The Association of HPV and Cancer

Moles, Warts and Skin Tags Removal

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It has been known for many decades that filterable transmissible agents, i.e. viruses, cause cutaneous and mucosal papillomas (warts) in animal models and in humans [1]. The oncogenic potential of papillomaviruses was first demonstrated by Payton Rous and J.W. Beard in the 1930s. They observed that epidermal papillomas induced in domestic rabbits by Shope cottontail rabbit papillomavirus (CRPV) could progress to squamous cell carcinomas, and that viral oncogenicity was enhanced by chemical cocarcinogens. However, the progression of human common and genital warts to cancer was virtually never observed, and so a link between HPV infection and human carcinogenesis was largely discounted. However, there were indications, first noted in the mid-1800s by the Italian physician, Rigoni-Stern, that cervical cancer had the epidemiological characteristics of a sexually transmitted infection. He astutely noted that cervical cancer was common among prostitutes, but rare in virgins or nuns [2]. Much later, in the mid-1970s, Alex Meisels and others observed that low-grade precancerous cervical lesions often contained areas of koilocytic atypia, characterized by vacuolated nuclei that histologically resembled nuclear abnormalities seen in cutaneous papillomas [3]. The dense bodies within the vacuolated nuclei were subsequently shown to contain typical HPV virion structures, reinforcing the idea that cervical neoplasia was virally induced. This led to the speculation that HPV might cause cervical cancer [4]. However, further investigations of the link between HPVs and cervical cancer were limited, in large measure by the inability to propagate HPVs in cultured cells or simple animal models. In the 1960s and 1970s, most of the attention was focused on the possibility that other STI agents, particularly herpes simplex virus 2, were the primary inducers of cervical carcinogenesis. However, the causal association with HSV was largely discounted by the mid-1980s, perhaps most convincingly in HSV2 serologic studies conducted by Vladimir Vonka [5].

In the mid-1970s, it was recognized that there were several HPV genotypes, based upon nucleic acid hybridization analysis of viral DNA extracted from wart-derived virions. However, the large number of distinct HPV genotypes (currently over 100), and the specific pathologies associated with them, were not appreciated. The advent of recombinant DNA technology and molecular cloning during this period proved to be the key technologic advances for further exploration of the biology of HPVs and their association with cancer. By the early 1980s, a number of distinct cutaneous and genital wart genotypes had been molecularly cloned into bacterial plasmids. Gerard Orth et al. identified an association between certain cutaneous types and skin cancer in a rare genetic disease, epidermodyspla-sia verruciformis [6]. Critically, in 1983, Harald zur Hausen et al. at the German Cancer Research Institute (DKFZ) reported the cloning of the sixteenth HPV genotype, in this case derived from a cervical cancer biopsy. Using this sequence as a probe, the group reported that HPV16 related sequences were detected by Southern blotting in approximately one-half of a set of cervical cancer tissue samples [7]. Shortly thereafter, the DKFZ group demonstrated that the E6 and E7 genes of HPV16 or HPV18 (another type they cloned soon after HPV16) were selectively retained and expressed in cervical cancers and cervical cancer-derived cell lines [8]. In 2008, Dr. zur Hausen received the Nobal Prize for Medicine for these groundbreaking discoveries. These findings launched studies of many groups that resulted in the classification of genital HPVs into two broad biological groups [9]. Low risk types, most often HPV6 and HPV11, cause genital warts and other benign genital neoplasia, but almost never cancer. The more than a dozen types designated high risk also normally cause benign neoplasia as part of their productive life cycle. However, these infections have an appreciable propensity for carcinogenic progression, particularly at the cervical transformation zone, where the columnar cells of the endocervix meet the stratified squamous cells of the ectocervix. Virtually all cervical cancers contain high-risk HPV DNA and a variable fraction of several other anogenital and oral cancer are also attributed to one of these viruses (Table 1).

Table 1 Estimate of annual incidence of cancers attributable to HPV infection

% Attributable

Attributable

Attributable

Site

to HPV

Total cancers

to HPV

to HPV16/18

Cervix

100

492,800

492,800

333,900

Anus

90

30,400

27,300

25,100

Vulva, vagina

40

40,000

16,000

12,800

Penis

40

26,300

10,500

6,600

Mouth

3

274,300

8,200

7,800

Oro-pharynx

12

52,100

6,200

5,500

All sites

10,862,500

561,100

402,900

Adapted from [10]

Adapted from [10]

It has been estimated that 5.2% of all human cancers are caused by HPV infection, with HPV16 alone accounting for 3.7% of all cancers [10].

Biological plausibility for a causative association between HPV infection and cancer was rapidly provided by laboratory studies. In the late 1980s/early 1990s, it was demonstrated that the E6 and E7 of high-risk types, but not low risk types, can independently transform certain rodent cell lines in vitro and cooperate to efficiently immortalize primary human epithelial cells, including cervical and foreskin keratinocytes [11]. These activities of high-risk E6 and E7 were attributed, at least in part, to their preferential ability to interact with and inactivate, respectively, p53 and pRb, the products of two tumor suppressor genes that are frequently inactivated by mutation in HPV-independent cancers [12, 13].

Surprisingly, the strong cancer association inferred from laboratory-based studies was not supported in the initial set of case/control epidemiological studies [14]. However, it was later determined that these studies were compromised by substantial misclassification of HPV status due to the use of relatively insensitive assays for measuring HPV DNA [15]. More sensitive and validated PCR-based assays that could simultaneously amplify the DNA of many HPV types were used in subsequent studies. These studies established a uniformly strong association between HPV infection and cervical cancer. Relative risks of greater than 100 were obtained in most studies conducted from the early 1990s onward, making high-risk HPV infection among the strongest risk factor ever observed for a specific cancer [16]. Several large prospective studies followed in the late 1990s. They demonstrated that the entire spectrum of cervical neoplasia from low grade dysplasias through carcinoma in situ, the accepted precursor of cervical cancer, arises from incident HPV infection [17]. By the beginning of the twenty-first century, there was essentially uniform agreement that sexually transmitted infection by high-risk HPVs was the central cause of cervical cancer [16]. However, HPV infection is considered a necessary, but not sufficient, cause of cervical cancer, since, although virtually all cases contain HPV DNA, most cervical HPV infections do not progress to cancer. The clear implication that could be drawn from this series of discoveries is that prevention of high-risk HPV infection would prevent cervical cancer, as well as a substantial proportion of other anogenital and oral cancers, thus providing the impetus for the development and commercialization of prophylactic HPV vaccines.

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