RARE-15. Astroblastoma, MN1 altered comprises two molecularly and clinically distinct subgroups defined by the fusion partners BEND2 and CXXC5

In the recent 5th edition of the WHO classification of CNS tumors, ‘Astroblastoma, MN1 altered’ is recognized a distinct brain tumor type, occurring in children and young adults. Due to its rarity and novelty, little is known about clinical and molecular traits. Therefore, we initiated an international effort and collected tissue samples, clinical and molecular data from 176 patients with Astroblastoma, MN1 altered, identified by their distinct DNA methylation profiles. DNA methylation-based t-SNE clustering analyses revealed that Astroblastoma, MN1 altered tumors form one distinct main cluster (n=158) showing MN1:BEND2 and single cases with EWSR1:BEND2 fusions and a further adjacent, but distinct smaller cluster (n=18) mostly defined by MN1:CXXC5 fusions. Both fusion partner-defined groups show a median age of 12 years but distinct copy-number aberrations, characteristically a gain of chromosome 5 in one third of the CXXC5-fused group and a loss of chromosome 16q in one third of BEND2-fused cases. As previously reported, a vast majority of Astroblastoma, MN1 altered patients are female, which we confirm for the BEND2-fused group (85%). The CXXC5-fused group, however, shows 75% male patients. Interestingly, 9/10 tumors of the few male patients observed in the BEND2-fused group were all located infratentorially or in the spinal cord, whereas almost all female cases show a supratentorial location (85/87). Histologically, the BEND2-fused group was primarily reported as Astroblastoma (39%), whereas in the CXXC5-fused cases, 31% CNS-PNET and only 8% Astroblastoma histologies were originally assigned. Preliminary clinical analyses showed that the BEND2-fused group has a relatively good 5/10-year OS of 97%/89%, but a less favorable 5/10-year PFS of 48%/35%, in line with previous studies. Patients showing CXXC5-fused tumors (n=8) indicated 5/10-year OS and PFS rates of 83%/83% and 60%/60%, respectively. Additional survival and molecular analyses are being conducted to further characterize Astroblastoma, MN1 altered tumors and its molecular subgroups.