Carcinogenesis Advance Access published online on January 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgp006
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Epigenetic Profiling Reveals Etiologically Distinct Patterns of DNA Methylation in Head and Neck Squamous Cell Carcinoma
1 Department of Pathology and Laboratory Medicine
9 Department of Community Health Center for Environmental Health and Technology, Brown University, Providence, RI
2 Department of Biostatistics, Harvard School of Public Health, Boston, MA
3 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH
4 Department of Neurological Surgery
5 Department of Epidemiology and Biostatistics, University of California – San Francisco, San Francisco, CA
6 Division of Epidemiology and Community Health, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
7 Head and Neck Oncology Program, Dana-Farber Cancer Center, Boston, MA
8 Department of Environmental Health, Boston University School of Public Health, Boston, MA
To whom correspondence should be addressed: Carmen J. Marsit, PhD. Department of Pathology and Laboratory Medicine, Brown University, Box G-E537, Providence, RI, 02912. Phone: 401-863-6508. Fax: 401-863-9008. Email: carmen_marsit{at}brown.edu
Head and neck squamous cell carcinomas (HNSCC) represent clinically and etiologically heterogeneous tumors affecting over 40,000 patients per year in the United States. Previous research has identified individual epigenetic alterations, and, in some cases, the relationship of these alterations with carcinogen exposure or patient outcomes, suggesting that specific exposures give rise to specific types of molecular alterations in HNSCCs. Here we describe how different etiologic factors are reflected in the molecular character and clinical outcome of these tumors. In a case series of primary, incident HNSCC (n = 68), we examined the DNA methylation profile of 1413 autosomal CpG loci in 773 genes, in relation to exposures and etiologic factors. The overall pattern of epigenetic alteration could significantly distinguish tumor from normal head and neck epithelial tissues (P<0.0001) more effectively than specific gene methylation events. Amongst tumors there were significant associations between specific DNA methylation profile classes and tobacco smoking and alcohol exposures. Although there was a significant association between methylation profile and tumor stage (P<0.01), we did not observe an association between these profiles and overall patient survival after adjustment for stage, although, methylation of a number of specific loci falling in different cellular pathways were associated with overall patient survival. We found that the etiologic heterogeneity of HNSCC is reflected in specific patterns of molecular epigenetic alterations within the tumors, and that the DNA methylation profiles may hold clinical promise worthy of further study.
* These authors contributed equally to this work
Received October 8, 2008; revised November 24, 2008; accepted December 22, 2008.