HPV Associated Neoplasms: A Comprehensive Overview, Summaries of Pathology

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Kirti

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HPV Associated Neoplasms

At least 70 genetically distinct types of HPV have been identified. Some types (e.g., 1, 2, 4, and 7) cause benign squamous papillomas (warts) in humans. In contrast, high-risk HPVs (e.g., types 16 and 18) have been implicated in the genesis of squamous cell carcinomas of the cervix, anogenital region, and head and neck (particularly tumors arising in the tonsillar mucosa). In contrast to cervical cancers, genital warts have low malignant potential and are associated with low- risk HPVs, predominantly HPV- and HPV-

• (^) Oncogenic activities of E6- The E6 protein binds to and mediates the degradation of p53 and stimulates the expression of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, which contributes to the immortalization of cells. E6 from high- risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types, a distinction that likely accounts for the difference in cancer risk.

• (^) Oncogenic activities of E7- The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through the G1/S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types. E7 also inactivates the CDK inhibitors p21 and p27. Finally, E7 proteins from high-risk HPVs (types 16, 18, and 31) also bind and presumably activate cyclins A and E. So, high-risk HPV types express oncogenic proteins that inactivate tumor suppressors, activate cyclins, inhibit apoptosis, and combat cellular senescence. Thus, it is evident that HPV proteins promote many of the hallmarks of cancer.

• (^) The primacy of HPV infection in the causation of cervical cancer is confirmed by the effectiveness of HPV vaccines in preventing cervical cancer. However, infection with HPV itself is not sufficient for carcinogenesis. For example, when human keratinocytes are transfected with DNA from HPV types 16, 18, or 31 in vitro, they are immortalized but do not form tumors. Cotransfection with a mutated RAS gene results in full malignant transformation.
• (^) In addition to such genetic cofactors, HPV also acts in concert with environmental factors. These include cigarette smoking, coexisting microbial infections, dietary deficiencies, and hormonal changes, all of which have been implicated in the pathogenesis of cervical cancers.

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