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. 2024 Nov 4;26(11):2102-2112.
doi: 10.1093/neuonc/noae122.

Postzygotic mosaicism of SMARCB1 variants in patients with rhabdoid tumors: A not-so-rare condition exposing to successive tumors

Grégory Thomson  1 , Mathilde Filser  2 , Léa Guerrini-Rousseau  3 , Arnault Tauziede-Espariat  4 , Christine Bourneix  2 , Marion Gauthier-Villars  5 , Fatoumata Simaga  5 , Kévin Beccaria  6 , Cécile Faure-Conter  7 , Aurélien Maureille  8 , Hélène Zattara-Cannoni  9 , Nicolas Andre  10 , Natacha Entz-Werle  11 , Laurence Brugieres  3 , Ludovic Mansuy  12 , Philippe Denizeau  13 , Sophie Julia  14 , Olivier Ingster  15 , Sophie Lejeune  16 , Afane Brahimi  16 , Isabelle Coupier  17 , Valérie Bonadona  18 , Olivier Delattre  19 , Julien Masliah-Planchon  2 , Franck Bourdeaut  1   20
Affiliations

Postzygotic mosaicism of SMARCB1 variants in patients with rhabdoid tumors: A not-so-rare condition exposing to successive tumors

Grégory Thomson et al. Neuro Oncol. .

Abstract

Background: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.

Methods: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.

Results: Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.

Conclusions: The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT.

Keywords: ATRT; SMARCB1; germline; mosaicism; rhabdoid tumor.

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Conflict of interest statement

The authors declare that there are no conflict of interest related to this manuscript.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Cohort overview and final germline status following germline DNA reanalysis. (A) Organizational chart for germline testing. WT = wild-type, HET = heterozygous, LDO = large deletions only, IV = intragenic variants. (B) Final germline status for LDO, IV, and all RT patients.
Figure 2.
Figure 2.
Rhabdoid tumors in patients with mosaic variants occur in the same timeframe as patients with WT sequence, and exhibit WT-like survival outcomes compared to heterozygous patients. (A) Distribution of age at RT onset in patients with heterozygous (HET), mosaic, and wild type (WT) SMARCB1 germline sequence (*P = .0180, ns = P > .05). Each dot represents a patient and the vertical line indicates the median. (B) Germline status of patients depending on age at RT onset. (C) Kaplan–Meier survival curve of patients HET, mosaic and WT for SMARCB1 in germline DNA. (D) ATRT molecular subgroup depending on patient germline status.
Figure 3.
Figure 3.
Summary of cases with second or third SMARCB1-deficient tumors. Patients previously described are indicated (patients H6 and M16). (A) Patients with heterozygous SMARCB1 germline mutation. (B) Patients with mosaic SMARCB1 germline mutation. Schw = Schwannoma, Mal. L5 tumor = malignant L5 nerve root tumor, MPNST = malignant peripheral nerve sheath tumor, Schws = schwannomatosis, Intrap = intrapontine, DOD = dead of disease, NED = no evidence of disease, AWD = alive with disease.
Figure 4.
Figure 4.
Organizational chart for establishing germline status of parents of patients harboring heterozygous SMARCB1 variants. HET = heterozygous, WT = wild-type.
See this image and copyright information in PMC

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