Abstract 4053: One MicroRNA Has Prognostic Potential For Malignant Pleural Mesothelioma

Abstract

Abstract Introduction: The current inability to forecast outcomes for malignant pleural mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach, and hence compromises their prognosis. It was previously shown that microRNAs (miRs) have a role in the cancer process, and that they can serve as biomarkers for different tumors or histological types. Here we investigated whether specific miRs could differentiate a largely surgically-treated group of mesotheliomas into good or bad prognosis categories. Methods: In a retrospective study using snap frozen, immunohistochemically-proven mesothelioma surgical specimens, we looked for miRs associated with survival and time to progression. A training set of 44 and a test set of 98 mesothelioma tumor samples were analyzed by a custom ∼900 microRNA microarray platform and verified by qRT-PCR for cross-platform validation. Patients were segregated into good or bad time to progression (greater/less than 12 months) and into good or bad survival (greater/less than 15 months). Mann-Whitney tests for good vs. bad prognosis and Kaplan-Meier analysis were used to detect prognosticator miRs. The biological effect of the identified prognostic miR was tested in 2 mesothelioma cell lines. Functional implications as well as downstream targets of the potential prognostic miR were investigated in vitro. Results: In both the training and test sets, one miR was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma than in sarcomatoid cases, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Thresholds set within the training set for microarray reading were fully valid in the test-set, as was the comparable threshold using qRT-PCR. Increased expression of this specific miR predicted throughout a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulatory genes, known in mesothelioma, are mediated by this miR as was demonstrated through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. This suggests that a control mechanism might explain the clinical findings, supporting their validity. Conclusions: One miR has the potential to be a prognostic biomarker in mesothelioma and shows the ability to change proliferation, migration, invasion upon over-expression in mesothelioma cell lines. Further validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future, by allowing personalized treatment for patients who are more to benefit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4053.