Etiology Human Papillomaviruses

Causality requires a judgment based on scientific evidence from human and experimental studies, as strict causality studies are often not appropriate in humans. Evidence linking certain human papillomavirus (HPV) genotypes to cervical carcinoma is extensive and compelling. More than two decades of research has led to the fulfillment of criteria, as proposed by Hill, to establish a causal link between high risk HPV infection and cervical cancer (Table 1). HPV DNA was first isolated from biopsies of cervical cancer more than 30 years ago (1,2). HPV DNA is detected in 99.7% of cervical carcinomas worldwide. The evidence overwhelmingly demonstrates that persistent high risk HPV infection is a necessary but not sufficient cause of this cancer (3).

Harald zur Hausen's group in 1985 first cloned the archetypal and most common high risk HPV genotype, HPV-16, from a cervical cancer (4). A decade later, HPV was officially recognized as a human carcinogen by the World Health Organization (5). HPV has been found to induce transformation of human uterine cervix (6) and additionally, expression of high risk HPV whole genome (7) or the E6 and E7 viral oncogenes (8) immortalize human keratinocytes. Serum antibody to high risk HPV has also been found to be associated with malignant and premalignant lesions of the cervix (9,10). Recent preventive vaccine trials confirm that virus capsid-specific immunity is elicited in 99.7% patients (11) and protects against persistent HPV infection and the development of cervical intraepithelial neoplasia (CIN), the precancerous precursor to cervical cancer presently termed squamous intraepithelial lesions (SIL).

From: Current Clinical Oncology: Molecular Pathology of Gynecologic Cancer Edited by: A. Giordano, A. Bovicelli, and R. Kurman © Humana Press Inc., Totowa, NJ

Table 1

Association of HPV With Cervical Cancer

Criteria Compliance of HPV as a cause of cervical cancer

Strength of association One of the strongest ever observed for human cancer. High-

risk HPV DNA is present in 99.7% of cervical cancers (3). Serum antibody to high risk-HPV associated with malignant and premalignant lesions of the cervix (9,10). Consistent association between HPV DNA detection and cervical cancer across a large number of studies and diverse populations.

Only specific HPV types are associated with cervical cancer. HPV infection precedes CIN and occurs many years before the onset of cervical cancer. The epidemiology of HPV infection is consistent with the known sexually transmitted nature of cervical cancer. Biological gradient The risk to develop cervical cancer increases with viral load and persistent infection (40).

Plausibility Plausible based on coherence of previous in vitro studies in animals and observational studies in humans.

Coherence Does not conflict with what is known about the natural history and biology of the virus and disease progression.

Experimental evidence Identification of HPV DNA in biopsies of cervical cancer (1,2).

Production of virus by raft culture of CIN-derived cells Transformation of human uterine cervix by HPV (6). Expression of high-risk HPV whole genome (7) and E6 and E7 oncogenes (8) immortalization of human keratinocytes. Derepression of HPV E6 and E7 oncogenes has been observed in cervical tumor cells (102). Suppression of expression tumorigenesis in cervical carcinoma cell lines by blockade of HPV E6 and E7 oncogene expression (103).

Analogy Analogous both to the induction of cancers by animal papillomaviruses, and also a number of other viruses, such as HBV and EBV that are known to cause human cancers.

Application of epidemiological considerations for causal inference to human papillomavirus and cervical cancer. This table summarizes an extensive review from ref. 131.

Consistency

Specificity Temporality

Papillomaviruses are double-stranded DNA viruses belonging to the family Papovaviridae. Nearly 100 HPV genotypes have been designated to date and close to 100 other types have been identified (12). The papillomaviruses fall into two major groups, dermatotropic and mucosotropic. Dermatotropic HPV types have a propensity for cutaneous epithelium and are associated with generally benign warts. Mucosatropic HPV types target mucous membranes, commonly infecting the penis, perineum, perianal region, vagina, vulva, and cervix. Genital Mucosa Tropic HPV infections are considered the most common sexually transmitted infection in the United States (13) and previous studies estimate that up to 75% of sexually active men and women will become infected with HPV at some time in their life (14). The major manifestations of genital HPV infection include genital warts (condyloma acuminatum) and SILs of the anogenital region.

Approximately 35 of the nearly 100 types of HPV are specific for the anogenital epithelium and have varying potentials for malignant transformation. The International Agency for Research on Cancer (IARC) Multicenter Cervical Cancer Study Group recently reported that fifteen mucosatropic HPV types can be considered high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82); three can be considered probable high-risk types (26, 53, and 66); and 12 can be considered low-risk types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108) (15). Low-risk types, such as HPV6 and 11 do not integrate into the host genome and are only associated with lower-grade genital tract SILs and benign warts. Intermediate-risk types can cause higher-grade SILs, but rarely progress to the invasive stage. On the other hand high-risk HPV types, such as HPV16 and 18 are strongly associated with high-grade SILs (HSILs, previously CIN Grades 2 and 3) and invasive carcinoma.

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