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| 001 | 179883 | ||
| 005 | 20240229145557.0 | ||
| 024 | 7 | _ | |a 10.1007/s00401-022-02424-5 |2 doi |
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| 100 | 1 | _ | |a Federico, Aniello |0 P:(DE-He78)32c5110cd42ee8a96b18a3e8909bd0a9 |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance. |
| 260 | _ | _ | |a Heidelberg |c 2022 |b Springer |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1654168856_19461 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a #EA:B062#LA:B062# / 2022 Jun;143(6):697-711 |
| 520 | _ | _ | |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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| 650 | _ | 7 | |a ASCL1 |2 Other |
| 650 | _ | 7 | |a Atypical teratoid/rhabdoid tumor |2 Other |
| 650 | _ | 7 | |a DNA methylation profiling |2 Other |
| 650 | _ | 7 | |a GFAP |2 Other |
| 650 | _ | 7 | |a Gene expression |2 Other |
| 650 | _ | 7 | |a Neuroradiology |2 Other |
| 650 | _ | 7 | |a OLIG2 |2 Other |
| 650 | _ | 7 | |a Overall survival |2 Other |
| 650 | _ | 7 | |a Prognosis |2 Other |
| 650 | _ | 7 | |a Sonic hedgehog |2 Other |
| 700 | 1 | _ | |a Thomas, Christian |b 1 |
| 700 | 1 | _ | |a Miskiewicz, Katarzyna |b 2 |
| 700 | 1 | _ | |a Woltering, Niklas |b 3 |
| 700 | 1 | _ | |a Zin, Francesca |b 4 |
| 700 | 1 | _ | |a Nemes, Karolina |b 5 |
| 700 | 1 | _ | |a Bison, Brigitte |b 6 |
| 700 | 1 | _ | |a Johann, Pascal D |0 P:(DE-He78)3fdc3623477264cb5d0e14f256dbfbb8 |b 7 |u dkfz |
| 700 | 1 | _ | |a Hawes, Debra |b 8 |
| 700 | 1 | _ | |a Bens, Susanne |b 9 |
| 700 | 1 | _ | |a Kordes, Uwe |b 10 |
| 700 | 1 | _ | |a Albrecht, Steffen |b 11 |
| 700 | 1 | _ | |a Dohmen, Hildegard |b 12 |
| 700 | 1 | _ | |a Hauser, Peter |b 13 |
| 700 | 1 | _ | |a Keyvani, Kathy |b 14 |
| 700 | 1 | _ | |a van Landeghem, Frank K H |b 15 |
| 700 | 1 | _ | |a Lund, Eva Løbner |b 16 |
| 700 | 1 | _ | |a Scheie, David |b 17 |
| 700 | 1 | _ | |a Mawrin, Christian |b 18 |
| 700 | 1 | _ | |a Monoranu, Camelia-Maria |b 19 |
| 700 | 1 | _ | |a Parm Ulhøi, Benedicte |b 20 |
| 700 | 1 | _ | |a Pietsch, Torsten |b 21 |
| 700 | 1 | _ | |a Reinhard, Harald |b 22 |
| 700 | 1 | _ | |a Riemenschneider, Markus J |b 23 |
| 700 | 1 | _ | |a Sehested, Astrid |b 24 |
| 700 | 1 | _ | |a Sumerauer, David |b 25 |
| 700 | 1 | _ | |a Siebert, Reiner |b 26 |
| 700 | 1 | _ | |a Paulus, Werner |b 27 |
| 700 | 1 | _ | |a Frühwald, Michael C |b 28 |
| 700 | 1 | _ | |a Kool, Marcel |0 P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8 |b 29 |e Last author |u dkfz |
| 700 | 1 | _ | |a Hasselblatt, Martin |0 0000-0003-2707-8484 |b 30 |
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