TY  - JOUR
AU  - Thomas, Christian
AU  - Oehl-Huber, Kathrin
AU  - Bens, Susanne
AU  - Soschinski, Patrick
AU  - Koch, Arend
AU  - Nemes, Karolina
AU  - Oyen, Florian
AU  - Kordes, Uwe
AU  - Kool, Marcel
AU  - Frühwald, Michael C
AU  - Hasselblatt, Martin
AU  - Siebert, Reiner
TI  - Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor.
JO  - Genes, chromosomes & cancer
VL  - 60
IS  - 8
SN  - 1098-2264
CY  - New York, NY
PB  - Wiley-Liss
M1  - DKFZ-2021-00936
SP  - 586-590
PY  - 2021
N1  - 2021 Aug;60(8):586-590
AB  - Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which may be also present in the germline (rhabdoid tumor predisposition syndrome 1), as well as somatic copy-number neutral loss of heterozygosity (LOH). In some SMARCB1-deficient AT/RT underlying biallelic mutations cannot be identified. Here we report the case of a 24-months-old girl diagnosed with a large brain tumor. The malignant rhabdoid tumor showed loss of nuclear SMARCB1/INI1 protein expression and the diagnosis of AT/RT was confirmed by DNA methylation profiling. While FISH, MLPA, Sanger sequencing and DNA methylation data-based imbalance analysis did not disclose alterations affecting SMARCB1, OncoScan array analysis revealed a 28.29 Mb sized region of copy-number neutral LOH on chromosome 22q involving the SMARCB1 locus. Targeted next-generation sequencing did also not detect a single nucleotide variant but instead revealed insertion of an AluY element into exon 2 of SMARCB1. Specific PCR-based Sanger sequencing verified the Alu insertion (SMARCB1 c.199_200 Alu ins) resulting in a frame-shift truncation not present in the patient's germline. In conclusion, transposable element insertion represents a hitherto not widely recognized mechanism of SMARCB1 disruption in AT/RT, which might not be detected by several widely applied conventional diagnostics assays. This finding has particular clinical implications, if rhabdoid predisposition syndrome 1 is suspected, but germline SMARCB1 alterations cannot be identified. This article is protected by copyright. All rights reserved.
KW  - Alu element (Other)
KW  - SMARCB1 (Other)
KW  - transposable element insertion (Other)
KW  - typical teratoid/rhabdoid tumor (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33896072
DO  - DOI:10.1002/gcc.22954
UR  - https://inrepo02.dkfz.de/record/168504
ER  -