Page 183 - Molecular features of low-grade developmental brain tumours

and MMP19. Since the interaction of miR-320d was based on prediction tools, it could be that these MMPs are not responsive to this miRNA. Alternatively, combining miR-320d with other miRNAs predicted to target MMPs/TIMPs could be of interest in restoring the balance of the MMP/TIMP proteolytic system. Furthermore, the role of other differentially expressed miRNAs as well as other non-coding RNAs need to be further investigated.
In chapter 6, we identified higher expression of miR-519d and miR-4758 in GGs compared to control tissue, DNTs and other astrocytomas, including SEGAs and could therefore be considered as additional markers in the classification of LEATs. More recently, a decision tree based on the expression of miRNAs was proposed to help distinguish between PA, GG and DNT 90. In this study miR-4758 was confirmed as a marker to distinguish between GGs and DNTs. The PI3K/AKT3/P21 pathway, a pathway commonly deregulated in cancer, was also deregulated in GGs. In agreement with previous study, overexpression of miR-519d increased proliferation, which could be explained by the downregulation of CDKN1A, a key player of the PI3K/AKT3/P21 pathway 91. Overexpression of miR-4758 rescued the expression of CDKN1A and the associated increase in proliferation due to miR-519d, suggesting a tumour suppressive role for miR-4758.
Conclusion
In this thesis we used high-throughput RNA-Seq and methylation profiling in combination with systems-based computational approaches to investigate the molecular complexity of TSC related SEGAs. Investigating SEGAs on the level of genomics, epigenomics, transcriptomics and proteomics allowed us to identify important pathways in SEGA development/growth and gave us a good overview of the molecular background of these pediatric tumours. Therefore, such a comprehensive approach could also be interesting in the future for other low grade gliomas to get a more wholistic image of the molecular mechanisms at play. By combining both bioinformatics and wet-lab techniques in this thesis we identified the MAPK pathway as an important signaling route in SEGAs, suggesting that the MAPK pathway could be used as a target for treatment independent of, or in combination with mTOR inhibitors for TSC patients with SEGAs. This activation cannot be explained by the BRAFV600E mutation, which is a common genetic driver in GGs and other low-grade GNTs. The overexpression of LAMTOR1-5 provides initial evidence of a possible link between the MAPK and mTOR pathway in SEGAs and could therefore also play a role in other tumours where both pathways are affected. Additionally, we show how miRNAs can be used to target important pathways in SEGAs and GNTs and how they can be helpful in distinguishing certain tumour entities. In the past few years, research into the potential therapeutic value of miRNAs are encouraging and could therefore be of interest in developing new treatment strategies of SEGAs. Furthermore, with new techniques developing, such as single cell sequencing, research using multiplatform approaches can be further extended, which will increase the molecular dimensionality of our research.
GENERAL DISCUSSION
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