RESUMO

INTRODUCTION: Although studies of risk factor profiles have been conducted to identify biological markers to predict the natural history of cervical intraepithelial neoplasia (CIN) grade III, there is not sufficient information to support the routine clinical use of any biomarker. OBJECTIVES: The purpose of this study was to examine aberrant promoter methylation, which is implicated in cancer development and progression, in CIN III lesions in order to identify markers associated with more aggressive biological behavior that could be used to recognize women who are at higher risk of recurrence. PATIENTS AND METHODS: We used methylation-specific polymerase chain reaction to analyze promoter hypermethylation of 8 genes (p16, RARbeta, GSTP1, MGMT, p14, TIMP3, E-cad and DAPk) in 33 uterine cervix cones with CIN III that were also submitted to human papillomavirus (HPV) genotyping. All 33 patients in this study had been clinically followed after conization with Papanicolaou smears, colposcopy, and biopsy when indicated, every 6 months during 5 years. RESULTS: Of the 33 patients, 12 (36%) underwent immediate hysterectomy after conization for having compromised cone margins, 14 (43%) have not relapsed, and 7 (21%) presented CIN relapse. The frequency of HPV infection in this group was 97% and no significant difference between the groups was observed. HPV of high oncogenic risk was present in 29 (87.9%) cases; HPV 16 was the most frequent (69.7%), while HPV 18 was found in 33.3%; however, it was associated with HPV 16 in 15.1%. Concomitant infection by HPV 6/11 was detected in 21.2% (15.1% with HPV 16 and 6.1 with HPV 18). 85.7% (6/7) of patients with recurrence had HPV 18 vs 0% (0/14) of patients without recurrence (P = 0.0001). At least 1 of the 8 genes was found hypermethylated in all samples. Concomitant hypermethylation of several genes was frequently found. However, CIN relapse was only seen in the cases with hypermethylation of 3 or more of the 8 genes studied (P = 0.0039). CONCLUSION: We suggest that aberrant promoter methylation may play a role and may serve as a useful biomarker in the recurrence of CIN.

Assuntos

Alphapapillomavirus/isolamento & purificação , Biomarcadores Tumorais/genética , Metilação de DNA , Infecções por Papillomavirus/complicações , Regiões Promotoras Genéticas , Displasia do Colo do Útero/genética , Neoplasias do Colo do Útero/genética , Adulto , Proteínas Reguladoras de Apoptose/genética , Caderinas/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Conização , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas Quinases Associadas com Morte Celular , Progressão da Doença , Feminino , Glutationa S-Transferase pi/genética , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Papillomavirus Humano 6/isolamento & purificação , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Receptores do Ácido Retinoico/genética , Recidiva , Inibidor Tecidual de Metaloproteinase-3/genética , Proteínas Supressoras de Tumor/genética , Infecções Tumorais por Vírus/complicações , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologia

Assuntos

Humanos , Animais , Cobaias , Leptospira/genética , Leptospirose/diagnóstico , Leptospirose/microbiologia , Reação em Cadeia da Polimerase