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Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous

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Abstract

Multifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) in SMARCB1 were performed in germline and tumor samples. Tumor samples underwent genome-wide DNA methylation and CNA analysis. The median age at diagnosis of 21 patients was 0.6 years. Two-thirds of ATRTs and extra-CNS MRTs were diagnosed synchronously. Although kidney tumors predominated, including two patients with bilateral involvement, at least 30% of cases lacked renal involvement. Histopathologic review confirmed MRTs in all cases and INI1 expression loss in all tumors tested. Fourteen (78%) of 18 patients tested had heterozygous germline SMARCB1 abnormalities. At least one allelic SMARCB1 abnormality was confirmed in 81 and 88% of ATRTs and extra-CNS MRTs, respectively. Unsupervised hierarchical clustering analysis of DNA methylation in 27 tumors and comparison with a reference group of 150 ATRTs classified the CNS tumors (n = 14) as sonic hedgehog (64%), tyrosinase (21%), and MYC (14%). The MYC subgroup accounted for 85% of 13 extra-CNS MRTs. Of 16 paired ATRTs and extra-CNS MRTs, the tumors in seven of eight patients showed a different pattern of genome-wide DNA methylation and/or CNAs suggestive of non-clonal origin. CNS and extra-CNS tumors had an identical SMARCB1 amplification (n = 1) or very similar DNA methylation pattern (n = 1) suggestive of clonal origin. All patients died of tumor progression. The clinical and molecular characteristics of multifocal ATRTs and extra-CNS MRTs are heterogeneous with most patients harboring a cancer predisposition. Although independent tumor origin was confirmed in most cases, metastatic spread was also documented. The recognition of their distinct molecular characteristics is critical in selecting new biologic therapies against these deadly cancers.

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Acknowledgements

This work was supported by the United States National Institutes of Health Cancer Center Support (CORE) Grant P30 CA21765 and by the American Lebanese Syrian Associated Charities (ALSAC). We thank Geoffrey Neale, PhD and Emily Walker for assistance in performing the DNA methylation studies.

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Author notes

  1. Emilia M. Pinto and Dima Hamideh contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Emilia M. Pinto, Armita Bahrami, Brent A. Orr & Gerard P. Zambetti

  2. Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Dima Hamideh, Alberto S. Pappo, Amar Gajjar & Alberto Broniscer

  3. Department of Biostatistics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Tong Lin & Stanley Pounds

  4. Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap Street, Memphis, TN, 38103, USA

    Alberto S. Pappo, Amar Gajjar & Alberto Broniscer

  5. Department of Neurological Surgery, Children’s Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA, 15224, USA

    Sameer Agnihotri & Alberto Broniscer

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  1. Emilia M. Pinto
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Correspondence to Alberto Broniscer.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

Primers and conditions used to sequence SMARCB1 (DOCX 26 kb)

Online Resource 2

Raw data of chromosomal gains and losses in 27 multifocal synchronous or metachronous tumors. Areas of copy gain are highlighted in red and those of copy loss in yellow. Light blue stripes across tumors outline recurrent areas of gains or losses in at least three tumors. While a cutoff of -0.2 or lower was considered an area of chromosomal loss, +0.2 or higher values represented areas of chromosomal gains (XLSX 485 kb)

Online Resource 3

Coronal computed tomography without contrast showing bilateral kidney involvement in patient 14 (TIFF 2020 kb)

Online Resource 4

Coronal T2-weighted magnetic resonance imaging showing pedunculated bladder mass in patient 16 (TIFF 2020 kb)

Online Resource 5

Bladder mass observed during cystoscopy in patient 16 (TIFF 316 kb)

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Pinto, E.M., Hamideh, D., Bahrami, A. et al. Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous. Acta Neuropathol 136, 315–326 (2018). https://doi.org/10.1007/s00401-018-1814-2

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