What is the role of human papillomavirus (HPV) in the pathophysiology of cervical cancer?

Updated: Feb 12, 2019
  • Author: Cecelia H Boardman, MD; Chief Editor: Warner K Huh, MD  more...
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Answer

HPV comprises a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make up the viral capsid.

To date, more than 115 different genotypes of HPV have been identified and cloned. A large multinational cervical cancer study found that more than 90% of all cervical cancers worldwide are caused by 8 HPV types: 16, 18, 31, 33, 35, 45, 52, and 58. Three types—16, 18, and 45—cause 94% of cervical adenocarcinomas. [32] HVP type 16 may pose a risk of cancer that is an order of magnitude higher than that posed by other high-risk HPV types. [33]

The World Health Organization (WHO) International Agency for Research on Cancer Monograph Working Group has grouped HPV types of the mucosotropic alpha genus according to the evidence supporting their association with cervical cancer (see Table 1, below). [33]

Table 1. Human Papillomavirus Types Associated With Cervical Cancer (Open Table in a new window)

HPV Alpha Group

Types

Evidence for Cervical Cancer Causation

1

16

Most carcinogenic HPV type, known to cause cancer at several sites

18,31,33,35,39,45,51,52,56,58, 59

Sufficient evidence

2A

68

Limited evidence in humans and strong mechanistic evidence

2B

26,53,66,67,70,73,82

Limited evidence in humans

30,34,69,85,97

Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans

3

6,11

Inadequate epidemiological evidence and absence of carcinogenic potential in mechanistic studies

HPV = human papillomavirus.

The HPVs that infect the human cervix fall into 2 broad risk categories. The low-risk types (eg, HPV 6 and 11) are associated with condylomata and a very small number of low-grade squamous epithelial lesions (SILs) but are never found in invasive cancer. The high-risk types (eg, HPV 16) vary in prevalence according to the cervical disease state.

Upon integration into the human genome, the linearization of high-risk HPV DNA places the E6 and E7 genes in a position of enhanced replication. E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, and the functional loss of the TP53 and RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in progression to malignancy.


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