Ramaswamy, Vijay

Abstract Background Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined. Methods We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as “Astroblastoma, MN1-altered” under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses. Results DNA methylation analyses identified 3 groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Groups A and C. Conclusions Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency—dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.