Journal Article

DKFZ-2022-00945

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance.

Federico, A. (First author)DKFZ* ; Thomas, C. ; Miskiewicz, K. ; Woltering, N. ; Zin, F. ; Nemes, K. ; Bison, B. ; Johann, P. D.DKFZ* ; Hawes, D. ; Bens, S. ; Kordes, U. ; Albrecht, S. ; Dohmen, H. ; Hauser, P. ; Keyvani, K. ; van Landeghem, F. K. H. ; Lund, E. L. ; Scheie, D. ; Mawrin, C. ; Monoranu, C.-M. ; Parm Ulhøi, B. ; Pietsch, T. ; Reinhard, H. ; Riemenschneider, M. J. ; Sehested, A. ; Sumerauer, D. ; Siebert, R. ; Paulus, W. ; Frühwald, M. C. ; Kool, M. (Last author)DKFZ* ; Hasselblatt, M.

2022
Springer Heidelberg

This record in other databases:  

Please use a persistent id in citations: doi:10.1007/s00401-022-02424-5

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.

Keyword(s): ASCL1 ; Atypical teratoid/rhabdoid tumor ; DNA methylation profiling ; GFAP ; Gene expression ; Neuroradiology ; OLIG2 ; Overall survival ; Prognosis ; Sonic hedgehog

Note: #EA:B062#LA:B062# / 2022 Jun;143(6):697-711

---

Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---