Premium
Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor
Author(s) -
Thomas Christian,
OehlHuber Kathrin,
Bens Susanne,
Soschinski Patrick,
Koch Arend,
Nemes Karolina,
Oyen Florian,
Kordes Uwe,
Kool Marcel,
Frühwald Michael C.,
Hasselblatt Martin,
Siebert Reiner
Publication year - 2021
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22954
Subject(s) - smarcb1 , atypical teratoid rhabdoid tumor , sanger sequencing , biology , germline , loss of heterozygosity , genetics , alu element , dna methylation , germline mutation , multiplex ligation dependent probe amplification , cancer research , mutation , exon , epigenetics , genome , gene , allele , human genome , chromatin remodeling , medulloblastoma , gene expression
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.