Page 178 - Molecular features of low-grade developmental brain tumours

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CHAPTER 7
control, which might contribute to the observed clinical differences in patients with TSC1/TSC2 mutation. Additionally, we did not find any differences in overall expression of inflammation, mTOR activation, glial and neuronal markers between TSC1/TSC2 mutated SEGAs. However, it must be noted that we only evaluated the positive area of the tumour and not the number of cells effected or the positivity within cells. It has been suggested that TSC1/TSC2 epigenetic silencing might contribute to tumour formation in TSC and could explain cases where the second hit mutation in TSC1/TSC2 is not found 34,35. In accordance with a previous study, we did not find evidence of epigenetic silencing of TSC1 or TSC2 in SEGAs 27.
Figure 1. Methylation profile of TSC tubers. a. Principle component analysis (PCA) plot of all CpGs and b. a heatmap based on the top 5% most variable CpGs showing the clustering of tubers and control
cortex. Not all variance could be explained by the diagnosis (tuber or control cortex).
The ERK/MAPK pathway is often affected in pLGGs and LEATs, including mutations in the BRAF oncogene, such as the the BRAF c.1799T>A (p.V600E; BRAFV600E) mutation 36-38. This mutation results in constitutive activation of ERK/MAPK signaling pathway and is found in PA, PXA, GGs (shown also in chapter 6), DIG, and DNET 1,39-43. In chapter 2 we assessed the prevalence of the BRAFV600E mutation in a large cohort of TSC related SEGAs and found no evidence of either BRAFV600E or other mutations in BRAF. A previous study reported the BRAFV600E mutation in a small set of SEGAs of which only two were diagnosed with definite TSC 41. Therefore, our results suggest that SEGAs derived from patients with TSC, are negative for the BRAFV600E mutation. Recently, we showed that the overall mutation burden is low in SEGAs, which is similar to other pediatric brain tumours 26,44. This suggests that other
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