No abstract

Although human papillomavirus (HPV) was identified as an etiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major sub-networks up-regulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal HPV decline in women with invasive cancer who were previously unable to clear the virus.

Despite screening programs, Brazil has a high cervical cancer mortality rate. The objective of this cross-sectional study was to analyze knowledge, attitudes, and practices related to the Pap smear and to understand why women fail to submit to this screening test. A structured questionnaire was used to interview 138 women: 90 with high grade intraepithelial neoplasia and 48 with invasive cervical cancer. Inadequate practices were more frequent among women with invasive cancer. In terms of difficulties in obtaining medical care, more than 80% of women reported lack of motivation, 60% reported that physicians failed to conduct a complete physical examination, and some 50% reported that physicians' schedules were busy. Having a Pap smear usually depended on a physician's request and the woman being symptomatic. Women over than 56 years old showed more frequent inadequate knowledge, attitudes and practices. However, those with more schooling were more knowledgeable of the Pap smear procedure. Age and less schooling could be barriers against women participating in screening programs, but socioeconomic problems must also be considered for improving practices related to the Pap smear.

Spontaneous regression of cervical intraepithelial neoplasia grade 2 (CIN2) lesions has been recognized since 1955, but predictors of this are poorly understood. Among the predictive markers studied, p16(INK4a) has been suggested to be of some value in monitoring the diagnosis of CIN2. In this clinical trial, 90 Brazilian women, diagnosed to CIN2 and high-risk human papillomavirus infection, were randomized into two groups of equal size: 45 women whose lesions were excised and 45 women subjected to prospective follow-up at 3-month intervals at least for 1 year (mean 6.8 months). p16(INK4a) expression was analyzed in paraffin-embedded sections using immunohistochemical staining. Among the 45 women in the follow-up group, 42% experienced spontaneous regression, 11% showed persistence, 22% progressed to CIN3, and 20% had partial regression to CIN1 or ASCUS (atypical squamous cell undetermined signifiance). p16(INK4a) expression was detected in 68.9% of the patients. In univariate survival (Cox) analysis, no significant difference in regression was obtained between p16(INK4a)-negative and -positive CIN2 lesions (adjusted HR = 1.1; 95% CI 0.6-2.0). In conclusion, p16(INK4a) expression could be useful in the diagnosis of CIN2. However, it failed to predict the outcome of CIN2. Because of its high spontaneous regression rate, follow-up could be considered as a management option of CIN2 in young and compliant women.

Recent data implicate that cytokine gene polymorphisms are important in pathogenesis of various neoplastic and nonneoplastic human diseases, and it was recently suggested that polymorphisms in interleukin (IL)-6 might increase the risk of gynecological malignancies, including cervical carcinomas. The aim of this case-control study is to compare the IL-6 polymorphisms in cervical cancer patients and healthy controls and to assess whether any of these polymorphisms would increase the risk of developing cervical cancer. The material in this case-control study consists of 56 patients with cervical carcinoma and 253 population-based control subjects, all ethnic Brazilian women. Control subjects were cancer-free women, following a negative cervical cytology and colposcopy. IL-6 genotyping was performed using a polymerase chain reaction-based restriction fragment length polymorphism. Distribution of the GG, GC, and CC genotypes in cases and controls was significantly different (P= 0.033). Compared with the GG genotype as reference, the adjusted odds ratio for the combined GC and CC genotypes in cancer patients was 1.90 (95% confidence interval, 1.1-3.4). These data suggest that women carrying at least one C genotype in their IL-6 promoter region (-174G-->C) are at higher risk of developing cervical cancer.

