dr. Mildred-Scheel-Stiftung, Germany (to C.N.A.); and research for CALGB 9865 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, Chairman).
The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
ABSTRACT