ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance
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ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance. / Federico, Aniello; Thomas, Christian; Miskiewicz, Katarzyna; Woltering, Niklas; Zin, Francesca; Nemes, Karolina; Bison, Brigitte; Johann, Pascal D; Hawes, Debra; Bens, Susanne; Kordes, Uwe; Albrecht, Steffen; Dohmen, Hildegard; Hauser, Peter; Keyvani, Kathy; van Landeghem, Frank K H; Lund, Eva Løbner; Scheie, David; Mawrin, Christian; Monoranu, Camelia-Maria; Parm Ulhøi, Benedicte; Pietsch, Torsten; Reinhard, Harald; Riemenschneider, Markus J; Sehested, Astrid; Sumerauer, David; Siebert, Reiner; Paulus, Werner; Frühwald, Michael C; Kool, Marcel; Hasselblatt, Martin.
in: ACTA NEUROPATHOL, Jahrgang 143, Nr. 6, 06.2022, S. 697-711.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance
AU - Federico, Aniello
AU - Thomas, Christian
AU - Miskiewicz, Katarzyna
AU - Woltering, Niklas
AU - Zin, Francesca
AU - Nemes, Karolina
AU - Bison, Brigitte
AU - Johann, Pascal D
AU - Hawes, Debra
AU - Bens, Susanne
AU - Kordes, Uwe
AU - Albrecht, Steffen
AU - Dohmen, Hildegard
AU - Hauser, Peter
AU - Keyvani, Kathy
AU - van Landeghem, Frank K H
AU - Lund, Eva Løbner
AU - Scheie, David
AU - Mawrin, Christian
AU - Monoranu, Camelia-Maria
AU - Parm Ulhøi, Benedicte
AU - Pietsch, Torsten
AU - Reinhard, Harald
AU - Riemenschneider, Markus J
AU - Sehested, Astrid
AU - Sumerauer, David
AU - Siebert, Reiner
AU - Paulus, Werner
AU - Frühwald, Michael C
AU - Kool, Marcel
AU - Hasselblatt, Martin
N1 - © 2022. The Author(s).
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
KW - Central Nervous System Neoplasms/genetics
KW - DNA Methylation
KW - Hedgehog Proteins/genetics
KW - Humans
KW - Neoplasms, Neuroepithelial/genetics
KW - Prognosis
KW - Rhabdoid Tumor/genetics
KW - SMARCB1 Protein/genetics
KW - Teratoma/genetics
U2 - 10.1007/s00401-022-02424-5
DO - 10.1007/s00401-022-02424-5
M3 - SCORING: Journal article
C2 - 35501487
VL - 143
SP - 697
EP - 711
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 6
ER -