ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

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 -