title: Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers.
abstract: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Dohun
authors.initials: D
authors.lastname: Pyeon
authors.forename: Michael A
authors.initials: MA
authors.lastname: Newton
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.forename: Johan A
authors.initials: JA
authors.lastname: den Boon
authors.forename: Srikumar
authors.initials: S
authors.lastname: Sengupta
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Craig D
authors.initials: CD
authors.lastname: Woodworth
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Connor
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Haugen
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Smith
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: Lubomir P
authors.initials: LP
authors.lastname: Turek
authors.forename: Paul
authors.initials: P
authors.lastname: Ahlquist
mesh_terms: D000328:Adult; D002453:Cell Cycle / Q000235:genetics*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D015894:Genome, Human; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*
chemical_list: D012333:RNA, Messenger