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Examination of a CpG Island Methylator Phenotype and Implications of Methylation Profiles in Solid Tumors

Departments of ¹ Genetics and Complex Diseases, ² Biostatistics, and ³ Environmental Health, Harvard School of Public Health; ⁴ International Mesothelioma Program, Division of Thoracic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and ⁵ Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, New Hampshire

Requests for reprints: Karl T. Kelsey, Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. Phone: 617-432-3313; Fax: 617-432-0107; E-mail: kelsey{at}hsph.harvard.edu.

The CpG island methylator phenotype (CIMP), thoroughly described in colorectal cancer and to a lesser extent in other solid tumors, is important in understanding epigenetics in carcinogenesis and may be clinically useful for classification of neoplastic disease. Therefore, we investigated whether this putative phenotype exists in exposure-related solid tumors, where somatic gene alterations and enhanced clonal growth are selected for by carcinogens, and examined the ability of methylation profiles to classify malignant disease. We studied promoter hypermethylation of 16 tumor suppressor genes and 3 MINT loci (acknowledged classifiers of CIMP) in 344 bladder cancers, 346 head and neck squamous cell carcinomas (HNSCC), 146 non–small-cell lung cancer (NSCLC), and 71 malignant pleural mesotheliomas (MPM). We employed rigorous statistical methods to examine the distribution of promoter methylation and the usefulness of these profiles for disease classification. In bladder cancer, HNSCC, and NSCLC, there was a significant correlation (P < 0.0001) between methylation of the three MINT loci and methylation index, although the distribution of methylated loci varied significantly across these disease. Although there was a significant (P < 0.001) association between gene methylation profile and disease, rates of misclassification of each disease by their methylation profile ranged from 28% to 32%, depending on the classification scheme used. These data suggest that a form of CIMP exists in these solid tumors, although its etiology remains elusive. Whereas the gene profiles of hypermethylation among examined loci could not unequivocally distinguish disease type, the existence of CIMP and the relative preponderance of hypermethylation in these cancers suggest that methylation analysis may be clinically useful as a targeted screening tool. (Cancer Res 2006; 66(21): 10621-9)

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