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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary.

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THE ROLE OF VIRUSES IN ONCOGENESIS: HUMAN PAPILLOMAVIRUSES AND CERVICAL CANCER AS A PARADIGM

, M.P.H., Dr.P.H.,*.

Departments of Oncology and Epidemiology, McGill University, Montreal, Canada

Like other malignant neoplasms of humans, cervical cancer is a disease with multifactorial causes and long latency. Unlike most other cancers, however, in which multiple environmental, biologic, and lifestyle determinants contribute independently or jointly to carcinogenesis, cervical cancer has been shown to have a central causal agent, human papillomavirus (HPV) infection, whose contribution to the risk of the disease is much greater than that of any other recognized determinant (IARC, 1995). Recently, there has been much attention to the fact that it is virtually impossible to find cervical carcinoma specimens devoid of traces of HPV DNA, which strongly suggests that HPV infection could be a necessary cause for this malignancy (Franco et al., 1999a; Walboomers et al., 1999). If this is really the case, then it would be a first in cancer research; no human cancer has yet been shown to have a necessary cause, so clearly identified. Some of the well-studied models in cancer causation, such as tobacco smoking in lung cancer and chronic hepatitis B in liver carcinoma, are among the strongest epidemiologic associations that one can find, but they do not represent causal relations that are necessary. Lung cancers may occur in people who never smoked and had only minimal exposure to environmental tobacco smoke, frequently as a result of exposure to occupation-related carcinogens, and liver cancer may occur in individuals who never had hepatitis B, e.g., via aflatoxin exposure or hepatitis C.

The implications of this finding are substantial and have spawned new approaches to preventing cervical cancer on two fronts: (i) via screening for HPV infection as the biological surrogate that reveals asymptomatic cervical cancer precursor lesions and (ii) via primary immunization against HPV infection to prevent the onset of such precursor lesions. While there is now intense research in these two fronts the debate still continues concerning issues related to the etiologic mechanism whereby HPV infection initiates cervical carcinogenesis. This brief overview addresses the epidemiologic characteristics of HPV infection and cervical cancer and the recent progress using new approaches to preventing cervical cancer.

Global Importance of Cervical Cancer

Cervical cancer is one of the most common malignant diseases of women. In the US each year there are approximately 12,800 new cases of invasive cervical cancer with 4,600 deaths due to this disease (Ries et al., 2000). On average during the last decade, an estimated 371,000 new cases of invasive cervical carcinoma were diagnosed annually worldwide, representing nearly 10 percent of all female cancers. Its incidence is the third among women, after breast and colorectal cancer (Parkin et al., 1999). The highest risk areas are in Central and South America, Southern and Eastern Africa, and the Caribbean, with average incidence rates around 40 per 100,000 women per year. While risk in western Europe and North America is considered relatively low at less than 10 new cases annually per 100,000 women, rates are 10 times higher in some parts of Northeastern Brazil, where the cumulative lifetime risk can approach 10 percent (Muir et al., 1987).

Every year, an estimated 190,000 deaths from cervical cancer occur worldwide, with over three-fourths of them in developing countries, where mortality from this disease is the highest among deaths caused by neoplasms (Pisani et al., 1999). Less than 50 percent of women affected by cervical cancer in developing countries survive longer than five years whereas the 5-year survival rate in developed countries is about 66 percent (Pisani et al., 1999). Moreover, cervical cancer generally affects multiparous women in the early post-menopausal years. In high-fertility developing countries these women are the primary source of moral values and education for their children. The premature loss of these mothers has important social consequences for the community.

Emergence of HPV Infection as the Main Etiologic Factor in Cervical Cancer

Prominent among the risk factors for cervical cancer is the role of two measures of sexual activity, namely number of sexual partners and age at first intercourse (Herrero, 1996), and also the sexual behavior of the woman's male partners (Brinton et al., 1989a). The consistency of the sexually-transmitted disease model for cervical neoplasia led much of the laboratory and epidemiologic research in attempting to identify the putative microbial agent or agents acting as etiologic factor. Research conducted during the late 1960s and 1970s attempted to unveil an etiologic role for the Herpes simplex viruses (HSV). Although HSV was proven to be carcinogenic, in vitro and in vivo clinical studies eventually demonstrated that only a fraction of cervical carcinomas contained traces (viral DNA) of HSV infection and epidemiologic studies failed to demonstrate that the association between HSV and cervical cancer was the primary causal element (Franco, 1991).

