MYCN Amplification Research Articles

The survivin-ran inhibitor LLP-3 decreases oxidative phosphorylation, glycolysis and growth of neuroblastoma cells

BackgroundNeuroblastoma (NB), the most common extracranial solid malignancy in children, carries a poor prognosis in high-risk disease, thus requiring novel therapeutic approaches. Survivin is overexpressed in NB, has pro-mitotic and anti-apoptotic functions, and impacts on oxidative phosphorylation (OXPHOS) and aerobic glycolysis. The subcellular localization and hence function of survivin is directed by the GTPase Ran.AimTo determine efficacy and modes of action of the survivin-Ran inhibitor LLP-3 as a potential novel therapy of NB.MethodsSurvivin and Ran mRNA expression in NB tumors was correlated to patient survival. Response to LLP-3 in NB cell lines was determined by assays for viability, proliferation, apoptosis, clonogenicity and anchorage-independent growth. Interaction of survivin and Ran was assessed by proximity-linked ligation assay and their subcellular distribution by confocal immunofluorescence microscopy. Expression of survivin, Ran and proteins important for OXPHOS and glycolysis was determined by Western blot, hexokinase activity by enzymatic assay, interaction of survivin with HIF-1α by co-IP, and OXPHOS and glycolysis by extracellular flux analyzer.ResultsHigh mRNA expression of survivin and Ran is correlated with poor patient survival. LLP-3 decreases viability, induces apoptosis, and inhibits clonogenic and anchorage-independent growth in NB cell lines, including those with MYCN amplification, and mutations of p53 and ALK. LLP-3 inhibits interaction of survivin with Ran, decreasing their concentration both in the cytoplasm and the nucleus. LLP-3 impairs flexibility of energy metabolism by inhibiting both OXPHOS and glycolysis. Metabolic inhibition is associated with mitochondrial dysfunction and attenuated hexokinase activity but is independent of HIF-1α.ConclusionLLP-3 attenuates interaction and concentration of survivin and Ran in NB cells. It controls NB cells with diverse genetic alterations, associated with inhibition of OXPHOS, aerobic glycolysis, mitochondrial function and HK activity. Thus, LLP-3 warrants further studies as a novel drug against NB.

Predicting MYCN amplification in paediatric neuroblastoma: development and validation of a 18F-FDG PET/CT-based radiomics signature

ObjectivesTo develop and validate an 18F-FDG PET/CT-based clinical-radiological-radiomics nomogram and evaluate its value in the diagnosis of MYCN amplification (MNA) in paediatric neuroblastoma (NB) patients.MethodsA total of 104 patients with NB were retrospectively included. We constructed a nomogram to predict MNA based on radiomics signatures, clinical and radiological features. The multivariable logistic regression and the least absolute shrinkage and selection operator (LASSO) were used for feature selection. Radiomics models are constructed using decision trees (DT), logistic regression (LR) and support vector machine (SVM) classifiers. A clinical-radiological (C-R) model was developed using clinical and radiological features. A clinical-radiological-radiomics (C-R-R) model was developed using the C-R model of the best radiomics model. The prediction performance was verified by receiver operating characteristic (ROC) curve analysis, calibration curve analysis and decision curve analysis (DCA) in the training and validation cohorts.ResultsThe present study showed that four radiomics signatures were significantly correlated with MNA. The SVM classifier was the best model of radiomics signature. The C-R-R model has the best discriminant ability to predict MNA, with AUCs of 0.860 (95% CI, 0.757–0.963) and 0.824 (95% CI, 0.657–0.992) in the training and validation cohorts, respectively. The calibration curve indicated that the C-R-R model has the goodness of fit and DCA confirms its clinical utility.ConclusionOur research provides a non-invasive C-R-R model, which combines the radiomics signatures and clinical and radiological features based on 18F-FDGPET/CT images, shows excellent diagnostic performance in predicting MNA, and can provide useful biological information with stratified therapy.Critical relevance statementRadiomic signatures of 18F-FDG-based PET/CT can predict MYCN amplification in neuroblastoma.Key points• Radiomic signatures of 18F-FDG-based PET/CT can predict MYCN amplification in neuroblastoma.• SF, LDH, necrosis and TLG are the independent risk factors of MYCN amplification.• Clinical-radiological-radiomics model improved the predictive performance of MYCN amplification.Graphical

Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures

Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.

