Clinical features of ATRX or DAXX mutated neuroblastoma

Kurihara, Sho; Hiyama, Eiso; Onitake, Yoshiyuki; Yamaoka, Emi; Hiyama, Keiko

doi:10.1016/j.jpedsurg.2014.09.029

Cited by 48 publications

(39 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Until recently, the impact of chromatin remodeling on telomere lengthening mechanisms has not been fully appreciated. A recent study reported that inactivation of the chromatin remodeler ATRX critically impairs ALT processes in NB . Our studies now suggest a role for ARID1A in reducing telomere lengthening in NB by recruitment of the transcriptional suppressor SIN3A to the TERT promoter.…”

Section: Discussionsupporting

confidence: 68%

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

Bui

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

Aggressive, high‐risk neuroblastoma (NB) exhibits an immature differentiation state, profound epigenetic dysregulation and high telomerase activity. It has been suggested that aggressive NB may be treatable by inducing differentiation whereas therapeutic targeting of telomerase is under investigation for multiple cancer types. While epigenetic regulation of the telomerase reverse transcriptase (TERT) promoter has been described in high‐risk NB, the exact molecular mechanisms are still not completely understood. Here we used quantitative real‐time polymerase chain reaction (PCR), chromatin immunoprecipitation qPCR, quantitative telomeric repeat amplification protocol, and immunoblot techniques to investigate epigenetic regulation of TERT in wild‐type and genetically modified NB cell lines. We demonstrated that TERT expression is reduced during 13‐cis retinoic acid‐induced NB differentiation and that this inversely correlated with increased expression of AT‐rich interaction domain 1A (ARID1A), a subunit of the SWItch/sucrose nonfermentable chromatin remodeling complex. We showed that ARID1A directly caused suppression of TERT and was reliant on DNA binding and co‐occupancy of the TERT promoter by the SIN3 transcription regulator family member A (SIN3A) repressor complex allowing NB differentiation to proceed. Finally, using data from NB patient cohorts, we reported a significant correlation between low ARID1A expression, elevated expression of TERT, and poorly differentiated, high‐risk NB. These results provide insights into a key epigenetic pathway responsible for modulating TERT‐driven NB progression, which could represent a target for therapeutic intervention.

show abstract

Section: Discussionsupporting

confidence: 68%

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

Bui

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…Putative loss‐of‐function genetic alterations in the RNA‐helicase ATRX (α‐thalassemia/mental retardation syndrome X‐linked) have been identified in up to 10% of neuroblastomas; they are enriched in older patients and may help explain the more indolent phenotype observed in this population . Similar to other tumors, neuroblastomas that are deficient in ATRX appear to undergo the telomerase‐independent telomere maintenance mechanism termed alternate lengthening of telomeres , which may be a marker of an indolent course with primary chemotherapy resistance . Other chromatin remodeling proteins are also significantly mutated in neuroblastoma as single nucleotide alterations or deletions of the AT‐rich interactive domain 1A/1B (ARID1A/1B) genes have also been detected in a significant subset of clinically aggressive neuroblastomas .…”

Section: Somatic Mutationsmentioning

confidence: 99%

“…[40][41][42] Similar to other tumors, neuroblastomas that are deficient in ATRX appear to undergo the telomerase-independent telomere maintenance mechanism termed alternate lengthening of telomeres, which may be a marker of an indolent course with primary chemotherapy resistance. [99][100][101] Other chromatin remodeling proteins are also significantly mutated in neuroblastoma as single nucleotide alterations or deletions of the AT-rich interactive domain 1A/1B (ARID1A/1B) genes have also been detected in a significant subset of clinically aggressive neuroblastomas. 39 Other recurrent somatic mutations have been detected rarely in neuroblastoma tumors (5% of primary tumors), including genetic alterations in PTPRD, odd Oz/ten-m homolog 3 (ODZ3), protein tyrosine phosphatase nonreceptor type 11 (PTPN11), MYCN (P44L [a substitution of proline with leucine at codon 44]), and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS).…”

Section: Somatic Mutationsmentioning

confidence: 99%

Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations

Bosse

Maris

2015

Cancer

188

161

View full text Add to dashboard Cite

Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus, which has catalyzed not only a more comprehensive understanding of neuroblastoma tumorigenesis, but has also revealed novel oncogenic vulnerabilities that are being leveraged therapeutically. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN amplification, for risk stratification. Given the relative paucity of recurrent activating somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed towards aberrantly regulated pathways in relapsed disease. This review will summarize the current state of knowledge of neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma.

show abstract

“…In NB, ATRX alterations have been associated with activated alternative lengthening of telomere (ALT) . In our study, 5% (14/283) of cases showed an ATRX variation (SNV/InDel or focal CNA).…”

Section: Discussionmentioning

confidence: 48%

“…Recent reports have highlighted chromatin remodeling as an important player in oncogenesis, with the main mechanisms of action consisting in tumor suppression, but variations in CRG/EMGs might also play a role in oncogenesis via gain of function . CRG alterations have previously been identified in NB patients, targeting ARIDs , ATRX , DAXX or SMARCA4 …”

Section: Discussionmentioning

confidence: 99%

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

Bellini

Bessoltane‐Bentahar

Bhalshankar

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

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.

show abstract

Clinical features of ATRX or DAXX mutated neuroblastoma

Cited by 48 publications

References 31 publications

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations

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

Contact Info

Product

Resources

About