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000179883 1001_ $$0P:(DE-He78)32c5110cd42ee8a96b18a3e8909bd0a9$$aFederico, Aniello$$b0$$eFirst author$$udkfz
000179883 245__ $$aATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance.
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000179883 500__ $$a#EA:B062#LA:B062# / 2022 Jun;143(6):697-711
000179883 520__ $$aAtypical 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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000179883 650_7 $$2Other$$aASCL1
000179883 650_7 $$2Other$$aAtypical teratoid/rhabdoid tumor
000179883 650_7 $$2Other$$aDNA methylation profiling
000179883 650_7 $$2Other$$aGFAP
000179883 650_7 $$2Other$$aGene expression
000179883 650_7 $$2Other$$aNeuroradiology
000179883 650_7 $$2Other$$aOLIG2
000179883 650_7 $$2Other$$aOverall survival
000179883 650_7 $$2Other$$aPrognosis
000179883 650_7 $$2Other$$aSonic hedgehog
000179883 7001_ $$aThomas, Christian$$b1
000179883 7001_ $$aMiskiewicz, Katarzyna$$b2
000179883 7001_ $$aWoltering, Niklas$$b3
000179883 7001_ $$aZin, Francesca$$b4
000179883 7001_ $$aNemes, Karolina$$b5
000179883 7001_ $$aBison, Brigitte$$b6
000179883 7001_ $$0P:(DE-He78)3fdc3623477264cb5d0e14f256dbfbb8$$aJohann, Pascal D$$b7$$udkfz
000179883 7001_ $$aHawes, Debra$$b8
000179883 7001_ $$aBens, Susanne$$b9
000179883 7001_ $$aKordes, Uwe$$b10
000179883 7001_ $$aAlbrecht, Steffen$$b11
000179883 7001_ $$aDohmen, Hildegard$$b12
000179883 7001_ $$aHauser, Peter$$b13
000179883 7001_ $$aKeyvani, Kathy$$b14
000179883 7001_ $$avan Landeghem, Frank K H$$b15
000179883 7001_ $$aLund, Eva Løbner$$b16
000179883 7001_ $$aScheie, David$$b17
000179883 7001_ $$aMawrin, Christian$$b18
000179883 7001_ $$aMonoranu, Camelia-Maria$$b19
000179883 7001_ $$aParm Ulhøi, Benedicte$$b20
000179883 7001_ $$aPietsch, Torsten$$b21
000179883 7001_ $$aReinhard, Harald$$b22
000179883 7001_ $$aRiemenschneider, Markus J$$b23
000179883 7001_ $$aSehested, Astrid$$b24
000179883 7001_ $$aSumerauer, David$$b25
000179883 7001_ $$aSiebert, Reiner$$b26
000179883 7001_ $$aPaulus, Werner$$b27
000179883 7001_ $$aFrühwald, Michael C$$b28
000179883 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b29$$eLast author$$udkfz
000179883 7001_ $$00000-0003-2707-8484$$aHasselblatt, Martin$$b30
000179883 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-022-02424-5$$n6$$p697-711$$tActa neuropathologica$$v143$$x0001-6322$$y2022
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