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Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations


Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

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We thank the Genomics and Proteomics Core Facility of the German Cancer Research Center (DKFZ) for the performance of methylation analyses and Dr. Stefan Uhrig and Dr. Gnana Prakash Balasubramanian for the help with the detection of gene fusions in the gene panel sequencing raw data. Part of this work was undertaken at UCLH/UCL which received funding from the National Institute of Health Research (NIHR) (Sebastian Brandner). We thank the DKFZ Heidelberg Center for Personalized Oncology (DKFZ-HIPO) for technical support and funding through HIPO_036. In other parts, this work was supported by an Illumina Medical Research Grant and the German Cancer Consortium (DKTK) joint funding project ‘Next Generation Molecular Diagnostics of Malignant Gliomas’.

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Correspondence to David Capper.

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David T. W. Jones, Andreas von Deimling and David Capper share senior authorship.

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Reinhardt, A., Stichel, D., Schrimpf, D. et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 136, 273–291 (2018).

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  • Anaplastic pilocytic astrocytoma
  • Pilocytic astrocytoma with anaplasia
  • Methylation profile based classification
  • Panel sequencing
  • ATRX
  • BRAF
  • NF1
  • FGFR1
  • MGMT
  • CDKN2A/B
  • Molecular characterization
  • DNA copy number alterations