Ovarian cancer (OC) has the highest mortality rate of all gynaecological cancers, which is attributable to a limited understanding of its early development, culminating in a lack of diagnostics for early detection. Although animal models have advanced our knowledge of OC biology, few recapitulate initiating pathogenic events. Thus, novel models of early OC are needed to support early-stage biomarker discovery.
Recently, we characterised a precursor lesion of OC in the Fanconi anaemia complementation group D2 knock-out (Fancd2-/-) animal model [1-3]. However, its relevance to studying early human OC was previously unknown. This study assessed its similarity (precursor and ovarian tumours) to two human ovarian cancer specimens, i.e., high-grade serous carcinomas (HGSOC) (n=3) and serous borderline tumours (n=6). Subsequently, the Fancd2-/- model was employed to provide proof-of-concept evidence that secreted extracellular vesicle (EV) encapsulated nucleic acid biomarkers of early-stage OC can be detected.
RNA-sequencing of laser capture microdissected tissue revealed similar upregulation (FDR<0.05) of key epithelial OC markers (e.g. E-cadherin, Muc16 [CA-125], Wfdc2 [HE4]), in both mouse (n=7) and human (n=3-6) samples. EVs isolated from mouse (n=9-11) and human (n=3-6) conditioned explant tissue media resulted in five shared upregulated EV-derived microRNAs (FDR<0.05). These were considered candidate early OC biomarkers, as they were also upregulated and detectable in the mouse precursor lesion media. Finally, qPCR analysis of matched patient serum confirmed these microRNAs were differentially upregulated in HGSOC patients (p<0.05). This research validated the Fancd2-/- model as a clinically relevant system and identified candidate secreted EV biomarkers for early OC detection.