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Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma

¹ Department of Molecular Genetics, The Ohio State University; ² Department of Internal Medicine, Division of Hematology/Oncology, The Ohio State University Medical Center; ³ Molecular, Cellular, and Developmental Biology Graduate Program; ⁴ Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ⁵ Division of Toxicology and Cancer Risk Factors, German Cancer Research Center; Departments of ⁶ Head and Neck Surgery and ⁷ General Pathology, University of Heidelberg, Heidelberg, Germany; and ⁸ Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Christoph Plass, German Cancer Research Center (DKFZ), Division C010, Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-42-3300; Fax: 49-6221-42-3359; E-mail: c.plass{at}dkfz.de.

Key Words: DNA methylation • 5-aza-2'-deoxycitidine (5-aza-dC) • head and neck squamous cell carcinoma (HNSCC)

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive cancer. In advanced stages, the patient has poor chances of receiving effective treatment, and survival rates are low. To facilitate timely diagnosis and improve treatment, elucidation of early detection markers is crucial. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable mark. A genome-wide screen using Restriction Landmark Genomic Scanning found a set of genes that are most commonly methylated in head and neck cancers. Five candidate genes: septin 9 (SEPT9), sodium-coupled monocarboxylate transporter 1 (SLC5A8), functional smad-suppressing element on chromosome 18 (FUSSEL18), early B-cell factor 3 (EBF3), and iroquois homeobox 1 (IRX1) were methylated in 27% to 67% of the HNSCC patient samples tested. Furthermore, 50% of the methylated tumor samples shared methylation between two of the five genes (most commonly between EBF3 and IRX1), and 15% shared methylation between three of the five genes. Expression analysis revealed candidate gene down-regulation in 25% to 93% of the HNSCC samples, and 5-aza-2'-deoxycytidine treatment was able to restore expression in at least 2 of 5 HNSCC cell lines for all of the genes tested. Overexpression of the three most frequently down-regulated candidates, SLC5A8, IRX1, and EBF3, validated their tumor suppressor potential by growth curve analysis and colony formation assay. Interestingly, all of the candidates identified may be involved in the transforming growth factor β signaling pathway, which is often disrupted in HNSCC. [Cancer Res 2008;68(12):4494–99]

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