PATH-34. CLINICOPATHOLOGIC CHARACTERIZATION OF DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA, H3-WILDTYPE AND IDH-WILDTYPE: AN AGGRESSIVE AND GENOMICALLY COMPLEX GROUP OF TUMORS AFFECTING CHILDREN AND ADULTS

Abstract Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (pHGG) was newly introduced in the 2021 WHO CNS5. pHGG is further divided into distinct methylation subtypes (MYCN, A/B, RTK1, RTK2). Compared to adult-type diffuse gliomas, relatively little is known about pHGG, especially in the adult population and we therefore aimed to more fully understand the clinicopathological spectrum of pHGG. Our cohort of methylation-profiling-confirmed pHGGs (n=299) included pediatric (n=211) and adult (n=88) populations (age range=0-79 years). The mean age was highest in the A/B subtypes (27.7 years) and lowest in the MYCN subtype (13.5 years). Median survival (18 months for the entire cohort), MGMT promoter methylation status, and history of prior radiation did not differ between the pediatric and adult populations. MGMT promoter methylation was highest in RTK1C (51%) and lowest in subtype A (0%). All those with history of prior radiation (n=37) were classified as RTK1, with subclass distribution differing between patients with history of prior radiation (RTK1A=7.3%, RTK1B=41.8%, RTK1C=50.9%) versus those without (RTK1A=41.8%, RTK1B=21.5%, RTK1C=36.7%). Interestingly, the genomic somatic copy number alteration (SCNA) load did not differ for RTK1 based on prior radiation history status. However, adult pHGG did harbor a higher SCNA load than pediatric pHGG (p< 0.01). The higher SCNA load was driven by genomic copy number losses rather than amplifications, including adult pHGG harboring more CDKN2A/B and RB1 deletions. Amplifications of MET, CDK4, PDGFRA, MYC, and KIT were present across all subtypes, but were enriched in RTK1. MYCN amplification was enriched in the MYCN subtype. EGFR, MDM4, and CDK6 amplifications did not have subtype predilection. Overall, while the pediatric and adult pHGG have similar outcomes, there are differences in their genomic structures, most notably in adult pHGG harboring a higher SCNA load. Overall, pHGG represent a biologically diverse set of clinically aggressive tumors that warrant further intensive study.

Chromosome 1p36 candidate gene ZNF436 predicts the prognosis of neuroblastoma: a bioinformatic analysis

BackgroundGenetic 1p deletion is reported in 30% of all neuroblastoma and is associated with the unfavorable prognosis of neuroblastoma. The expressions and prognosis of 1p candidate genes in neuroblastoma are unclear.MethodsPublic neuroblastoma cohorts were obtained for secondary analysis. The prognosis of 1p candidate genes in neuroblastoma was determined using Kaplan-Meier and cox regression analysis. The prediction of the nomogram model was determined using timeROC.ResultsFirst, we confirmed the bad prognosis of 1p deletion in neuroblastoma. Moreover, zinc finger protein 436 (ZNF436) located at 1p36 region was down-regulated in 1p deleted neuroblastoma and higher ZNF436 expression was associated with the longer event free survival and overall survival of neuroblastoma. The expression levels of ZNF436 were lower in neuroblastoma patients with MYCN amplification or age at diagnosis ≥ 18months, or with stage 4 neuroblastoma. ZNF436 had robust predictive values of MYCN amplification and overall survival of neuroblastoma. Furthermore, the prognostic significance of ZNF436 in neuroblastoma was independent of MYCN amplification and age of diagnosis. Combinations of ZNF436 with MYCN amplification or age of diagnosis achieved better prognosis. At last, we constructed a nomogram risk model based on age, MYCN amplification and ZNF436. The nomogram model could predict the overall survival of neuroblastoma with high specificity and sensitivity.ConclusionsChromosome 1p36 candidate gene ZNF436 was a prognostic maker of neuroblastoma.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for <PR; p=.0014). VMAT2 H-score was not significantly associated with PR or higher versus less than PR, though patients with PR or higher had lower VMAT2 staining intensity (p=.005). VMAT2 H-score was significantly lower in patients with complete response (median 40 vs. 210 for patients with <complete response; p=.0049). VMAT2 H-scores were significantly higher in ganglioneuroblastoma (vs. neuroblastoma; p=.037), differentiated/poorly differentiated tumors (vs. undifferentiated; p=.0047), and tumors lacking MYCN amplification (vs. MYCN amplified; p=.0011). Markers of lower NET and VMAT2 protein expression are associated with higher likelihood of response to 131 I-MIBG therapy in patients with relapsed/refractory neuroblastoma. Increased VMAT2 protein expression is associated with a more differentiated disease phenotype.

Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma.

MYCN amplification occurs in approximately 20-30% of neuroblastoma patients and correlates with poor prognosis. The TH-MYCN transgenic mouse model mimics the development of human high-risk neuroblastoma and provides strong evidence for the oncogenic function of MYCN. In this study, we identified mitotic dysregulation as a hallmark of tumor initiation in the pre-cancerous ganglia from TH-MYCN mice that persists through tumor progression. Single-cell quantitative-PCR of coeliac ganglia from 10-day-old TH-MYCN mice revealed overexpression of mitotic genes in a subpopulation of premalignant neuroblasts at a level similar to single cells derived from established tumors. Prophylactic treatment using antimitotic agents barasertib and vincristine significantly delayed the onset of tumor formation, reduced pre-malignant neuroblast hyperplasia, and prolonged survival in TH-MYCN mice. Analysis of human neuroblastoma tumor cohorts showed a strong correlation between dysregulated mitosis and features of MYCN amplification, such as MYC(N) transcriptional activity, poor overall survival, and other clinical predictors of aggressive disease. To explore the therapeutic potential of targeting mitotic dysregulation, we showed that genetic and chemical inhibition of mitosis led to selective cell death in neuroblastoma cell lines with MYCN over-expression. Moreover, combination therapy with antimitotic compounds and BCL2 inhibitors exploited mitotic stress induced by antimitotics and was synergistically toxic to neuroblastoma cell lines. These results collectively suggest that mitotic dysregulation is a key component of tumorigenesis in early neuroblasts, which can be inhibited by the combination of antimitotic compounds and pro-apoptotic compounds in MYCN-driven neuroblastoma.

Chelators as Antineuroblastomas Agents.

Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.

Aryl hydrocarbon receptor is a tumor promoter in MYCN-amplified neuroblastoma cells through suppression of differentiation

Neuroblastoma is the most common extracranial solid tumor in children. MYCN amplification is detected in almost half of high-risk cases and is associated with poorly differentiated tumors, poor patient prognosis and poor response to therapy, including retinoids. We identify the aryl hydrocarbon receptor (AhR) as a transcription factor promoting the growth and suppressing the differentiation of MYCN-amplified neuroblastoma. A neuroblastoma specific AhR transcriptional signature reveals an inverse correlation of AhR activity with patients' outcome, suggesting AhR activity is critical for disease progression. AhR modulates chromatin structures, reducing accessibility to regions responsive to retinoic acid. Genetic and pharmacological inhibition of AhR results in induction of differentiation. Importantly, AhR antagonism with clofazimine synergizes with retinoic acid in inducing differentiation both invitro and invivo. Thus, we propose AhR as a target for MYCN-amplified neuroblastoma and that its antagonism, combined with current standard-of-care, may result in a more durable response in patients.

Posttreatment complications in pediatric cervical neuroblastoma: A retrospective case series at a tertiary cancer center.

