Fas/CD95 promoter polymorphism gene and its relationship with cervical carcinoma.

OBJECTIVE: Apoptosis is an important fail-safe control in human papillomavirus (HPV)-associated carcinogenesis. We tested the hypothesis that the A/G polymorphism at -670 of Fas promoter is associated with an increased risk for cervical cancer, using a matched case-control setting. METHODS: The material in this case-control study consisted of 91 patients with cervical carcinoma and 176 population-based control subjects, recruited between 2002 and 2004; all the ethnic Brazilian women had histologically confirmed cervical carcinoma. Control subjects were age-matched; healthy women who were selected following a negative cervical cytology and normal colposcopy. Fas genotyping was performed using a PCR-RFLP technique. RESULTS: No significant difference existed in the distribution of the Fas polymorphisms (wild, heterozygous, mutant) between the cases and controls. The heterozygous (OR: 4.85, 95% CI: 1.1-22.6) genotypes among the younger (< 48 yrs) cancer patients were almost 5-fold increased, as compared with the wild type. No such increase was observed among the patients older than 48 years. CONCLUSIONS: Our data suggest that 670A/G polymorphism in the promoter region of the death receptor Fas is associated with an increased risk of cervical cancer among Brazilian women under 48 years. The mechanisms would be the inhibition of apoptosis by Fas -670G allele-mediated down-regulation of Fas transcription.

p16(INK4a) Expression does not predict the outcome of cervical intraepithelial neoplasia grade 2.

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.

Interleukin-6 polymorphisms and the risk of cervical cancer.

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.

Prognostic value of P53 codon 72 polymorphism in invasive cervical cancer in Brazil.

OBJECTIVE: The prognostic value of p53 codon72 polymorphism was analyzed in Brazilian women with cervical cancer. METHODS: The present study consists of 148 women diagnosed and treated for invasive cervical carcinoma (FIGO stages Ib-IIIb) between 1992 and 2002. Demonstration of p53 polymorphism was performed in DNA extracted from paraffin-embedded sections using the polymerase chain reaction (PCR). RESULTS: Among the 148 women, arg/arg was found in 99 (67%) and, arg/pro in 49 (33%). The overall survival (OS) curves (univariate) were different between arg/arg and arg/pro patients (P = 0.01). There was slightly increased risk of death for arg/arg patients (crude HR 2.2 CI 95% 1.2-4.0), which was not confounded by FIGO stages (adjusted HR 2.4 CI 95% 1.3-4.3). For disease-free survival (DFS), two situations were considered: (1) 124 women who received any treatment, and (2) 118 who received FIGO-recommended treatment. In the first group, 59% of arg/arg patients presented recurrence as compared to 32% in the arg/pro group (P = 0.02), whereas in the second group, 61% of the arg/arg and 34% arg/pro showed recurrence (P = 0.04). The risk of recurrence adjusted by FIGO stage for the 124 patients was 2.4 (CI 95% 1.0-3.7) and for the 118 it was 1.9 (CI 95% 1.0-3.4). These adjusted models showed no confounding and no interaction. CONCLUSIONS: Despite the prognostic significance of p53 polymorphism in univariate survival analysis, there was no or only marginal evidence on the independent prognostic value of p53arg/arg in multivariate analysis. The more ominous prognosis of the homozygous (arg/arg) patients was explained by the primary treatment, independent on the FIGO stage.

c-Myc protein expression is not an independent prognostic predictor in cervical squamous cell carcinoma.

The c-myc protein is known to regulate the cell cycle, and its down-regulation can lead to cell death by apoptosis. The role of c-myc protein as an independent prognostic determinant in cervical cancer is controversial. In the present study, a cohort of 220 Brazilian women (mean age 53.4 years) with FIGO stage I, II and III (21, 28 and 51%, respectively) cervical squamous cell carcinomas was analyzed for c-myc protein expression using immunohistochemistry. The disease-free survival and relapse-rate were analyzed using univariate (Kaplan-Meier) survival analysis for 116 women who completed the standard FIGO treatment and were followed up for 5 years. Positive c-myc staining was detected in 40% of carcinomas, 29% being grade 1, 9% grade 2, and 2% grade 3. The distribution of positive c-myc according to FIGO stage was 19% (17 women) in stage I, 33% (29) in stage II, and 48% (43) in stage III of disease. During the 60-month follow-up, disease-free survival in univariate (Kaplan-Meier) survival analysis (116 women) was lower for women with c-myc-positive tumors, i.e., 60.5, 47.5 and 36.6% at 12, 36, and 60 months, respectively (not significant). The present data suggest that immunohistochemical demonstration of c-myc does not possess any prognostic value independent of FIGO stage, and as such is unlikely to be a useful prognostic marker in cervical squamous cell carcinoma.

C-Myc protein expression is not an independent prognostic predictor in cervical squamous cell carcinoma

The c-myc protein is known to regulate the cell cycle, and its down-regulation can lead to cell death by apoptosis. The role of c-myc protein as an independent prognostic determinant in cervical cancer is controversial. In the present study, a cohort of 220 Brazilian women (mean age 53.4 years) with FIGO stage I, II and III (21, 28 and 51 percent, respectively) cervical squamous cell carcinomas was analyzed for c-myc protein expression using immunohistochemistry. The disease-free survival and relapse-rate were analyzed using univariate (Kaplan-Meier) survival analysis for 116 women who completed the standard FIGO treatment and were followed up for 5 years. Positive c-myc staining was detected in 40 percent of carcinomas, 29 percent being grade 1, 9 percent grade 2, and 2 percent grade 3. The distribution of positive c-myc according to FIGO stage was 19 percent (17 women) in stage I, 33 percent (29) in stage II, and 48 percent (43) in stage III of disease. During the 60-month follow-up, disease-free survival in univariate (Kaplan-Meier) survival analysis (116 women) was lower for women with c-myc-positive tumors, i.e., 60.5, 47.5 and 36.6 percent at 12, 36, and 60 months, respectively (not significant). The present data suggest that immunohistochemical demonstration of c-myc does not possess any prognostic value independent of FIGO stage, and as such is unlikely to be a useful prognostic marker in cervical squamous cell carcinoma