Affiliations of authors: D. T. W. Wong, Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, MA; K. Münger, Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, Boston.
Correspondence to: Karl Münger, Ph.D., Department of Pathology and Harvard Center for Cancer Biology, 200 Longwood Ave., D2/544A, Boston, MA 02115-5701 (e-mail: karl_munger{at}hms.harvard.edu).
Papillomaviruses, small DNA viruses with a pronounced tropism for epithelial cells, have been isolated from many organisms. In humans, approximately 100 different virus types have been described, and this list is likely to grow. The human papillomaviruses (HPVs) are associated with a large spectrum of epithelial lesions. Most of these are benign hyperplasias (warts) that only very rarely progress to cancers. A subgroup of HPVs, i.e., the "high-risk" HPVs, however, are associated with lesions that have a propensity to undergo carcinogenic progression. Most notably, almost all human cervical carcinomas contain and express high-risk HPV sequences. During carcinogenic progression, the virus frequently becomes integrated into the host genome. Hence, carcinogenic progression usually represents a biologic dead end for the virus and is not part of the normal viral life cycle. There are no typical hotspots for viral integration in the host genome, but integration is quite specific with respect to the viral DNA. After integration, only two viral genes, E6 and E7, are consistently expressed in HPV-associated cancers. In addition, the integration event almost always disrupts expression of the main viral transcription/replication factor E2, which functions as a transcriptional repressor of viral gene expression. As a consequence, the expression of E6 and E7, which is still driven by viral promoter/enhancer sequences, is dysregulated and is often higher in tumors [reviewed in (1,2)]. The E6 and E7 genes of the high-risk HPVs encode oncoproteins that target the p53 and retinoblastoma tumor suppressors, respectively, for degradation [reviewed in (3)]. In addition, expression of high-risk HPV E6 increases telomerase activity (4).
In conjunction with a large body of epidemiologic data that links high-risk HPV to cervical cancer, these molecular studies led a panel of experts convened by the International Agency for Research on Cancer in 1995 to conclude that the high-risk HPV types 16 and 18 are carcinogenic to humans (5). In addition to cancer of the uterine cervix, these same high-risk HPVs are also associated with other anogenital tract carcinomas, including penile, anal, and vulvar cancers. In addition, another group of HPVs is associated with cutaneous cancers, including epidermodysplasia verruciformis. The predominant HPV type recovered from such lesions is HPV5 [reviewed in (6)].
The mucosal lining of the oral cavity and the upper digestive tract is also susceptible to HPV infections. HPV6, a low-risk HPV that was originally isolated from benign genital warts (condyloma acuminatum), is highly associated with respiratory papillomas [reviewed in (7)]. In contrast, however, the link of high-risk HPV infections and the development of cancer at this anatomic location has been more tenuous. Previous estimations of viral prevalence in such lesions have covered a very wide range, from less than 10% to up to 100% [reviewed in (8,9)].
In this issue of the Journal, Gillison et al. (10) have carefully analyzed more than 250 fresh specimens of head and neck squamous cell carcinoma (HNSCC). Analysis of HPV status was linked to an extensive molecular, histopathologic, and epidemiologic evaluation of these cases. A total of 25% of all of the lesions were HPV positive, and cases with integrated and episomal forms of the virus were detected. In situ hybridization analyses showed that the lesions but not the surrounding stroma or normal tissue were HPV positive. HPV16, the most prevalent viral type in cervical cancer, also represents the most commonly detected type in HNSCC. In agreement with other recent reports (11,12), this study shows that a specific subset of HNSCC, oropharyngeal carcinoma, is most highly associated with HPV. As predicted from the ability of HPV E6 to abrogate p53 function, HPV-positive oropharyngeal tumors are less frequently associated with p53 mutations than HPV-negative cases. They also appear to be less associated with abuse of alcohol and tobacco products, the most notorious risk factors of oropharyngeal squamous cell carcinoma. Importantly, however, this study reveals that HPV-positive oropharyngeal carcinoma may constitute a distinct class of disease with a more favorable prognostic outcome than the HPV-negative counterparts. These tumors are commonly of a poorly differentiated, nonkeratinizing, "basaloid" subtype. This is similar to HPV-associated carcinomas of the vulva (13), anus (14), and penis (15). These findings are exciting because, in addition to providing a solid etiologic link between high-risk HPV infection and a subgroup of HNSCC, they promise improvements in diagnosis and also possibly treatment. These are pressing issues, given that the incidence and survival associated with oral cancer have essentially remained unchanged over the last 30 years (16).
Many questions, however, remain. Some reports have suggested that high-risk HPVs associated with HNSCC may be very similar but not identical to HPVs associated with cervical carcinoma (17,18). In particular, there has been a report (19) that showed that HNSCC-associated HPV16 subtypes have characteristic alterations in the promoter/enhancer region that make them particularly active in oral keratinocytes. In this article by Gillison et al., the authors analyzed the nucleotide sequence of the E6 oncogene in HPV16-positive tumors and found evidence for tumor variations in 52 of 56 cases. While this rate is reportedly similar to that seen in cervical cancer, seven of the 17 distinct variants that were identified in the study by Gillison et al. are novel and have not been detected previously. Since HPVs replicate by utilizing the core cellular DNA synthesis machinery, they undergo mutations at a low rate and their genomes are quite stable. A more thorough examination of HPVs associated with oral cancers, including an analysis of promoter/enhancer sequences, will be necessary to further address these issues.
Given the large number of HPV types that have already been characterized, polymerase chain reaction or Southern blot-based detection techniques for these viruses are inevitably plagued by the possibility that lesions that score as HPV negative do, in fact, harbor HPVs that evade detection by these methods. For example, HPV types that are more closely related to the cutaneous HPV5 are not easily detected by standard methods and have only recently been discovered in many nonmelanoma skin cancers by use of specific reagents (2022). At least one of the tumors studied in the article by Gillison et al. remained untyped, and it might, therefore, be possible that it may represent a novel type or a highly divergent variant. Hence, it is conceivable that other subtypes of HNSCC may also be associated with HPV infections.
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