Exosomal microRNA profiles as diagnostic biomarkers of ovarian cancer

DESCRIPTION (provided by applicant): Detection of ovarian cancer at Stage I results in 5-year survivals of greater than 90%; however, only 23% of ovarian cancers are diagnosed early, with 67% being diagnosed with metastatic disease. Thus, new markers are being sought to accurate identify patients with ovarian cancer, particularly in early stage. Emerging evidence suggests the potential involvement of altered regulation of microRNAs (microRNA) in the pathogenesis of human cancers. Several reports have recently demonstrated that microRNA are also active players in human oncogenic signaling pathways and that microRNA profiles from tumor biopsies can be used to diagnose tumour types and prognosis. microRNA-expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify microRNA genes that might represent downstream targets of activated oncogenic pathways or that target protein-coding genes involved in cancer. The over-expressions of hsa-miR-21, hsa-mir-141, hsa-miR-200a, hsa-miR-200b, hsa-miR-200c, hsa-miR-203, hsa-miR-205, and hsa-miR-214 have been shown to diagnosis the presence of ovarian cancer and to correlate with poor survival in patients with ovarian cancer. While microRNA profiling has shown promise in the diagnosis of ovarian cancer, at this time, its application is limited to evaluation of tissue biopsies. To have utility as a diagnostic/screening tool, tumor-associated microRNA needs to be identified prior to clinical symptoms or a demostrable mass. Our proposal to utilize circulating tumor exosome-associated microRNA as diagnostic/screening markers is based on our two observations: (1) the production and release of exosomes by tumor cells and (2) the presence of specific microRNAs associated with circulating tumor-derived exosomes. In our preliminary studies, we have demonstrated that the microRNA signatures of circulating tumor-derived exosomes from ovarian cancer patients parallel the profiles of microRNAs expressed in the corresponding tumor. Our hypothesis is that identification of specific microRNA associated with circulating ovarian tumor-derived exosomes represent early markers for detection of ovarian cancer. They may also identify staging, prognosis and response to therapy for patients with ovarian cancer. To address this hypothesis, we will initially isolate and quantitate circulating exosomes from patients with ovarian serous adenocarcinoma at various stages and grades and compare with similar material isolated from women diagnosed with benign ovarian masses (and using material from women without cancer as controls). The microRNA associated with circulating tumor-derived exosomes will be profiled to define all microRNA associated with circulating exosomes. The presence of specific microRNA will be correlated with the presence or absence of malignant disease (and compared to CA125 levels as the gold standard ). After identifying microRNAs associated with exosomes, the presence of specific microRNAs will be defined for different stages to correlate the specific exosomal microRNAs with staging. PUBLIC HEALTH RELEVANCE: Detection of ovarian cancer at Stage I results in 5-year survivals of greater than 90%; however, only 23% of ovarian cancers are diagnosed early, with 67% being diagnosed with metastatic disease. While miRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, prognosis and response to treatment, its utility as a diagnostic tool is limited due to its application to tumor biopsies. Our proposal to utilize circulating tumor exosome-associated miRNA as early detection/screening markers is based on our two observations: (1) the production and release of exosomes by tumor cells and (2) the presence of specific oncogenic miRNA associated with circulating tumor-derived exosomes. Based on our data, we propose that identification of specific miRNA associated with circulating ovarian tumor-derived exosomes are early markers for the presence of ovarian cancer and may also define stage, prognosis and response to therapy.