Histological Anaplasia and Chromosome 6 Chromothripsis as Predictive Factors of Aggressivity in Low-grade Glioma, MYB/MYBL1-Altered

In the Central Nervous System (CNS), MYB/MYBL1 alterations are found in two tumor types: angiocentric glioma (AG), and diffuse astrocytoma (DA). These tumors share clinical features (mainly epileptic pediatric tumors located in the supratentorial area), a histopathological pattern (AG can look like DA) and seem to be associated with comparably favorable prognoses. However, aggressive cases of AG have been reported in the literature, one of them harboring a MYB::QKI fusion. This study aims to compare and contrast aggressive cases of low-grade gliomas (LGGs), MYB/MYBL1-altered to typically indolent cases in order to identify factors (clinical, radiological or histomolecular) associated with aggressive forms of AG and DA. We retrospectively reviewed and fully characterized 28 LGGs (14 AGs and 14 DAs) with MYB/MYBL1 alterations in terms of clinical course, radiology, histopathology and molecular biology (including DNA-methylation profiling). While most AGs and DAs in our cohort had a favorable oncological outcome, we describe three cases of AG and one case of DA with tumor progression and one terminal case of AG. Initial signs of histopathological anaplasia were exclusively found in aggressive AGs (2/3) but their significance in DA is unclear as they were encountered in the aggressive case but also in two indolent cases, and because DA seem to respond well to chemotherapy. Two aggressive AGs also were found to have a chromosome 6 chromothripsis and harbored additional molecular alterations in their initial tumor sample (KRAS, hTERT, and TP53 mutations). No radiological pattern, fusion partner or methylation cluster was associated with progression in LGG, MYB/MYBL1-altered. These cases with an aggressive clinical course raise the question of potential higher grades of LGG, MYB/MYBL1-altered, which need to be confirmed by additional reports.