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Genome-Wide Promoter Analysis Uncovers Portions of the Cancer Methylome

¹ Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine and ² Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; Departments of ³ Gynecologic Oncology and ⁴ Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; ⁵ Department of Pathology, Portuguese Oncology Institute, University of Porto, Porto, Portugal; ⁶ OncoMethylome Sciences S.A, CHU Niveau +4, Tour 4 dePharmacie (bâtiment 36), Liege, Belgium; ⁷ Laboratory of Molecular Medicine and Biotechnology, University Campus Bio-Medico School of Medicine, Rome, Italy; and ⁸ Bioinformatics and Computational Genomics (Biobix), Faculty of Agricultural and Applied Biological Sciences, University of Ghent, Ghent, Belgium

Requests for reprints: David Sidransky, Division of Head and Neck Cancer Research, The Johns Hopkins School of Medicine, 1550 Orleans Street, 5 North 03, Baltimore, MD 21231. Phone: 410-502-5155; Fax: 410-614-1411; E-mail: dsidrans{at}jhmi.edu and Wim Van Criekinge, OncoMethylome Sciences S.A, CHU Niveau +4, Tour 4 dePharmacie (bâtiment 36), Avenue de l'Hospital 14000, Sart-Tilman, Liege, Belgium. Phone: 32-0-436-698-60; Fax: 32-0-436-698-61; E-mail: Wim.vancriekinge{at}OncoMethylome.com.

Key Words: cancer • genome-wide • methylation

DNA methylation has a role in mediating epigenetic silencing of CpG island genes in cancer and other diseases. Identification of all gene promoters methylated in cancer cells "the cancer methylome" would greatly advance our understanding of gene regulatory networks in tumorigenesis. We previously described a new method of identifying methylated tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of re-expression on microarray analysis. In this study, we modified and greatly improved the selection of candidates based on new promoter structure algorithm and microarray data generated from 20 cancer cell lines of 5 major cancer types. We identified a set of 200 candidate genes that cluster throughout the genome of which 25 were previously reported as harboring cancer-specific promoter methylation. The remaining 175 genes were tested for promoter methylation by bisulfite sequencing or methylation-specific PCR (MSP). Eighty-two of 175 (47%) genes were found to be methylated in cell lines, and 53 of these 82 genes (65%) were methylated in primary tumor tissues. From these 53 genes, cancer-specific methylation was identified in 28 genes (28 of 53; 53%). Furthermore, we tested 8 of the 28 newly identified cancer-specific methylated genes with quantitative MSP in a panel of 300 primary tumors representing 13 types of cancer. We found cancer-specific methylation of at least one gene with high frequency in all cancer types. Identification of a large number of genes with cancer-specific methylation provides new targets for diagnostic and therapeutic intervention, and opens fertile avenues for basic research in tumor biology. [Cancer Res 2008;68(8):2661–70]

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