Neuroblastomas rarely occur as primary tumors in the cervical region. Therefore, very little has been reported regarding treatment strategies, complications, and outcomes of these cervical neuroblastomas. The goal of this study is to review the presentation, management, and outcomes of all primary cervical pediatric neuroblastoma cases at a single tertiary care center. A retrospective cohort review of all neuroblastoma patients treated at a single center were performed. All patients with primary cervical neuroblastoma were reviewed for demographic information, tumor characteristics, treatment, and outcomes. Thirty (1.8%) patients were found to have undergone treatment for cervical neuroblastoma tumors diagnosed on average at 2.1 years old. Most presented with a swollen neck/palpable mass ± Horner's syndrome. Based on features including tumor staging, N-myc proto-oncogene protein (MYCN) amplification status, histology, most were deemed intermediate or high risk. Treatment strategies centered around chemotherapeutic regimens with surgery when possible as well as various adjuvant treatments including radiation therapy, immunotherapy, bone marrow transplant, and a neuroblastoma vaccine. Ten (33.3%) of patients experienced treatment-related complications and four (13.3%) died as a result of their disease progression. All four patients were high-risk patients, two of which had MYCN amplification. Cervical neuroblastomas generally have favorable outcomes. These tumors can be treated effectively with chemotherapy and surgical intervention with various adjuvant therapies. MYCN amplification and higher stage disease presentation contribute to worse outcomes.

Machine learning methods revealed the roles of immune-metabolism related genes in immune infiltration, stemness, and prognosis of neuroblastoma.

Immunometabolism plays an important role in neuroblastoma (NB). However, the mechanism of immune-and metabolism-related genes (IMRGs) in NB remains unclear. This study aimed to explore the effects of IMRGs on the prognosis, immune infiltration and stemness of patients with NB using machine learning methods. R software (v4.2.1) was used to identify the differentially expressed IMRGs, and machine learning algorithm was used to screen the prognostic genes from IMRGs. Then we constructed a prognostic model and calculated the risk scores. The NB patients were grouped according to the prognosis scores. In addition, the genes most associated with the immune infiltration and stemness of NB were analyzed by weighted gene co-expression network analysis (WGCNA). There were 89 differentially expressed IMRGs between the MYCN amplification and the MYCN non-amplification group, among which CNR1, GNAI1, GLDC and ABCC4 were selected by machine learning algorithm to construct the prognosis model due to their better prediction effect. Both the K-M survival curve and the 5-year Receiver operating characteristic (ROC) curve indicated that the prognosis model could predict the prognosis of NB patients, and there was significant difference in immune infiltration between the two groups according to the median of risk score. We verified the effects of IMRGs on the prognosis, immune infiltration and stemness of NB. These findings could provide help for predicting prognosis and developing immunotherapy in NB.

MYCN Amplifications and Metabolic Rewiring in Neuroblastoma.

Cancer is a disease caused by (epi)genomic and gene expression abnormalities and characterized by metabolic phenotypes that are substantially different from the normal phenotypes of the tissues of origin. Metabolic reprogramming is one of the key features of tumors, including those established in the human nervous system. In this work, we emphasize a well-known cancerous genomic alteration: the amplification of MYCN and its downstream effects in neuroblastoma phenotype evolution. Herein, we extend our previous computational biology investigations by conducting an integrative workflow applied to published genomics datasets and comprehensively assess the impact of MYCN amplification in the upregulation of metabolism-related transcription factor (TF)-encoding genes in neuroblastoma cells. The results obtained first emphasized overexpressed TFs, and subsequently those committed in metabolic cellular processes, as validated by gene ontology analyses (GOs) and literature curation. Several genes encoding for those TFs were investigated at the mechanistic and regulatory levels by conducting further omics-based computational biology assessments applied on published ChIP-seq datasets retrieved from MYCN-amplified- and MYCN-enforced-overexpression within in vivo systems of study. Hence, we approached the mechanistic interrelationship between amplified MYCN and overexpression of metabolism-related TFs in neuroblastoma and showed that many are direct targets of MYCN in an amplification-inducible fashion. These results illuminate how MYCN executes its regulatory underpinnings on metabolic processes in neuroblastoma.

Impact of BCL-2 Expression on Course of Disease in Neuroblastoma.

