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. 2018 Aug;136(2):315-326.
doi: 10.1007/s00401-018-1814-2. Epub 2018 Feb 10.

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

Emilia M Pinto  1 , Dima Hamideh  2 , Armita Bahrami  1 , Brent A Orr  1 , Tong Lin  3 , Stanley Pounds  3 , Gerard P Zambetti  1 , Alberto S Pappo  2   4 , Amar Gajjar  2   4 , Sameer Agnihotri  5 , Alberto Broniscer  6   7   8
Affiliations

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

Emilia M Pinto et al. Acta Neuropathol. 2018 Aug.

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.

Keywords: Atypical teratoid rhabdoid tumor; Children; DNA methylation; Malignant rhabdoid tumor; Multifocal.

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Figures

Fig 1
Fig 1
Unsupervised hierarchical clustering analysis of genome-wide DNA methylation in 27 central nervous system (CNS; n=14) and extra-CNS tumors (n=13) compared to 150 previously published atypical teratoid rhabdoid tumors
Fig 2
Fig 2
Unsupervised hierarchical clustering analysis of 16 paired central nervous system (CNS) and extra-CNS tumors in 8 patients
Fig 3
Fig 3
Pattern of chromosomal gains (red) and losses (blue) in the entire genome except for sex chromosomes of 16 paired central nervous system (CNS) and extra-CNS tumors. The 22 non-sex chromosomes are displayed on the left vertical axis
See this image and copyright information in PMC

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