Aneuploidy in neuroblastoma tumors is not associated with inactivating point mutations in the STAG2 gene

Djos, Anna; Fransson, Susanne; Kogner, Per; Martinsson, Tommy

doi:10.1186/1471-2350-14-102

Cited by 5 publications

(4 citation statements)

References 19 publications

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“…ATRX is part of a complex responsible for deposition of H3.3 variants at naked DNA and, hence, widely affects the expression of different genes (44). In addition, mutations in other epigenetic components, including EZH2 (45), stromal antigen 2 ( STAG2 ) (46), and AT-rich interaction domain 1AB ( ARID1A/B ) (47), are found in neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

et al. 2018

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High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death. Retinoic acid (RA)–resistant neuroblastoma cells were sensitive to GSK-J4. In addition, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Furthermore, GSK-J4 and RA combination increased differentiation and ER stress over GSK-J4 effects and limited the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, PUMA induction by GSK-J4 sensitized tumors to the B cell lymphoma 2 (BCL-2) inhibitor venetoclax, demonstrating that epigenetic-targeted therapies and BCL-2 homology domain 3 mimetics can be rationally combined to treat this high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust antineuroblastoma activity.

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Section: Discussionmentioning

confidence: 99%

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

et al. 2018

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“…Subsequently, the loss of expression of STAG2 has been reported in colorectal, gastric and prostate carcinomas; however there are few mutations in STAG2 in these carcinomas . Similarly, somatic mutation of STAG2 is rare in acute leukemias (Chung et al, 2012) and neuroblastoma tumors (Djos et al, 2013). In contrast, in myeloid neoplasms, recurrent mutations and deletions have been detected in another study (Kon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Loss of STAG2 causes aneuploidy in normal human bladder cells

Li¹,

Zhang²,

Tang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to determine how the function of human stromal antigen 2 (STAG2) plays an important role in proper chromosome separation. STAG2 mRNA in normal bladder cells and bladder tumor cells was evaluated by RT-PCR. The protein levels of STAG2 in normal bladder cells and bladder tumor cells were determined Loss of STAG2 function in cells by western blot. A cell proliferation assay was used to measure the growth of tumor cells and STAG2-inhibited normal cells, and STAG2-inhibited normal cells were subjected to karyotype analysis. Both STAG-2 mRNA and protein expression levels were lower in bladder cancer cells compared to the controls. Knockdown of STAG2 caused aneuploidy in normal bladder cells, leading to a decreased expression of the cohesin complex components SMC1, SMC3 and RAD21, but there was no obvious effect of STAG2 knockdown on cell proliferation. Our study indicated that abnormal expression of STAG2 could cause aneuploidy in normal bladder cells.

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“…EP300 is mutated in a small proportion of Rubinstein-Taybi syndrome cases [ 94 ] and in cancers exhibiting instable genomes, which can be a result of alterations to chromatin-remodeling [ 95 ]. Although inactivating point mutations in STAG2 are not likely to be directly related to aneuploidy [ 96 ], more recent studies have shown that frequent sequence variations are inversely related to chromosomal copy number changes [ 97 ]. CDK6 mutations causing clinical conditions and several cancers are involved in processes related to aneuploidization [ 98 , 99 ].…”

Section: Resultsmentioning

confidence: 99%

Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism

Iourov

Zelenova

et al. 2015

International Journal of Genomics

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Somatic genome variations (mosaicism) seem to represent a common mechanism for human intercellular/interindividual diversity in health and disease. However, origins and mechanisms of somatic mosaicism remain a matter of conjecture. Recently, it has been hypothesized that zygotic genomic variation naturally occurring in humans is likely to predispose to nonheritable genetic changes (aneuploidy) acquired during the lifetime through affecting cell cycle regulation, genome stability maintenance, and related pathways. Here, we have evaluated genomic copy number variation (CNV) in genes implicated in the cell cycle pathway (according to Kyoto Encyclopedia of Genes and Genomes/KEGG) within a cohort of patients with intellectual disability, autism, and/or epilepsy, in which the phenotype was not associated with genomic rearrangements altering this pathway. Benign CNVs affecting 20 genes of the cell cycle pathway were detected in 161 out of 255 patients (71.6%). Among them, 62 individuals exhibited >2 CNVs affecting the cell cycle pathway. Taking into account the number of individuals demonstrating CNV of these genes, a support for this hypothesis appears to be presented. Accordingly, we speculate that further studies of CNV burden across the genes implicated in related pathways might clarify whether zygotic genomic variation generates somatic mosaicism in health and disease.

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Aneuploidy in neuroblastoma tumors is not associated with inactivating point mutations in the STAG2 gene

Cited by 5 publications

References 19 publications

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

Loss of STAG2 causes aneuploidy in normal human bladder cells

Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism

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