The antiapoptotic BCL-2 protein has implications for maturation and differentiation of neural tissue and acts as a strong modulator of carcinogenesis in different tumors. Recent research focuses not only on its benefit as a prognostic factor, but also as a potential therapeutic target. The role of BCL-2 in neuroblastoma, the most common extracranial solid tumor in childhood, remains controversial. The aim of our study was to determine the gene expression level of BCL-2 in a large cohort of neuroblastoma patients and its correlation with clinical parameters. Tumor samples and clinical data were collected from 100 neuroblastoma patients treated according to the NB2004 protocol of the German Society of Pediatric Oncology and Hematology. BCL-2 gene expression levels were measured by quantitative reverse transcription polymerase chain reaction and correlated with clinical parameters. BCL-2 expression was detected in all tumor samples. Relative BCL-2 expression levels were higher in females versus males (1.839 vs. 1.342; p = 0.0143), in patients with low versus high International Neuroblastoma Staging System stage (2.051 vs. 1.463; p = 0.0206), in nonmetastatic versus metastatic disease (1.801 vs. 1.342; p = 0.0242), as well as in patients without presurgical chemotherapy (2.145 vs. 1.402; p = 0.0016), but was not associated with overall survival and MYCN amplification. Our study demonstrates the ubiquitous expression of BCL-2 in neuroblastoma and suggests the possibility for targeted therapy with BCL-2 inhibitors, even in lower-stage neuroblastoma. It also underlines the need for further research on concomitant genetic alterations for a better understanding of the impact of BCL-2 on this pediatric tumor type.

Prognostic Value of Metabolic Parameters and Textural Features in Pretreatment 18F-FDG PET/CT of Primary Lesions for Pediatric Patients with Neuroblastoma

Our study evaluated the prognostic value of the metabolic parameters and textural features in pretreatment 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) of primary lesions for pediatric patients with neuroblastoma. In total, 107 pediatric patients with neuroblastoma who underwent pretreatment 18F-FDG PET/CT were retrospectively included and analyzed. All patients were diagnosed by pathology, and baseline characteristics and clinical data were collected. The four metabolic parameters and 43 textural features of 18F-FDG PET/CT of the primary lesions were measured. The prognostic significance of metabolic parameters and other clinical variables was assessed using Cox proportional hazards regression models. Differences in progression-free survival (PFS) and overall survival (OS) in relation to parameters were examined using the Kaplan-Meier method. During a median follow-up period of 34.3 months, 45 patients (42.1%) experienced tumor recurrence or progression, and 21 patients (19.6%) died of cancer. In univariate Cox regression analysis, age, location of disease, International Neuroblastoma Risk Group Staging System (INRGSS) stage M, neuron-specific enolase (NSE), lactate dehydrogenase (LDH), four positron emission tomography (PET) metabolic parameters, and 33 textural features were significant predictors of PFS. In multivariate analysis, INRGSS stage M (hazard ratio [HR]=19.940, 95% confidence interval [CI]=2.733-145.491, P=0.003), skewness (＞0.173; PET first-order features; HR=2.938, 95% CI=1.389-6.215, P=0.005), coarseness (＞0.003; neighborhood gray-tone difference matrix; HR=0.253, 95% CI=0.132-0.484, P＜0.001), and variance (＞103.837; CT first-order gray histogram parameters; HR=2.810, 95% CI=1.160-6.807, P=0.022) were independent predictors of PFS. In univariate Cox regression analysis, gender, INRGSS stage M, MYCN amplification, NSE, LDH, two PET metabolic parameters, and five textural features were significant predictors of OS. In multivariate analysis, INRGSS stage M (HR=7.704, 95% CI=1.031-57.576, P=0.047), MYCN amplification (HR=3.011, 95% CI=1.164-7.786, P=0.023), and metabolic tumor volume (＞138.788; HR=3.930, 95% CI=1.317-11.727, P=0.014) were independent predictors of OS. The metabolic parameters and textural features in pretreatment 18F-FDG PET/CT of primary lesions are predictive of survival in pediatric patients with neuroblastoma.

