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ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance
A. Federico, C. Thomas, K. Miskiewicz, N. Woltering, F. Zin, K. Nemes, B. Bison, PD. Johann, D. Hawes, S. Bens, U. Kordes, S. Albrecht, H. Dohmen, P. Hauser, K. Keyvani, FKH. van Landeghem, EL. Lund, D. Scheie, C. Mawrin, CM. Monoranu, B. Parm...
Jazyk angličtina Země Německo
Typ dokumentu časopisecké články
Grantová podpora
Ha3/017/20
IZKF Münster
DKH 70113981
Deutsche Krebshilfe
70114040
Deutsche Krebshilfe
- MeSH
- gen SMARCB1 genetika metabolismus MeSH
- lidé MeSH
- metylace DNA MeSH
- nádory centrálního nervového systému * genetika MeSH
- neuroepitelové nádory * genetika MeSH
- prognóza MeSH
- proteiny hedgehog genetika metabolismus MeSH
- rhabdoidní nádor * genetika MeSH
- teratom * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
Asklepios Kinderklinik Sankt Augustin Sankt Augustin Germany
Department of Neuropathology Institute for Pathology University of Würzburg 97080 Würzburg Germany
Department of Neuropathology Regensburg University Hospital Regensburg Germany
Department of Neuropathology University Giessen Giessen Germany
Department of Neuropathology University Magdeburg Magdeburg Germany
Department of Neuropathology University of Bonn Medical Centre Bonn Germany
Department of Paediatrics and Adolescent Medicine University of Copenhagen Copenhagen Denmark
Department of Pathology Aarhus University Hospital Aarhus Denmark
Department of Pathology and Laboratory Medicine Children's Hospital Los Angeles Los Angeles CA USA
Department of Pathology McGill University Montreal QC Canada
Department of Pathology Rigshospitalet Copenhagen Denmark
Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czech Republic
Department of Pediatric Oncology 2nd Department of Pediatrics Semmelweis University Budapest Hungary
Division of Paediatric Neurooncology German Cancer Research Center Heidelberg Germany
Hopp Children's Cancer Center Heidelberg Germany
Institute of Human Genetics Ulm University and Ulm University Medical Center Ulm Germany
Institute of Neuropathology University Hospital Münster Pottkamp 2 48149 Münster Germany
Institute of Neuropathology University of Duisburg Essen Essen Germany
Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands
Citace poskytuje Crossref.org
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- $a 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.
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