Human Papilloma Virus (HPV) and Cervical Cancer
Cervical cancer is the second-most prevalent cancer in women and, despite encouraging improvements in screening leading to earlier detection, cervical cancer still kills many women every year. The risk of cervical cancer is increased by infection with certain types of human papilloma virus (HPV). Elucidating the links between HPV genetic factors and environmental factors, and cancer onset, progression, and outcome, may lead to better prognostic and diagnostic tests, and treatment and prevention options.
Exactly what causes a person to develop cancer? There are cancers that have clear environmental risk factors, for example, lung cancer and smoking. There are cancers that have clear genetic risk factors, for example some families carry a mutation in one of several particular genes, that causes breast cancer. However, there are some smokers that don’t develop lung cancer, and only a small proportion (5-10%) of breast cancers can be attributed to hereditary mutations. The complex, and still poorly understood relationship between an individual’s genetic profile and the environment in which they live is the key to how a person develops cancer, how the cancer affects them, and how they respond to particular cancer therapies.
LICR has made a major commitment to determining the relationship between HPV infection and cervical cancer. In 1985, LICR scientists at the São Paulo Branch in Brazil, a country with one of highest incidences of cervical cancer in the world, launched a comprehensive research program to study the links between HPV infection, social factors, and cervical cancer. LICR investigators have carried out several long-term studies of cervical cancers in women in different areas in Brazil, particularly in regions of the country in which the prevalence of HPV is high.
Relationship between HPV Infection and Cervical Intraepithelial Neoplasia
In 1993, LICR scientists began a large cohort study of the natural history of HPV infection and risk of cervical lesions in collaboration with researchers from McGill University, and the University of Toronto in Canada. The medical and pathological histories of two thousand women from São Paulo were followed over a five year period, and the collaboration used the data obtained to assess the prevalence and incidence of HPV infection and cervical intraepithelial neoplasia (increased growth and proliferation of the cervix’s epithelial cells) in a large number of women.
Several HPV types were identified, confirming a previous observation that different regions of the world have different HPV strains. This information is important as it enables the investigators to deduce a potential vaccine formulation that is appropriate to that particular region. Furthermore, the investigators showed that the cancer risk profiles of women having oncogenic and non-oncogenic HPV infections were different, which has implications for the planning of specific preventive strategies, based on education campaigns and/or HPV vaccines, that are aimed at reducing the risk of cervical cancer. The natural history studies showed that HPV infections were very common in sexually active women, particularly those at younger ages. However, the majority of HPV infections are transient, and do not seem to be important in cervical carcinogenesis.
Only a small fraction of women infected with high-risk HPV types eventually progressed to high-grade intraepithelial lesions and cervical cancer. This established an important role in cancer development for other factors, such as diet, oral contraceptive use, tobacco smoking, co-infection with human immunodeficiency virus (HIV) or other sexually transmitted diseases. The most recent studies indicate that the risk for disease progression seems to be associated with the persistence of infection with high-risk HPV types, and with the amount of virus present, the ‘viral burden’. Thus early screening and treatment of HPV infection, together with education campaigns concerning lifestyle factors, may well decrease the risk of intraepithelial lesions developing into cervical cancer.
Molecular Epidemiology of HPV
The LICR team is studying the nucleotide sequence variations of two different oncogenic HPV strains, HPV-16 and HPV–18, as a tool for epidemiological studies of viral transmission and persistence. The team has found that intratypic sequence variations in HPV-16 are an important predictor of progression from benign to malignant cervical lesions. The investigators also found that ‘non-European’ sequence variants of HPV-16 and HPV-18 were more strongly associated with risk of cervical neoplasia than ‘European’ variants, when compared with other oncogenic HPVs and low oncogenic risk HPVs. The realization that non-European variants of HPV-16 and HPV-18 may confer increased oncogenic risk may explain why there is a disproportionately high incidence of cervical cancer in different regions of the world that are populated by ‘non-European’ races.
Sequence differences in the HPV genomes are important for determining the infectious potential of different variants, but they are also very important for identifying antigenic epitopes for HPV vaccines. Antigenic epitopes are protein sequences in HPV strains that are recognized, and thus targeted, by the immune system. Little is known about the influence of different HLA molecules (HLA haplotypes) in an individual’s immune response to HPV. Each HLA molecule presents specific protein fragments for recognition by the immune system, and the LICR team has found that susceptibility to cervical cancer has been associated with the presence and absence of certain HLA haplotypes. In fact, the LICR’s studies suggest that different HLA haplotypes are involved in genetic susceptibility to squamous cell carcinoma (SCC) as well as HPV infection in Brazilian women. Understanding the role that certain HLA molecules play in immune responses against HPV infections and subsequent cervical carcinogenesis will help to develop better approaches for preventing and treating cervical cancer through vaccination and immunotherapy, respectively.HPV vaccine
Recently, LICR, through its São Paulo Branch, partnered with Merck, Sharp & Dohme to coordinate a Phase II trial in Brazil for a Quadrivalent HPV Vaccine designed to induce immune recognition of four HPV strains (HPV-6, -11, -16, and -18). The first analysis has been conducted, and the team is currently implementing Phase III efficacy programs for the HPV vaccine. If proven safe and effective, a vaccine that prevents infection with common pathogenic HPV types will be a major advance in the control of anogenital (anal, cervical, and penile) cancers.