Studies of a restricted signature of circulating miRNAs as non-invasive biomarker in glioma: from the molecular function to the clinical application

Gliomas are diffusely growing brain tumours and challenging cancers for diagnosis and treatment. The identification of genetic and epigenetic markers has led to an integrated diagnosis, composed of a histological diagnosis, and a molecular profile of the tumour. Among the key genetic events, mutations of the isocitrate dehydrogenase (IDH) genes are noteworthy. Altered miRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a very stable form, making them interesting candidate as biomarkers. Several circulating miRNAs have been evaluated in gliomas as single biomarkers. However, it is widely recognized that single miRNA profiles may provide a low accuracy as cancer biomarkers, mostly due to the multifactorial nature of tumour and to the large number of targets for a single miRNA. In this thesis work we identified a ten-serum miRNA signature dysregulated between IDH wild-type and IDH mutant patients that shows diagnostic and prognostic value. Interestingly, among them, the combination of miR-1-3p, miR-26a-1-3p and miR-487b-3p led to an improvement of the diagnostic performance, compared to each single miRNA of the signature, and also allows to discriminate glioma patients from healthy subjects. We also found that alteration of miR-1-3p, miR-26a-1-3p and miR-487b-3p in serum may reflect their changes in tumour tissue, and cell lines recapitulate what observed in glioma patients. Moreover, we showed that the combination of miR-1/-26a-1/-487b acts as tumour suppressor in IDH-wt glioma cells by exerting an increased adverse effect on cell viability, proliferation and migration, and inducing apoptosis and cell cycle arrest. Finally, we identified predicted important targets of the restricted miRNA signature which are part of potential targetable enriched pathways. Altogether these results suggest that a restricted miRNA signature could provide a complementary approach, using circulating miRNAs from blood, to help patients diagnosis and monitoring of brain tumour growth.