Journal Article

DKFZ-2020-02944

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases.

Holdhof, D. ; Johann, P. D.DKFZ* ; Spohn, M. ; Bockmayr, M. ; Safaei, S. ; Joshi, P.DKFZ* ; Masliah-Planchon, J. ; Ho, B. ; Andrianteranagna, M. ; Bourdeaut, F. ; Huang, A. ; Kool, M.DKFZ* ; Upadhyaya, S. A. ; Bendel, A. E. ; Indenbirken, D. ; Foulkes, W. D. ; Bush, J. W. ; Creytens, D. ; Kordes, U. ; Frühwald, M. C. ; Hasselblatt, M. ; Schüller, U.

2021
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-020-02250-7

Abstract: Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

Keyword(s): ATRT ; BRG1 ; DNA methylation ; RNA sequencing ; Rhabdoid ; SMARCA4

Note: 2021 Feb;141(2):291-301

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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 2021

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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 ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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