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ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

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  • Aniello Federico
  • Christian Thomas
  • Katarzyna Miskiewicz
  • Niklas Woltering
  • Francesca Zin
  • Karolina Nemes
  • Brigitte Bison
  • Pascal D Johann
  • Debra Hawes
  • Susanne Bens
  • Uwe Kordes
  • Steffen Albrecht
  • Hildegard Dohmen
  • Peter Hauser
  • Kathy Keyvani
  • Frank K H van Landeghem
  • Eva Løbner Lund
  • David Scheie
  • Christian Mawrin
  • Camelia-Maria Monoranu
  • Benedicte Parm Ulhøi
  • Torsten Pietsch
  • Harald Reinhard
  • Markus J Riemenschneider
  • Astrid Sehested
  • David Sumerauer
  • Reiner Siebert
  • Werner Paulus
  • Michael C Frühwald
  • Marcel Kool
  • Martin Hasselblatt
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Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

Original languageEnglish
JournalActa Neuropathologica
Volume143
Issue number6
Pages (from-to)697-711
Number of pages15
ISSN0001-6322
DOIs
Publication statusPublished - Jun 2022

Bibliographical note

© 2022. The Author(s).

    Research areas

  • ASCL1, Atypical teratoid/rhabdoid tumor, DNA methylation profiling, Gene expression, GFAP, Neuroradiology, OLIG2, Overall survival, Prognosis, Sonic hedgehog

ID: 77659324