Neuroblastoma and the epigenome

Fetahu, Irfete S.; Taschner‐Mandl, Sabine

doi:10.1007/s10555-020-09946-y

Cited by 57 publications

(41 citation statements)

References 195 publications

(225 reference statements)

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“…Insight into the biology of NBL initiation and progression may help improve the survival of NBL patients. Previous studies have shown that MYCN amplification, copy number alterations, and rearrangements of oncology genes are putative causes contributing to NBL ( Fetahu and Taschner-Mandl, 2021 ). A large-scale study demonstrated that patients aged >18 months at diagnosis had a low survival rate ( Moroz et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Five-RNA–Based Signature and Identification of Candidate Drugs for Neuroblastoma

Zhang

et al. 2021

Front. Genet.

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Neuroblastoma (NBL) originating from the sympathetic nervous system is the most prevalent solid tumor in infancy. Although there is sufficient variability in prognosis among different age pyramids, age-related gene expression profiles and biomarkers remain poorly explored. The present study aimed to construct a signature based on differentially expressed genes (DEGs) between two age groups in NBL. Univariate Cox regression, multivariate Cox regression, and LASSO analyses were used to identify the optimal prognostic factors. The prediction ability of the model was assessed using the receiver operating characteristic (ROC) curve and C-index. Functional enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes and gene ontology databases. A total of 1,160 DEGs were identified between the two groups, and 204 DEGs impacted the survival of NBL. Functional enrichment analysis revealed that the DEGs were involved in retinol metabolism, cholesterol metabolism, and glycolysis/gluconeogenesis pathways. Five RNAs, namely F8A3, PDF, ANKRD24, FAXDC2, and TMEM160 were recruited into the signature. They were correlated with COG risk classification, INSS stage, and histology. MYCN amplification was linked to FAXDC2, TMEM160, PDF, and F8A3. The expression levels of ANKRD24, PDF, and TMEM160 were lower in the hyperdiploid groups. Only FAXDC2 levels were different in the different MKI grades. The ROC curve showed that the five-RNA–based signatures effectively predicted the OS of NBL (3-years AUC = 0.791, 5-years AUC = 0.816) in the TARGET cohort. The predictive capability was also validated by the GSE49711 cohort (3-years AUC = 0.851, 5-years AUC = 0.848). The C-index in the TARGET and GSE49711 cohorts was 0.749 and 0.809, respectively. The potential mechanisms of the five RNAs were also explored via gene set enrichment analysis, and candidate drugs targeting the five genes, including dabrafenib, vemurafenib, and bafetinib, were screened. In conclusion, we constructed a five-RNA–based signature to predict the survival of NBL and screened candidate agents against NBL.

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Section: Discussionmentioning

confidence: 99%

Development and Validation of a Five-RNA–Based Signature and Identification of Candidate Drugs for Neuroblastoma

Zhang

et al. 2021

Front. Genet.

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“…Medulloblastoma is the most commonly seen embryonal tumor in children (approximately 25% of all brain malignancies in children), but it represents < 1% in adults (mainly in young adults < 40 years old) [76,77]. Neuroblastoma is another embryonic cancer involving the sympathetic nervous system that is mainly seen in infants and young children [78]. As metformin is only approved for the treatment of type 2 diabetes mellitus, which is not commonly seen in children, we have excluded patients aged < 25 years in the study (Figure 1).…”

Section: Limitationsmentioning

confidence: 99%

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

Tseng

2021

Biomolecules

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The risk of malignant brain tumors associated with metformin use has rarely been investigated in humans. This retrospective cohort study investigated such an association. Patients with new-onset type 2 diabetes mellitus diagnosed from 1999 to 2005 in the nationwide database of Taiwan’s national health insurance were used to enroll study subjects. We first identified an unmatched cohort of 153,429 ever users and 16,222 never users of metformin. A cohort of 16,222 ever users and 16,222 never users matched on propensity score was then created from this unmatched cohort. All patients were followed up from 1 January 2006 until 31 December 2011. The incidence density was calculated and hazard ratios were derived from Cox regression incorporated with the inverse probability of treatment weighting using a propensity score. The results showed that 27 never users and 155 ever users developed malignant brain tumors in the unmatched cohort. The incidence rate was 37.11 per 100,000 person-years in never users and 21.39 per 100,000 person-years in ever users. The overall hazard ratio comparing ever users versus never users was 0.574 (95% confidence interval: 0.381–0.863). The respective hazard ratios comparing the first (<27.13 months), second (27.13–58.33 months), and third (>58.33 months) tertiles of cumulative duration of metformin therapy versus never users were 0.897 (0.567–1.421), 0.623 (0.395–0.984), and 0.316 (0.192–0.518). In the matched cohort, the overall hazard ratio was 0.317 (0.149–0.673) and the respective hazard ratios were 0.427 (0.129–1.412), 0.509 (0.196–1.322), and 0.087 (0.012–0.639) for the first, second, and third tertile of cumulative duration of metformin therapy. In conclusion, this study shows a risk reduction of malignant brain tumors associated with metformin use in a dose–response pattern. The risk reduction is more remarkable when metformin has been used for approximately 2–5 years.

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“…Many GWAS-defined neuroblastoma susceptibility genes have been identified including CASC15 , BRCA1 -associated RING domain protein 1 ( BARD1 ), LMO1 , DUSP12 , DDX4 , IL31RA , HSD17B12 , HACE1 , LIN28B , LINC00340 , LOC729177 ( FLJ44180 ), and NEFL . These genes display oncogenic or tumor-suppressive functions related to the disease (43) , (44) . The discovery of these susceptibility loci demonstrates the utility of analyzing GWAS signals for clues into the underlying biology driving neuroblastoma genesis.…”

Section: Genetic Risk Factorsmentioning

confidence: 99%

Molecular Basis and Clinical Features of Neuroblastoma

2021

JMA J

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Neuroblastoma, a neoplasm of the sympathetic nervous system, originates from neuroblastoma stem cells during embryogenesis. It exhibits unique clinical features including a tendency for spontaneous regression of tumors in infants and a high frequency of metastatic disease at diagnosis in patients aged over 18 months. Genetic risk factors and epigenetic dysregulation also play a significant role in the development of neuroblastoma. Over the past decade, our understanding of this disease has advanced considerably. This has included the identification of chromosomal copy number aberrations specific to neuroblastoma development, risk groups, and disease stage. However, high-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. New therapeutic approaches have been developed, either as alternatives to conventional chemotherapy or in combination, to overcome the dismal prognosis. Particularly promising strategies are targeted therapies that directly affect cancer cells or cancer stem cells while exhibiting minimal effect on healthy cells. This review summarizes our understanding of neuroblastoma biology and prognostic features and focuses on novel therapeutic strategies for this intractable disease.

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Neuroblastoma and the epigenome

Cited by 57 publications

References 195 publications

Development and Validation of a Five-RNA–Based Signature and Identification of Candidate Drugs for Neuroblastoma

Development and Validation of a Five-RNA–Based Signature and Identification of Candidate Drugs for Neuroblastoma

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

Molecular Basis and Clinical Features of Neuroblastoma

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