Global DNA Methylation Level in Whole Blood as a Biomarker in Head and Neck Squamous Cell Carcinoma
- Debra Ting Hsiung1,
- Carmen J. Marsit1,
- E. Andres Houseman2,
- Karen Eddy1,
- C. Sloane Furniss1,
- Michael D. McClean3 and
- Karl T. Kelsey1
- Departments of 1Genetics and Complex Diseases and 2Biostatistics, Harvard School of Public Health and 3Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts
- 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.
Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol exposures, although dietary factors, particularly folate, and human papillomavirus, are also risk factors. Epigenetic alterations are increasingly implicated in the initiation and progression of cancer. Genome-wide (global) hypomethylation seems to occur in early neoplasia and is a feature of genomic DNA derived from solid tumor tissues, including HNSCC. This study aimed to determine whether global methylation in DNA derived from whole blood, a proxy tissue, is associated with HNSCC and to assess potential modification of this property by environmental or behavioral risk factors.
Methods: Global DNA methylation levels were assessed using a modified version of the combined bisulfite restriction analysis of the LRE1 sequence in a population-based case-control study of HNSCC from the Boston area.
Results: Hypomethylation lead to a significant 1.6-fold increased risk for disease (95% confidence interval, 1.1-2.4), in models controlled for other HNSCC risk factors. Smoking showed a significant differential effect (P < 0.03) on blood relative methylation between cases and controls. Furthermore, in cases, variant genotype in the MTHFR gene and low folate intake showed relationships with decreased global methylation, whereas in controls, antibody response to human papillomavirus 16 was associated with an increased global methylation level.
Discussion: DNA hypomethylation in nontarget tissue was independently associated with HNSCC and had a complex relationship with the known risk factors associated with the genesis of HNSCC. (Cancer Epidemiol Biomarkers Prev 2007;16(1):108–14)
Footnotes
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↵4 C.S. Furniss, M.D. McClean, J.F. Smith, et al. Human papillomavirus 16 and head and neck squamous cell carcinoma, International Journal of Cancer, in press.
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Grant support: NIH grants CA78609, CA100679, ES007155, and ES05947. Flight Attendants Medical Research Institute Young Clinical Scientist Award (C.J. Marsit).
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted October 13, 2006.
- Received July 28, 2006.
- Revision received September 21, 2006.
