HPV is detectable by molecular methods in nearly all cases of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. Important risk factors for the development of CIN and invasive carcinoma thus are directly related to HPV exposure and include:
Male partner with multiple previous sexual partners
Persistent infection by high-risk strains of papillomavirus
Like most other DNA viruses, HPV uses host cell DNA polymerases to replicate its genome and produce virions. Virions must be shed from the surface of the squamous mucosa, yet under normal circumstances squamous cell maturation is accompanied by a cessation of DNA replication, which would prevent virus production. HPV “solves” this problem through the action of two viral oncoproteins, E6 and E7. The E6 and E7 proteins of “high risk” HPV variants inhibit p53 and RB, respectively (Chapter 6), two potent tumor suppressors that act to suppress the division of squamous cells as they mature. E6 and E7 thus have a central role in the life cycle of HPV and largely explain the carcinogenic activity of HPV in the cervix and other sites that are prone to HPV infection (e.g., vulva, penis, oropharynx).
HPV variants are classified as high-risk or low-risk types based on their propensity to induce carcinogenesis.
Fig.19.4Cervicaltransformationzoneshowingthetransitionfrommatureglycogenatedsquamousepithelium,toimmaturemetaplasticsquamouscells,tocolumnarendocervicalglandularepithelium.
http://ebooksmedicine.net
Low-risk HPV (6,11) (16, 18, others) hSIL (50,000/yr) Invasive cancer (13,000/yr) Metastasis (5000/yr) Persistent infection Viral integration Condyloma (hundreds of thousands/yr) SIL (~1 million/yr)
Fig.19.5Possibleconsequencesofhumanpapillomavirus(HPV)infection.Progressionisassociatedwithintegrationofvirusandacquisitionofadditionalmutationsasdiscussedinthetext.SIL, Squamousintraepitheliallesion;hSIL, High-gradecervicalintraepitheliallesion.
High-risk HPV infection is the most important risk factor for the development of SIL that can progress to carcinoma. Two high-risk HPV viruses, types 16 and 18, account for approximately 70% of cases of SIL and cervical carcinoma. In general, infections with high-risk HPV types are more likely to persist, which is a risk factor for progression to carcinoma. These HPV types also show a propensity to integrate into the host cell genome, an event that is linked to progression. Low-risk HPV variants (e.g., types 6 and 11) associated with the development of condylomas of the lower genital tract (
Fig. 19.5), by contrast, express E6 and
E7 variants with different or weaker activities and do not integrate into the host genome, remaining instead as free episomal viral DNA. Despite the strong association of HPV infection with cancer of the cervix, HPV is not sufficient to drive the neoplastic process. As mentioned later, HPV-infected high-grade precursor lesions do not invariably progress to invasive cancer. Diverse other factors such as immune and hormonal status and coinfection with other sexually transmitted agents are suspected to play a role. Collectively these factors favor the acquisition of somatically acquired mutations that involve both oncogenes and tumor suppressor genes. Viral integration appear to contribute to transformation in two ways: 1) integration always disrupts an HPV gene that negatively regulates E6 and E7, which leads to their increased expression; and 2) sometimes HPV integrates near a host cell oncogene such as MYC, leading to its overexpression as well.