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Promoter Methylation, BRAF Mutation Analysis and Topoisomerase IIa Expression for the Detection of Endometrial Carcinoma in Liquid Based Cytology Samples

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Journal of Cancer Therapy 2013年第5期4卷 19-27页

作者： Aris Spathis Vasileios Sioulas evaggelia aga Dionissios Aninos Christine Kottaridi Emmanouil Terzakis Charalambos Chrelias Petros Karakitsos 2nd Department of Gynecology St. Savvas Anticancer-Oncologic Hospital Athens Greece. 3rd Department of Obstetrics and Gynecology School of Medicine University General Hospital “ATTIKON” National and Kapodistrian University of Athens Athens Greece Department of Cytopathology School of Medicine University General Hospital “ATTIKON” National and Kapodistrian University of Athens Athens Greece

Cancer of the corpus uteri remains the most common gynecological related cancer in developed countries. Cytology, after the induction of liquid based cytology, has reemerged as a possible first line non-interventional diagnostic procedure with promising results. Apart from slide preparation for cytology diagnosis, LBC allows the application of elaborate molecular tests on the residual material. Samples from 74 symptomatic women were collected in ThinPrep?PreservCyt medium, from witch immunocytochemical and molecular tests were performed. Final diagnosis of 39 endometrioid carcinomas, 20 non-endometrioid carcinomas and 15 non-malignant was set after hysterectomy. Topoisomerase IIa expression was common (42%) in both types of cancer. Promoter methylation analysis revealed that hMLH1 is commonly methylated in cancers (52.7%), CDKN2A and MGMT less often (27.1%) and RARB rarely methylated (8.4%). BRAF activating mutation V600E was a rare event (8.4%) only found in low grade endometrioid carcinomas. Topoisomerase IIa expression correlated with BRAF mutations, hMLH1 and to lesser extent with CDKN2A methylation. Almost none of the biomarkers were positive in cytological negative or hyperplastic without atypia samples. Detection of methylation in any gene displayed sensitivity, specificity, PPV and NPV similar to cytology of cancer. However, inclusion of cytology diagnosis of hyperlasias with atypia increased sensitivity and NPV of cytology outperforming methylation of any gene. Further evaluation of the panel of promoter methylation, especially in cytology diagnoses of hyperplasia with or without atypia should be evaluated since initial results are promising. Even though methylation of MGMT and RARB are rare events, some patients could be benefit from specific chemotherapeutics that target either of them or the more frequently expressed topoisomerase IIa.

关键词： Endometrial Cancer Promoter Methylation Topoisomerase IIa BRAF Liquid Based Cytology

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