HG-68: COMBINED ALTERATIONS IN MAPK PATHWAY GENES, CDKN2A/B AND ATRX CHARACTERIZE ANAPLASTIC PILOCYTIC ASTROCYTOMA

Tumors with histological features of pilocytic astrocytoma but with increased mitotic activity and additional high grade features (i.e. microvascular proliferation, necrosis) have been designated anaplastic pilocytic astrocytomas (APA). Patients with such tumors are thought to have an unfavorable clinical outcome. The status of APA as a separate entity has not yet been established and molecular features have only partially been elucidated. We analyzed a large retrospective series of 98 cases with histological features of APA by genome wide DNA methylation profiling, copy number analysis, targeted sequencing and, in a subset, panel sequencing. Unsupervised hierarchical clustering analysis of 450k methylation data together with over 250 reference cases of 13 established glioma classes (glioblastoma, astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, pilocytic astrocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor and diffuse leptomeningeal glioneuronal tumor) allowed the identification of a distinct methylation cluster comprising 73 APA (“APA core group”). Most of the remaining cases clustered into other tumor classes. The median age of the APA core group was 43 years with only 6/69 (9%) of cases occurring in pediatric patients; 56/67 (84%) were located in the cerebellum. The most frequent molecular alterations were deletions of CDKN2A/B (64/73, 87%) followed by alterations of the MAPK pathway (19/24, 79%, mostly NF1 mutations and BRAF fusions) and loss of ATRX (31/69, 45%). Outcome analysis confirmed an aggressive course with 12/28 (43%) patients deceased (median survival 13 months). In summary, APA is characterized by increased patient age, predominant cerebellar location, frequent MAPK pathway alterations, CDKN2A/B deletion, ATRX loss and unfavorable prognosis.