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Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma
Author(s) -
Bellini Angela,
BessoltaneBentahar Nadia,
Bhalshankar Jaydutt,
Clement Nathalie,
Raynal Virginie,
Baulande Sylvain,
Bernard Virginie,
Danzon Adrien,
Chicard Mathieu,
ColmetDaage Léo,
Pierron Gaelle,
Le Roux Laura,
Planchon Julien M.,
Combaret Valérie,
Lapouble Eve,
Corradini Nadège,
Thebaud Estelle,
Gambart Marion,
ValteauCouanet Dominique,
Michon Jean,
LouisBrennetot Caroline,
JanoueixLerosey Isabelle,
Defachelles AnneSophie,
Bourdeaut Franck,
Delattre Olivier,
Schleiermacher Gudrun
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32361
Subject(s) - atrx , smarca4 , exome sequencing , arid1a , epigenetics , biology , chromatin remodeling , carcinogenesis , indel , gene , genome , genetics , exome , cancer research , computational biology , bioinformatics , mutation , single nucleotide polymorphism , genotype
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.