In the 1980s, a solid research base emerged implicating HPV infection as the sexually-transmitted cause of cervical cancer and its precursors. In 1995, the International Agency for Research on Cancer at the World Health Organization (WHO), in its monograph series of carcinogenicity evaluation classified HPV types 16 and 18 as carcinogenic to humans, HPV types 31 and 33 as probably carcinogenic, and other HPV types (except 6 and 11) as possibly carcinogenic (IARC, 1995). This classification was conservatively made on the basis of the available published evidence until 1994. Subsequent research has permitted a more inclusive grouping of genital HPV types on the basis of the presumed oncogenic potential. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 are considered to be of high oncogenic risk because of their frequent association with cervical cancer and cervical intraepithelial neoplasia (CIN), the precursor, pre-invasive lesion stage. The remaining genital types, e.g., HPV types 6, 11, 42–44, and some rarer types are considered of low or no oncogenic risk (Bosch et al., 1995). The latter types may cause subclinical and clinically visible benign lesions known as flat and acuminate condylomata, respectively.

Today, it is well established that infection with high oncogenic risk HPV types is the central causal factor in cervical cancer (IARC, 1995; Koutsky et al., 1992; Nobbenhuis et al., 1999). Relative risks for the association between HPV and cervical cancer are in the 20–70 range, which is among the strongest statistical relations ever identified in cancer epidemiology. Both retrospective and prospective epidemiologic studies have demonstrated the unequivocally strong association between viral infection and risk of malignancy, both as CIN or invasive disease (Bosch et al., 2002). Table 1-1 shows that HPV infection satisfies nearly all of standard causal criteria in chronic disease epidemiology. However, not all infections with high risk HPVs persist or progress to cervical cancer, thus suggesting that, albeit necessary, HPV infection is not sufficient to induce this disease; other factors, environmental or host-related, are also involved. Among these co-factors are: smoking (Ho et al., 1998a), high parity (Brinton et al., 1989b), use of oral contraceptives (Moreno et al., 2002), diets deficient in vitamins A and C (Potischman and Brinton, 1996), and genetic susceptibility traits, such as specific HLA alleles and haplotypes (Maciag et al., 2000) and polymorphisms in the p53 gene (Makni et al., 2000). Understanding the role of these cofactors is the subject of much ongoing research on the natural history of HPV infection and cervical cancer (see Figure 1-1).

TABLE 1-1. Causality Criteria in HPV and Cervical Cancer.

TABLE 1-1

Causality Criteria in HPV and Cervical Cancer.

FIGURE 1-1. Etiologic model in cervical carcinogenesis showing the primary role of HPV infection, its relation with sexual activity, and the putative role of cofactors.

FIGURE 1-1

Etiologic model in cervical carcinogenesis showing the primary role of HPV infection, its relation with sexual activity, and the putative role of cofactors.

Human Papillomaviruses

HPVs are small, double-stranded DNA viruses of approximately 55 nanometers (nm) with an icosahedral protein capsid containing 72 capsomers. The genome is circular and contains 7500–8000 base pairs (bp). HPVs have the following characteristics:

  • ∼8 kilobase (kb) DNA virus from Papillomaviridae family
  • Species- and tissue-specific
  • Cannot be cultivated
  • Over 150 genotypes identified, of which more than 40 infect the anogenital tract
  • High risk (oncogenic) types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
  • Induces both benign (caused by low risk types) and malignant (caused by high risk types) diseases
  • Two major viral oncogenes: E6 (binds to p53) and E7 (binds to retinoblastoma [Rb] protein)

Taxonomically, papillomaviruses used to be a subfamily in the Papovaviridae family but are now grouped independently as a family, the Papillomaviridae. As infectious agents, they are highly specific to their respective hosts. Different HPVs are classified as types on the basis of DNA sequence homology in the E6, E7, and L1 genes. More than 150 different HPV types have been catalogued so far (zur Hausen, 2000).

The epithelial lining of the anogenital tract is the target for infection by over 40 different mucosotropic HPV types. Clinical, subclinical, and latent HPV infections are the most common sexually-transmitted viral diseases today (Cox, 1995). Latent genital HPV infection can be detected in 5 to 40 percent of sexually active women of reproductive age (IARC, 1995). In most cases, genital HPV infection is transient or intermittent (Hildesheim et al., 1994; Ho et al., 1998b; Moscicki et al., 1998; Franco et al., 1999b; Liaw et al., 2001); the prevalence is highest among young women soon after the onset of sexual activity and falls gradually with age, possibly as a reflection of accrued immunity and decrease in sexual activity (meaning a decrease in number of sexual partners).

The carcinogenic mechanism following HPV infection involves the expression of two major viral oncogenes, E6 and E7, which produce proteins that interfere with tumor suppressor genes controlling the cell cycle. Once viral DNA becomes integrated into the host's genome, E6 and E7 become upregulated. While E7 complexes with the cell growth regulator Rb protein, causing an uncontrolled cell proliferation (Chellappan et al., 1992), the binding of E6 to p53 protein promotes the degradation of the latter, thus exempting the deregulated cell to undergo p53-mediated control (Thomas et al., 1996). The degradation of p53 by E6 leads to loss of DNA repair function and prevents the cell from undergoing apoptosis. The infected cell can no longer stop further HPV-related damages and becomes susceptible to additional mutations and genomic instability. Interestingly, the effect of the E6 and E7 proteins on p53 and Rb has been shown to occur only with high-risk HPVs but not with low-risk HPVs (Dyson et al., 1989).

Persistent HPV Infection as the Precursor Event in Cervical Carcinogenesis

Most women who engage in sexual activity will probably acquire HPV infection over a lifetime. As mentioned above, the vast majority of these infections will be transient with only a small proportion becoming persistent. We have found in our ongoing cohort study of Brazilian women that only 35 percent of the subjects who were infected at enrollment retain their infections after 12 months, with the mean duration being affected by the viral oncogenic potential (see Figure 1-2). Infections with oncogenic HPVs tend to last longer on average (13.5 months) than those with non-oncogenic types (8.2 months) (Franco et al., 1999b). A substantial increase in risk of CIN (see Figure 1-3) and cancer exists for women who develop persistent, long-term infections with oncogenic HPV types (Koutsky et al., 1992; Ho et al., 1998b; Nobbenhuis et al., 1999; Ylitalo et al., 2000; Moscicki et al., 2001; Schlecht et al., 2001).

FIGURE 1-2. Actuarial curves showing clearance of prevalent HPV infection according to type present at enrollment in a cohort study of asymptomatic women presenting for cervical cancer screening.

FIGURE 1-2

Actuarial curves showing clearance of prevalent HPV infection according to type present at enrollment in a cohort study of asymptomatic women presenting for cervical cancer screening. SOURCE: Adapted from Franco et al. (1999b).

FIGURE 1-3. Actuarial curves showing the cumulative incidence of cervical squamous intraepithelial lesions (SIL) according to HPV infection in the first two visits in a cohort study of asymptomatic women presenting for cervical cancer screening.

FIGURE 1-3

Actuarial curves showing the cumulative incidence of cervical squamous intraepithelial lesions (SIL) according to HPV infection in the first two visits in a cohort study of asymptomatic women presenting for cervical cancer screening. SOURCE: Adapted from (more...)

There is currently great interest in defining persistent infection and in obtaining additional markers of pathogenesis for predictive purposes. Studies of viral load and intratypic variation of HPVs indicate that persistent infections tend to yield higher viral loads than transient ones (Caballero et al., 1999) and those with non-European variants of HPVs 16 and 18 tend to be associated with higher risk of CIN as compared with those caused by European variants (Villa et al., 2000).

Defining viral persistence is critical because trials of HPV vaccine efficacy rely on the reduction of the risk of persistent infection as one of the primary outcomes. Similarly, concerning screening of cervical cancer by HPV testing, a main drawback is the low positive predictive value of a single test because of the relatively high prevalence of latent HPV infections in the population, particularly among young women. The predictive value would increase substantially if testing were to rely on repeated samplings, about 6 months apart, because of the aforementioned high prognostic value of persistent positivity. However, population screening cannot rely on repeated testing to be cost-effective and realistic as a public health measure. It would be highly desirable if one could, with a single HPV test, collect enough ancillary information on the virus and on the host that would allow determining whether or not a single instance of HPV positivity is likely to represent a persistent infection.

