General Medical Information

Cervical Cancer

G. Larry Maxwell and Andrew Berchuck

Cervical cancer is the most common gynecologic malignancy worldwide and accounts for over 400,000 cases annually. Molecular and epidemiologic studies have demonstrated that most cervical dysplasias and cancers are attributable to sexually transmitted human papillomavirus (HPV) infection. The peak incidence of HPV infection is in the third and fourth decades, and the incidence of cervical cancer increases from the third decade to a plateau between 40 and 50 years of age. Although HPV plays a major role in the development of most cervical cancers, invasive cervical cancer develops in only a small minority of women who are infected. This suggests that other genetic and/or environmental factors are involved in cervical carcinogenesis. For example, individuals who are immunosuppressed, such as those with human immunodeficiency virus infection, invasive cervical cancer is more likely to develop after HPV infection.

Human Papillomavirus
The HPV DNA sequence consists of 7,800 nucleotides divided into “early” and “late” open reading frames (ORFs). Early ORFs fall within the first 4,200 nucleotides of the genome and encode proteins (E1 to E8) important in viral replication and cellular transformation. Late ORFs (L1 and L2) are found within the latter half of the sequence and encode structural proteins of the virion. In oncogenic subtypes like HPV 16 and 18, transformation may be accompanied by integration of episomal HPV DNA into the host genome. Opening of the episomal viral genome usually occurs in the E1/E2 region, resulting in a linear fragment for insertion. The location of the opening may be significant because E2 acts as a repressor of the E6/E7 promotor and disruption of E2 can lead to unregulated expression of the E6/E7 transforming genes. HPV 16 DNA may be found in its episomal form in some cervical cancers, however, and unregulated E6/E7 transcription may occur independent of viral DNA integration into the cellular genome.

There are over 70 HPV subtypes, but only approximately a dozen affect the lower genital tract, and types 6, 11, 16, 18, 31, and 33 are most frequently observed. Types 6 and 11 rarely are oncogenic and usually are associated with low-grade dysplasia or condyloma, whereas types 16 and 18 account for 80% to 90% of cancers. Examination of the biologic effects of HPV-encoded proteins has shed light on the mechanisms of HPV-associated transformation. Expression of the E4 transcript results in the production of intermediate filaments that colocalize with cytokeratins. E4 proteins of oncogenic subtypes disrupt the cytoplasmic cytokeratin matrix, whereas those of nononcogenic strains do not. It has been suggested that this may facilitate the release of HPV particles in oncogenic subtypes such as HPV 16. The E5 oncogene encodes a 44–amino-acid protein that usually forms dimers within the cellular membrane. The transforming properties of E5 appear to involve potentiation of membrane-bound EGF receptors or PDGF receptors.

The E6 and E7 oncoproteins are the main transforming genes of oncogenic strains of HPV. Transfection of these genes in vitro results in immortalization and transformation of some cell lines. The HPV E7 protein acts primarily by binding to and inactivating the retinoblastoma (Rb) tumor suppressor gene product. E7 contains two domains, one of which mediates binding to Rb, whereas the other serves as a substrate for casein kinase II phosphorylation. Variations in oncogenic potential between HPV subtypes may be related to differences in the binding efficacy of E7 to Rb. High-risk HPV types contain E7 oncoproteins that bind Rb with more affinity than E7 from low-risk types. The transforming activity of E7 may be increased by casein kinase II mutation, implying a role for this binding site in the development of HPV-mediated neoplasms. The E6 proteins of oncogenic HPV subtypes bind to and inactivate the p53 tumor suppressor gene product (209,210). There also is a correlation between oncogenicity of various HPV strains and the ability of their E6 oncoproteins to inactivate p53. Inactivation of Rb and p53 by E6/E7 circumvents the need for mutational inactivation of these key growth regulatory genes.