Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas

Abstract

High-risk human papillomaviruses (HPVs) have been proposed to be associated with a subset of head and neck cancers (HNSCCs). However, clear biological evidence linking HPVmediated oncogenesis to the development of HNSCC is hardly available. An important biological mechanism underlying HPV-mediated carcinogenesis is the inactivation of p53 by the HPV E6 oncoprotein. In the present study we investigated this biological relationship between HPV and HNSCC. In total 84 HNSCC tumors were analyzed for the presence of high-risk HPV nucleic acids by DNA polymerase chain reaction-enzyme immunoassay (PCR-EIA) and E6 reverse transcriptase (RT)-PCR as well as for the presence of mutations in the p53 gene. We found 20/84 HPV16 DNA-positive cases with one or more DNA assays, 10 of which were consistently positive with all assays. Only 9/20 cases showed E6 mRNA expression, indicative for viral activity. Only these nine E6 mRNA-positive cases all lacked a p53 mutation, whereas both the other HPV DNA-positive and HPV-DNA negative tumors showed p53 mutations in 36% and 63% of the cases, respectively. Moreover, only in lymph node metastases of HPV E6 mRNA-positive tumors both viral DNA and E6 mRNA were present. Our study provides strong biological evidence for a plausible etiological role of high-risk HPV in a subgroup of HNSCC. Analysis of E6 mRNA expression by RT-PCR or alternatively, semiquantitative analyses of the viral load, seem more reliable assays to assess HPV involvement in HNSCC than the very sensitive DNA PCR analyses used routinely. © 2001 Wiley-Liss, Inc. Key words: papillomavirus; head and neck cancer; squamous cell carcinoma; p53 mutations; E6 oncoproteinMucosotropic high-risk human papillomaviruses (HPVs), known to cause cervical and other anogenital cancers, have been proposed to play a role in the etiology of head and neck squamous cell carcinomas (HNSCCs). 1 The presence of high-risk HPV DNA in a subgroup of HNSCCs has supported this hypothesis. [2][3][4][5] Molecular studies have provided important data on the role and oncogenic mechanism of high-risk HPV in carcinogenesis. 6 -8 By expression of the viral oncoproteins E6 and E7, the virus dysregulates crucial cellular mechanisms such as the cell cycle and the apoptotic pathway. The E6 oncoprotein specifically inactivates wild-type p53, and the E7 oncoprotein inactivates Rb. In this way the high-risk HPV E6-mediated degradation of the p53 protein should be considered an alternative pathway for "classical" mutation to knock-out the p53 regulated pathways; it provides the biological basis to expect that tumors originating from HPV infection will show wild-type p53. Indeed, this general biological mechanism is supported by the finding that p53 mutations hardly occur in cervical carcinomas. 9,10 However, in most studies on head and neck cancer, HPV DNA presence and p53 mutations were overlapping, 2,11,12 an observation that gave rise to a long debate as to whether HPV is causally related to the development of a subset of these tumors.On the other hand, the inconsi...

Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus

“…The results of the present study are consistent with and provide further evidence for the hypothesis that HNSCCs develop by two different etiologies (Gillison et al, 2000;Van Houten et al, 2001;Herrero et al, 2003): one driven by exposure to environmental carcinogens (i.e. tobacco and alcohol) without HPV Figure 2 A genetic progression model of multi-step head and neck carcinogenesis is proposed.…”

HPV16 semiquantitative viral load and serologic biomarkers in oral and oropharyngeal squamous cell carcinomas

“…Indeed, 1 study showed a markedly higher viral load in HPV DNA containing oral and oropharyngeal SCCs with E6 mRNA expression than in those without. 6 Another study revealed that viral load was significantly higher among HPV DNA-positive cancers occurring in the tonsil, a subsite of the oropharynx, compared to HPV DNA-positive nonoropharyngeal cancers. 27 Most of these studies employed the gold-standard for HPV viral load assessment: real-time PCR.…”

“…HPV16 DNA from tumor specimens analyzed jointly with markers of expression of the viral oncogene E6, mutational patterns of the cancer suppressor gene TP53 and levels of allelic loss, have helped identify a subset of these cancers that may be the consequence of HPV infection. 1,2,[5][6][7][8] HPV viral load, a measure of the amount of viral DNA in biopsy specimens, alone or in conjunction with well-characterized HPV serologic assays, may clarify the role of HPV among oral and oropharyngeal cases. Antibodies against HPV E6 and E7 are markers of an invasive HPV-associated malignancy 9,10 and are rarely present among individuals with HPV DNA-negative oral and oropharyngeal tumors.…”

Human Papillomavirus in Non-Oropharyngeal Head and Neck Cancers: A Systematic Literature Review

“…Only data generated from primary squamous cell carcinomas (SCC) were extracted, and we excluded reports if: (1) the detection methods were not well-detailed, and/or (2) HPV data could not be extracted per anatomic site. We took care to avoid tallying overlapping patient cohorts [2][3][4][5][6][7][8][9][10][11][12][13]. The final extracted data included: county, year of publication, anatomical site, HPV type, detection method of including primers, and summary of findings for cancers, patient controls, benign lesions, potentially premalignant lesions, and premalignant lesions, when available.…”