Epigenetic and genetic alternation of PTEN in cervical neoplasm

Objectives. We studied the role of epigenetic and genetic changes of PTEN in the development of squamous cell carcinoma (SCC) of the uterine cervix and their value as a prognostic factor. Methods. Ten high-grade cervical intraepithelial neoplasia (CIN-H) and 62 SCC tissues were used in this study. Microdissection was performed before loss of PTEN function through methylation of promoter CpG islands, deletion and mutation were studied. The findings were verified with PTEN protein expression and correlated with clinicopathologic information. Results. PTEN mutation assessed by single-strand conformation polymorphism (PCR-SSCP) was not noted in any of the 62 SCC. Loss of heterozygosity (LOH) was only seen in eight SCC. PTEN promoter methylation was detected in 40% (4/10) of CIN-H and 58% (36/62) of SCC specimens. Loss of PTEN protein expression was associated with methylation of PTEN. PTEN methylation was not related to patient age, tumor grade or stage. Patients with persistent disease or who died of disease had a significantly higher percentage of PTEN methylation than those without evidence of recurrence. Multivariate Cox regression models confirmed PTEN was an important significant predictor both for total and disease-free survival after controlling age, pathologic grade and clinical stage. Conclusions. PTEN methylation and loss of PTEN expression are early events in the development of cervical cancer and may have prognostic significance. (C) 2004 Elsevier Inc. All rights reserved.