Genetic susceptibility to infection with human papillomavirus and development of cervical cancer in women in Brazil
Introduction
Squamous cell carcinoma of the cervix (SCCC) is an important cause of mortality in women in developing countries. Infection with oncogenic types of human papillomavirus (HPV) is considered the major risk factor for the development of malignancies in the uterine cervix [1].
Papillomaviruses are epitheliotropic viruses present in the skin and mucosa of several animals. In humans, more than 100 types have been described. Mucosal and genital HPVs, consisting of about 30 types, are divided into low-risk (HPVs 6, 11, 42, 43, and 44) and high-risk (HPVs 16, 18, 31, 33, 35, 45, 51, 52 and 56), according to their presence in malignant lesions of the cervix [2], [3]. The genome of these viruses is a double stranded DNA molecule of about 8000 bp. Three genomic regions have been identified: a late region (L), an early region (E), and a long control region (LCR). The early genes E1 and E2 encode proteins involved in viral DNA replication and control of viral transcription [3]. The products of genes E6 and E7 are essential in the process of HPV induced cellular immortalization and transformation [4]. The late genes L1 and L2 encode the viral capsid proteins. HPV genomes are found as episomes in the nucleus of infected cells of the normal cervix, where infective viral particles can be isolated. However, in some low-grade and in most of the high-grade lesions of the uterine cervix, including cancer, HPV genomes are found integrated into the host genome [3]. A disruption of the E1–E2 region is required for HPV genome integration. This event results in an increased expression and stabilization of the E6 and E7 transcripts. The E6 protein from high-risk HPVs binds cellular p53, promoting the degradation of p53 by the cellular ubiquitin proteolysis system. The E7 protein interacts with pRB and inactivates this cellular protein. As a consequence, E2F transcription factor is released from pRB–E2F complex, leading to transcriptional activation of several genes involved in cell proliferation. Such interactions of HPV E6 and E7 proteins interfere with two major pathways involved in the control of the cell cycle [4].
Infection with high-risk HPV types is frequent among sexually active women, with incidence ranging from 15 to 40% [2]. When additional cervical specimens are taken from these women in follow-up surveys, the majority of the infections are found to be transient. However, a small proportion of infected women have persistent infection with high-risk HPV types. Previous reports have demonstrated that women persistently infected with oncogenic HPV types are more likely to develop malignant cervical lesions [5]. Furthermore, persistent HPV infections associated with a high viral load are considered to be risk factors for persistent cervical lesions [6]. This could be explained by intrinsic features of some HPV types, particularly those of the high-risk type, but very little is known in this respect.
HPV is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenic process. A hereditary component for this neoplasia has been reported and several studies indicate that genetic background of the host is important for cervical cancer susceptibility [7], [8], [9]. To characterize genetic factors that could participate in the susceptibility to this tumor and disease outcome, polymorphic genes are being investigated. Among them are genes related to immune response (e.g. major histocompatibility complex (MHC) genes), genes involved in the metabolism of cigarette smoke and genes involved with cancer development (e.g. p53) [10], [11].
Section snippets
HLA antigens and risk of HPV infections and cervical neoplasia
Animal models have demonstrated that domestic rabbits differ in their ability to clear papillomavirus infection over time based on their MHC haplotypes [12]. The human MHC genes encode the cell surface human leukocyte antigen (HLA) class I (HLA A, B and C) and class II (HLA-DR, DQ and DP) molecules, which play an important role in the regulation of the immune system. Most nucleated cells express HLA class I genes, whereas HLA class II expression is restricted to specialized antigen-presenting
p53 codon 72 polymorphism and HPV persistence in cervical neoplasia
A p53 polymorphism in codon 72 has been described, which encodes either arginine or proline residues. Interestingly, the frequency of the arginine allele increases proportionally to the geographic latitude, while the proline allele shows an inverse effect, i.e., it is more frequent in Black populations, and the arginine allele predominates among Caucasians [43]. Associations with this polymorphism in human cancers have been reported. It has been observed that the p53 variants differ
Acknowledgements
I am grateful to the dedicated and skilled work of the following graduate students: Paulo C. Maciag, Tatiana Rabachini, Adriana Rossi and Jane Kaiano. I also acknowledge Dr. Eduardo Franco and his team at McGill University, Montreal, Canada, for study design, coordination and epidemiological analysis, and Dr. Greg Matlashewski’s group at the same University for some p53 polymorphism analysis. My deepest gratitude to my group at the Ludwig Institute for Cancer Research, in Sao Paulo, for their
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