LncRNA AC142119.1 facilitates the progression of neuroblastoma by epigenetically initiating the transcription of MYCN

BackgroundOncogene MYCN is closely related with malignant progression and poor prognosis of neuroblastoma (NB). Recently, long non-coding RNAs (lncRNAs) have been recognized as crucial regulators in various cancers. However, whether lncRNAs contribute to the overexpression of MYCN in NB is unclear.MethodsMicroarray analysis were applied to analyze the differentially expressed lncRNAs between MYCN-amplified and MYCN-non-amplified NB cell lines. Bioinformatic analyses were utilized to identify lncRNAs nearby MYCN locus. qRT-PCR was used to detect the expression level of lncRNA AC142119.1 in NB cell lines and tissues. Gain- and loss-of-function assays were conducted to investigate the biological effect of AC142119.1 in NB. Fluorescence in situ hybridization, RNA pull-down, RNA immunoprecipitation, mass spectrometry, RNA electrophoretic mobility shift, chromatin immunoprecipitation and chromatin isolation by RNA purification assays were performed to validate the interaction between AC142119.1 and WDR5 protein as well as MYCN promoter.ResultsAC142119.1 was significantly elevated in NB tissues with MYCN amplification, advanced INSS stage and high risk, and associated with poor survival of NB patients. Moreover, enforced expression of AC142119.1 reinforced the proliferation of NB cells in vitro and in vivo. Additionally, AC142119.1 specifically recruited WDR5 protein to interact with MYCN promoter, further initiating the transcription of MYCN and accelerating NB progression.ConclusionsWe identified a novel lncRNA AC142119.1, which promoted the progression of NB through epigenetically initiating the transcription of MYCN via interacting with both WDR5 protein and the promoter of MYCN, indicating that AC142119.1 might be a potential diagnostic biomarker and therapeutic target for NB.

Associations between neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and prognosis in patients with neuroblastoma.

Recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) is a new inflammatory marker that is effective in determining the prognosis of many solid tumors, chemotherapy responses, survival, and their recurrence rate. Therefore, we performed a retrospective study to investigate the effect of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio (PLR) on risk factors and prognosis in these patients. In this study, 246 pediatric patients with neuroblastoma who were diagnosed, treated, and followed up during 2000-2021 in Division of Pediatric Oncology, Çukurova University Faculty of Medicine, were included. Required information of patients was obtained from archive files, Mergentech hospital program, and E-pulse system. Median value for NLR was found to be 1.06, for PLR it was found as 92. The relationship of NLR values with age, stage, risk group, and Shimada was found to be statistically signifıcant with p<.001, vanillylmandelic acid (VMA) (p=.006) also depicted the signifıcant value. Likewise, the relationship of PLR values with age (p<.001), stage (p=.022), Shimada (p=.004), and N-Myc amplification (p=.039) was found to be statistically significant as well. Survival analysis showed that no statistically significant difference was observed among the higher and lower values of NLR. Survival rates were noticed to be higher in the lower values of NLR (10-year overall survival [OS] 55% vs. 49%, 10-year event-free survival (EFS) 54% vs. 43%), albeit nonsignificant. Pretreatment evaluation of NLR and PLR values in patients with neuroblastoma may be instructive in respect of prognosis and risk group.

A novel clinical tool and risk stratification system for predicting the event-free survival of neuroblastoma patients: A TARGET-based study.

