Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor
Standard
Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor. / Thomas, Christian; Oehl-Huber, Kathrin; Bens, Susanne; Soschinski, Patrick; Koch, Arend; Nemes, Karolina; Oyen, Florian; Kordes, Uwe; Kool, Marcel; Frühwald, Michael C; Hasselblatt, Martin; Siebert, Reiner.
In: GENE CHROMOSOME CANC, Vol. 60, No. 8, 08.2021, p. 586-590.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor
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
N1 - © 2021 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
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.
U2 - 10.1002/gcc.22954
DO - 10.1002/gcc.22954
M3 - SCORING: Journal article
C2 - 33896072
VL - 60
SP - 586
EP - 590
JO - GENE CHROMOSOME CANC
JF - GENE CHROMOSOME CANC
SN - 1045-2257
IS - 8
ER -