No abstract

The rapid progress in molecular biology has allowed the identification of the genes involved in different functions of normal cells and has also improved our understanding of the mechanisms of human carcinogenesis. The human papillomavirus (HPV) is a small double-stranded DNA tumor virus and its genes can manipulate cell cycle control to promote viral persistence and replication. The E6 and E7 proteins of high-risk HPV bind to cell cycle regulatory proteins and interfere with both G1/S and G2/M cell cycle checkpoints much more effectively than the low-risk HPV. The difference between the ability of low and high-risk HPV types to induce immortalization and transformation may well lie in their abilities to interact with the various cell cycle components, resulting in the loss of multiple cell cycle checkpoints, which are important in host genome fidelity, thus potentially resulting in accumulation of genetic abnormalities. Cervical cancer is one of the leading malignancies in women worldwide, with substantial morbidity and mortality. According to current concepts, HPV is recognized as the single most important causal agent in the pathogenesis of this cancer. HPV infection clearly precedes the development of malignancy, while being regularly associated with cervical cancer precursor lesions (all grades of squamous intraepithelial lesions). HPV-infected low-grade squamous intraepithelial lesion (SIL) has three possible outcomes: a) it may regress; b) it can persist; or c) it can make a clinical progression to in situ or invasive carcinoma. It has been well established by prospective cohort studies that the spontaneous regression rate increases in parallel with follow-up duration. In contrast, the clinical progression of lesions usually takes place quite rapidly, i.e. during the first two years from diagnosis. The mechanisms responsible for this divergent clinical behavior of HPV-associated squamous intraepithelial lesions are largely unknown, but currently under intense study in different laboratories worldwide.

The p53 codon 72 polymorphism seems to be associated with HPV-carcinogenesis, although controversial data have been reported. A series of Brazilian women with cervix carcinomas were analyzed. Ninety-nine (67%) of 148 women were found to be homozygous (arg/arg) for the arginine polymorphism, and 49 (33%) were heterozygous (arg/pro). This polymorphism may be an important determinant of the risk for cervix cancer, but does not seem to be sufficient for carcinogenesis. Key words: p53 polymorphism, codon 72, genetic polymorphism, cervix cancer, human papillomavirus. Cancer of the uterine cervix is the second most frequent malignancy in women in developing countries, and responsible for substantial morbidity and mortality worldwide. Almost all cervical carcinomas harbor HPV-DNA sequences, and generally the viral E6 and E7 oncoproteins are expressed in these carcinomas (Walboomers et al., 1999). The E6 and E7 of the oncogenic HPV types bind to p53 and pRb proteins, respectively. The fact that the E6 protein from the high-risk HPV can induce degradation of p53 has led to the proposal that this p53 inactivation pathway could play a key role in cervical carcinogenesis (Syrjänen and Syrjänen, 1999;Brenna and Syrjänen, 2003).Since its detection in 1987, several studies have linked genetic polymorphism of the p53 codon 72 to carcinogenesis and progression of cervical cancer. A person can carry one of two variations of the p53 gene in codon 72: either p53 arg or p53 pro. It was suggested that oncoprotein E6 inactivates p53arg(72) more easily than pro(72), bearing some association with the outcome of HPV infections. Indeed, it has been proposed that women who are homozygous for p53arg might have a higher susceptibility to the effects of oncogenic HPV types (Storey et al., 1998;Maciag and Villa, 1999, Makni et al., 2000).The material of the present study consists of 148 Brazilian women diagnosed and treated for HPV-positive invasive cervix cancer (clinical stages I-III) in two clinics: a) Maternity Hospital Leonor Mendes de Barros of the São Paulo State Health Secretariat; and b) Women's Health Care Center of the State University of Campinas. The Ethics Committees of both hospitals approved the research plan, and written informed consent was obtained from all patients. Diagnostic biopsies from all women were available for the study. The samples were fixed in formalin, embedded in paraffin, and processed for 4-µm-thick HEstained sections. The histological diagnosis of carcinoma was confirmed according to routine procedures.The demonstration of a codon 72 p53 genetic polymorphism was performed in DNA extracted from paraffin-embedded sections, using the Polymerase Chain Reaction (PCR) technique. In brief, 4-µm sections of the tumor were treated with xylene, ethanol, proteinase K, phenol and chloroform. Pellets were resuspended in milliQ water and stored at -20°C. Then, 5 µL aliquots of DNA were sub-