Journalartikel
Autorenliste: 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 Lobner; Scheie, David; Mawrin, Christian; Monoranu, Camelia-Maria; Ulhoi, Benedicte Parm; Pietsch, Torsten; Reinhard, Harald; Riemenschneider, Markus J.; Sehested, Astrid; Sumerauer, David; Siebert, Reiner; Paulus, Werner; Fruehwald, Michael C.; Kool, Marcel; Hasselblatt, Martin
Jahr der Veröffentlichung: 2022
Seiten: 697-711
Zeitschrift: Acta Neuropathologica
Bandnummer: 143
Heftnummer: 6
ISSN: 0001-6322
eISSN: 1432-0533
Open Access Status: Hybrid
DOI Link: https://doi.org/10.1007/s00401-022-02424-5
Verlag: Springer
Abstract:
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.
Zitierstile
Harvard-Zitierstil: Federico, A., Thomas, C., Miskiewicz, K., Woltering, N., Zin, F., Nemes, K., et al. (2022) ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance, Acta Neuropathologica, 143(6), pp. 697-711. https://doi.org/10.1007/s00401-022-02424-5
APA-Zitierstil: Federico, A., Thomas, C., Miskiewicz, K., Woltering, N., Zin, F., Nemes, K., Bison, B., Johann, P., Hawes, D., Bens, S., Kordes, U., Albrecht, S., Dohmen, H., Hauser, P., Keyvani, K., van Landeghem, F., Lund, E., Scheie, D., Mawrin, C., ...Hasselblatt, M. (2022). ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance. Acta Neuropathologica. 143(6), 697-711. https://doi.org/10.1007/s00401-022-02424-5
Schlagwörter
ASCL1; Atypical teratoid; ATYPICAL TERATOID/RHABDOID TUMORS; DNA methylation profiling; GFAP; LOCATION; Neuroradiology; OLIG2; Overall survival; rhabdoid tumor; SONIC HEDGEHOG; SURROGATES
