Results

RDF/XMLNTriplesTurtleShow queryShare ▶
SubjectPredicateObject
http://purl.uniprot.org/citations/35501487http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35501487http://www.w3.org/2000/01/rdf-schema#comment"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."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.org/dc/terms/identifier"doi:10.1007/s00401-022-02424-5"xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Kool M."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Nemes K."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Thomas C."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Siebert R."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Albrecht S."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"van Landeghem F.K.H."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Hauser P."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Monoranu C.M."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Sumerauer D."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Reinhard H."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Federico A."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Paulus W."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Pietsch T."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Miskiewicz K."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Mawrin C."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Fruhwald M.C."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Hasselblatt M."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Kordes U."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Riemenschneider M.J."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Lund E.L."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Keyvani K."xsd:string
http://purl.uniprot.org/citations/35501487http://purl.uniprot.org/core/author"Sehested A."xsd:string
▶