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001     168504
005     20240229133610.0
024 7 _ |a 10.1002/gcc.22954
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024 7 _ |a 1045-2257
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024 7 _ |a 1098-2264
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037 _ _ |a DKFZ-2021-00936
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Thomas, Christian
|0 0000-0002-6642-7774
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245 _ _ |a Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor.
260 _ _ |a New York, NY
|c 2021
|b Wiley-Liss
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336 7 _ |a Journal Article
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500 _ _ |a 2021 Aug;60(8):586-590
520 _ _ |a 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.
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650 _ 7 |a Alu element
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650 _ 7 |a SMARCB1
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650 _ 7 |a transposable element insertion
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650 _ 7 |a typical teratoid/rhabdoid tumor
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700 1 _ |a Oehl-Huber, Kathrin
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700 1 _ |a Bens, Susanne
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700 1 _ |a Soschinski, Patrick
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700 1 _ |a Koch, Arend
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700 1 _ |a Nemes, Karolina
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700 1 _ |a Oyen, Florian
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700 1 _ |a Kordes, Uwe
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700 1 _ |a Kool, Marcel
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700 1 _ |a Frühwald, Michael C
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700 1 _ |a Hasselblatt, Martin
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700 1 _ |a Siebert, Reiner
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773 _ _ |a 10.1002/gcc.22954
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