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. 2019 Nov 15;145(10):2781-2791.
doi: 10.1002/ijc.32361. Epub 2019 May 31.

Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

Angela Bellini  1   2   3 , Nadia Bessoltane-Bentahar  1   2   3 , Jaydutt Bhalshankar  1   2   3 , Nathalie Clement  1   2   3 , Virginie Raynal  4   5 , Sylvain Baulande  6 , Virginie Bernard  7 , Adrien Danzon  1   2   3 , Mathieu Chicard  1   2   3 , Léo Colmet-Daage  1   2   3 , Gaelle Pierron  8 , Laura Le Roux  8 , Julien M Planchon  3   7 , Valérie Combaret  9 , Eve Lapouble  3   8 , Nadège Corradini  10 , Estelle Thebaud  11 , Marion Gambart  12 , Dominique Valteau-Couanet  13 , Jean Michon  3 , Caroline Louis-Brennetot  2   3   4 , Isabelle Janoueix-Lerosey  2   3   4 , Anne-Sophie Defachelles  14 , Franck Bourdeaut  1   2   3 , Olivier Delattre  2   3   4   8 , Gudrun Schleiermacher  1   2   3
Affiliations

Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

Angela Bellini et al. Int J Cancer. .

Abstract

In neuroblastoma (NB), genetic alterations in chromatin remodeling (CRGs) and epigenetic modifier genes (EMGs) have been described. We sought to determine their frequency and clinical impact. Whole exome (WES)/whole genome sequencing (WGS) data and targeted sequencing (TSCA®) of exonic regions of 33 CRGs/EMGs were analyzed in tumor samples from 283 NB patients, with constitutional material available for 55 patients. The frequency of CRG/EMG variations in NB cases was then compared to the Genome Aggregation Database (gnomAD). The sequencing revealed SNVs/small InDels or focal CNAs of CRGs/EMGs in 20% (56/283) of all cases, occurring at a somatic level in 4 (7.2%), at a germline level in 12 (22%) cases, whereas for the remaining cases, only tumor material could be analyzed. The most frequently altered genes were ATRX (5%), SMARCA4 (2.5%), MLL3 (2.5%) and ARID1B (2.5%). Double events (SNVs/small InDels/CNAs associated with LOH) were observed in SMARCA4 (n = 3), ATRX (n = 1) and PBRM1 (n = 1). Among the 60 variations, 24 (8.4%) targeted domains of functional importance for chromatin remodeling or highly conserved domains but of unknown function. Variations in SMARCA4 and ATRX occurred more frequently in the NB as compared to the gnomAD control cohort (OR = 4.49, 95%CI: 1.63-9.97, p = 0.038; OR 3.44, 95%CI: 1.46-6.91, p = 0.043, respectively). Cases with CRG/EMG variations showed a poorer overall survival compared to cases without variations. Genetic variations of CRGs/EMGs with likely functional impact were observed in 8.4% (24/283) of NB. Our case-control approach suggests a role of SMARCA4 as a player of NB oncogenesis.

Keywords: SMARCA4; SWI/SNF; chromatin remodeling complex; epigenetic modifier; neuroblastoma.

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Figures

Figure 1
Figure 1
Genetic variations in chromatin remodeling and epigenetic modifier genes across a series of 283 NB patients and 30 NB cell lines analyzed by TSCA and/or WGS/WES approaches. In the lower part of the figure, genes found to be altered (n = 14) are arranged in rows; cases for whom a genetic variation is detected in the studied genes (n = 56) are arranged in columns, respectively. The 60 SNVs, InDels, and focal CNAs detected in the 56 cases are represented by colored cases. Double events (SNV/inDels and LOH) are represented by colored cases surrounded by a black square. In the lower part of the graph, the 9 SNVs, InDels and CNAs detected in 7 NB cell lines are represented. The overall frequencies are indicated in the upper half of the figure. Nonsynonymous SNVs are represented in green, stop‐gain SNVs are represented in red, InDels are represented in blue, focal CNA in purple and large deletions in brown. The right data grid summarizes clinical information of each neuroblastoma sample.
Figure 2
Figure 2
Example of double event detection (SNV and copy number loss in SMARCA4 gene) by TSCA and aCGH data analysis in NBSW80. (a) The IGV profile from TSCA analysis revealed the presence of one SNV in SMARCA4 (C>T; chr19: 11132500) gene with variant allele fraction of 87%. (b) The comparison between the copy number profiles obtained by TSCA revealed a second event with copy number loss in the SMARCA4 gene.
Figure 3
Figure 3
Partial loss event detected in MLL2 gene in CLB‐Re NB cell line. (a) The copy number profile obtained by TSCA shows the presence of a partial loss starting in MLL2 gene. (b) SNP6.0 array‐based copy number encompassing the Chromosome 12 confirms the presence of a large loss with a breakpoint within the MLL2 gene.
Figure 4
Figure 4
Example of double event (LOH and SNV in SMARCA4 gene) in SKNFI NB cell line. (a) The IGV profile from TSCA ampliseq analysis revealed the presence of one SNV in SMARCA4 gene (C>T; Chr19: 11170813) with variant allele fraction of 99%. (b) The copy number profile obtained by TSCA shows the presence of a second event with copy number loss in the same gene. (c) Immunoblot of SMARCA4 expression in different neuroblastoma and nonneuroblastoma cell lines. BIN67: Small cell carcinoma of the ovary of hypercalcemic type; A549: lung carcinoma; SKNSH, SKNFI, SKNBE(2C), IMR32 and TGW: neuroblastoma. (d) SNVs, inDels and focal CNAs identified in SMARCA4 gene mapping functional domains in patients enrolled in the study.
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