Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(3):416-422; 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
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1 Department of Pathology and Laboratory Medicine, Brown University, Box G-E537, Providence, RI 02912, USA
2 Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
3 Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, RI 02912, USA
4 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03766, USA
5 Department of Neurological Surgery
6 Department of Epidemiology and Biostatistics, University of California—San Francisco, San Francisco, CA 94143, USA
7 Division of Epidemiology and Community Health, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
8 Head and Neck Oncology Program, Dana-Farber Cancer Center, Boston, MA 02215, USA
9 Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA
* To whom correspondence should be addressed. Tel: +1 401 863 6508; Fax: +1 401 863 9008; Email: carmen_marsit{at}brown.edu
Head and neck squamous cell carcinomas (HNSCCs) represent clinically and etiologically heterogeneous tumors affecting >40 000 patients per year in the USA. 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. Among 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 was 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.
Abbreviations: FFPE, formalin-fixed paraffin embedded; HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; OOB, out of bag; RF, random forest
These authors contributed equally to this work. Received October 8, 2008; revised November 24, 2008; accepted December 22, 2008.