HPV Testing in Cervical Cancer Screening

Detection of HPV DNA in cervical specimens using a commercially available assay has been shown to have greater sensitivity but somewhat lower specificity to detect CIN and cervical cancer as compared with the conventional Pap cytology (Cuzick et al., 2000). This makes HPV testing a suitable alternative to the latter in screening programs in middle- and high-income countries where centralized laboratory resources are available. The costs associated with an increased number of women to be referred for colposcopy (because of the HPV test's higher false positive rate as compared to cytology) will likely be offset by the increased screening interval that could later be recommended if HPV testing is eventually used to replace cytology screening. The Pap test's low sensitivity forces screening programs to recommend repeat tests frequently to ensure that lesions will not be missed. In the US, fear of malpractice litigation has led to a conservative recommendation of annual Pap smears by many professional groups. Combination testing of Pap cytology and HPV testing has the potential to allow extending screening intervals (for women who are negative in both tests) to as long as 5 years, although this is yet to be proven a safe alternative in long-term follow-up studies.

Primary Prevention by HPV Vaccination

Two main types of HPV vaccines are currently being developed: prophylactic vaccines to prevent HPV infection and associated diseases, and therapeutic vaccines to induce regression of precancerous lesions or remission of advanced cervical cancer. DNA-free virus-like particles (VLP) synthesized by self-assembly of fusion proteins of the major capsid antigen L1 induce a strong humoral response with neutralizing antibodies. VLPs are thus the best candidate immunogen for HPV vaccine trials. Protection seems to be type-specific so that production of VLPs for a variety of high oncogenic risk types will be required. Such vaccines are already under evaluation in safety and efficacy trials in different populations and are sponsored by pharmaceutical companies and by the National Institutes of Health (Schiller, 1999). The preliminary results of one such a trial were extremely promising (Koutsky et al., 2002). It indicated that an HPV 16 VLP vaccine was 100 percent effective in preventing acquisition of persistent infection with HPV 16 and 90 percent effective in preventing any incident HPV 16 infection, transient or persistent. As a noteworthy secondary finding was the fact that all HPV 16-associated CIN cases occurred in the non-vaccinated group. Immunization against HPV may have greatest value in developing countries, where 80 percent of the global burden of cervical cancer occurs each year and where Pap screening programs have been largely ineffective.

Conclusions

During the last 20 years, the concerted effort among virologists, epidemiologists, and clinical researchers has helped to elucidate the role of infection by certain types of HPV as the necessary cause of cervical cancer. This has opened new frontiers for preventing a disease that is responsible for substantial morbidity and mortality, particularly among women living in resource-poor countries. Research on two prevention fronts has already begun in several populations in the form of preliminary trials assessing the efficacy of HPV vaccines and of studies of the value of HPV testing in cervical cancer screening (see Figure 1-4). Progress on both counts is very promising. While the benefits of vaccination against HPV infection as a cervical cancer prevention tool are at least a decade into the future, the potential benefits of HPV testing in screening for this disease can be realized now in most populations.

FIGURE 1-4. Opportunities for primary and secondary preventive approaches in the natural history of cervical cancer.

FIGURE 1-4

Opportunities for primary and secondary preventive approaches in the natural history of cervical cancer.

Primary prevention of cervical cancer can also be achieved through prevention and control of genital HPV infection. Health promotion strategies geared at a change in sexual behavior targeting all sexually-transmitted infections of public health significance can be effective in preventing genital HPV infection (Franco et al., 2001). Although there is consensus that symptomatic HPV infection (genital warts) should be managed via treatment, counseling, and partner notification, active case-finding of asymptomatic HPV infection is currently not recommended as a control measure. Further research is needed to determine the effectiveness of such a strategy and the significance of such infections concerning a woman's subsequent cancer risk.

Research on HPVs has progressed at a fast pace and has reached a volume of nearly 1,000 annual publications in Medline. The HPV-cervical cancer model has become a paradigm of progress in cancer research and among neoplastic diseases with infectious roots. After 20 years, we have reached the point where preventing cervical cancer via vaccination against HPV infection is in the foreseeable future. It would be disastrous, however, if countries relaxed their cervical cancer screening programs in anticipation of a successful HPV vaccine. Existing cytology-based screening programs that seem to work need to be constantly assessed for quality and coverage. Ongoing research on the efficacy and cost-effectiveness of HPV testing as a mass screening tool will help countries decide on the best approach for secondary prevention of cervical cancer and will probably lead to reduced morbidity and mortality from this disease.

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*

The author's research on the epidemiology of HPV infection and prevention of cervical cancer is funded by grants from the Canadian Institutes of Health Research (CIHR) and from the U.S. National Institutes of Health.

Copyright © 2004, National Academy of Sciences.
Bookshelf ID: NBK83702

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