Neuroblastoma (NB), considered the most common non-intracranial solid tumor in children, accounts for nearly 8% of pediatric malignancies. This study aimed to develop a simple and practical nomogram to predict event-free survival (EFS) in NB patients and establish a new risk stratification system. In this study, 763 patients primarily diagnosed with NB in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database were included and randomly assigned to a training set (70%) and a validation set (30%) in a 7:3 ratio. First, the independent prognostic factors of EFS for NB patients were identified through univariate and multivariate Cox regression analyses. Second, a nomogram was created based on these factors and was validated for calibration capability, discriminative, and clinical significance by C-curves, receiver operating characteristic (ROC) curves, and decision curve analysis. Finally, a new risk stratification system was established for NB patients based on the nomogram. The univariate Cox analysis demonstrated that NB patients with age at diagnosis >318 days, International Neuroblastoma Staging System (INSS) stage 4, DNA diploidy, MYCN amplification status, and children oncology group (COG) high-risk group had a relatively poor prognosis. However, according to the multivariate Cox regression analysis, only age, INSS stage, and DNA ploidy were independent predictive factors in NB patients regarding EFS, and a nomogram was created based on these factors. The area under the curve (AUC) values of the ROC curves for the 3-, 5-, and 10-year EFS of this nomogram were 0.681, 0.706, and 0.720, respectively. Additionally, the AUC values of individual independent prognostic factors of EFS were lower than those of the nomogram, suggesting that the developed nomogram had a higher predictive reliability for prognosis. In addition, a new risk stratification system was developed to better stratify NB patients and provide clinical practitioners with a better reference for clinical decision-making. NB patients' EFS could be predicted more accurately and easily through the constructed nomogram and event-occurrence risk stratification system, allowing clinicians to better differentiate NB patients and establish individualized treatment plans to maximize patient benefits.

Molecular genetic traits and risk factors for neuroblastoma

Neuroblastoma is the most common extracranial solid tumor in childhood, accounting for 815% of all malignant neoplasms in children. The uniqueness of the neuroblastoma etiology and pathogenesis creates significant difficulties for doctors due to the unpredictability of the course of the disease: the tumor can regress and lead to death in a short time, showing significant immunity to ongoing therapy. Early diagnosis of a tumor is necessary to understand the risk factors, the etiology, the mechanisms of neuroblastoma occurrence and further development. To date, a number of different risk factors have been identified, related both to genetic aspects and to aspects related to the course of pregnancy, birth and lifestyle of the childs parents. The list of these risk factors is still incomplete and research to identify new factors continues to this day. Morphological and molecular genetic diagnostics play an important role in this. Undifferentiated and low-differentiated variants of neuroblastoma are often associated with MYCN amplification and other chromosomal aberrations determined by molecular genetic research. Chromosomal instability plays an important role in the process of early tumor development, which probably causes the possibility of acquiring certain genetic changes, which also determines the prognosis and further therapeutic options. In this article, we have identified the most significant risk factors by comparing the results of various studies.

Target Genes of c-MYC and MYCN with Prognostic Power in Neuroblastoma Exhibit Different Expressions during Sympathoadrenal Development.

Deregulation of the MYC family of transcription factors c-MYC (encoded by MYC), MYCN, and MYCL is prevalent in most human cancers, with an impact on tumor initiation and progression, as well as response to therapy. In neuroblastoma (NB), amplification of the MYCN oncogene and over-expression of MYC characterize approximately 40% and 10% of all high-risk NB cases, respectively. However, the mechanism and stage of neural crest development in which MYCN and c-MYC contribute to the onset and/or progression of NB are not yet fully understood. Here, we hypothesized that subtle differences in the expression of MYCN and/or c-MYC targets could more accurately stratify NB patients in different risk groups rather than using the expression of either MYC gene alone. We employed an integrative approach using the transcriptome of 498 NB patients from the SEQC cohort and previously defined c-MYC and MYCN target genes to model a multigene transcriptional risk score. Our findings demonstrate that defined sets of c-MYC and MYCN targets with significant prognostic value, effectively stratify NB patients into different groups with varying overall survival probabilities. In particular, patients exhibiting a high-risk signature score present unfavorable clinical parameters, including increased clinical risk, higher INSS stage, MYCN amplification, and disease progression. Notably, target genes with prognostic value differ between c-MYC and MYCN, exhibiting distinct expression patterns in the developing sympathoadrenal system. Genes associated with poor outcomes are mainly found in sympathoblasts rather than in chromaffin cells during the sympathoadrenal development.

High Tumoral STMN1 Expression Is Associated with Malignant Potential and Poor Prognosis in Patients with Neuroblastoma.

Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification.