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Fundamental Differences in Cell Cycle Deregulation in Human Papillomavirus–Positive and Human Papillomavirus–Negative Head/Neck and Cervical Cancers

¹ McArdle Laboratory for Cancer Research; ² Institute for Molecular Virology; Departments of ³ Statistics and of Biostatistics and Medical Informatics and ⁴ Obstetrics and Gynecology; ⁵ Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, Wisconsin; ⁶ Departments of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts; ⁷ Department of Biology, Clarkson University, Potsdam, New York; ⁸ Department of Pathology, Veterans Affairs Medical Center; and ⁹ Department of Epidemiology, University of Iowa, Iowa City, Iowa

Requests for reprints: Paul Ahlquist, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1525 Linden Drive, Madison, WI 53706. Phone: 608-263-5916; Fax: 608-265-9214; E-mail: ahlquist{at}wisc.edu.

Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV⁺ HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV^– HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV⁺ HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV^– HNC. Moreover, HPV⁺ cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV⁺ HNC and HPV^– HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV⁺ and HPV^– cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV⁺ cancers. [Cancer Res 2007;67(10):4605–19]

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