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Background: Aberrant DNA methylation is one of the major epigenetic alterations in neuroblastoma., Objective: Exploring the prognostic significance of methylation driver genes in neuroblastoma could help to comprehensively assess patient prognosis., Methods: After identifying methylation driver genes (MDGs), we used the LASSO algorithm and stepwise Cox regression to construct methylation driver gene-related risk score (MDGRS), and evaluated its predictive performance by multiple methods. By combining risk grouping and MDGRS grouping, we developed a new prognostic stratification strategy and explored the intrinsic differences between the different groupings., Results: We identified 44 stably expressed MDGs in neuroblastoma. MDGRS showed superior predictive performance in both internal and external cohorts and was strongly correlated with immune-related scores. MDGRS can be an independent prognostic factor for neuroblastoma, and we constructed the nomogram to facilitate clinical application. Based on the new prognostic stratification strategy, we divided the patients into three groups and found significant differences in overall prognosis, clinical characteristics, and immune infiltration between the different subgroups., Conclusion: MDGRS was an accurate and promising tool to facilitate comprehensive pre-treatment assessment. And the new prognostic stratification strategy could be helpful for clinical decision making., (© 2023. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Purpose: Cell death plays an important role in tumourigenesis and progression; nevertheless, the clinical significance of cell death-related genes in neuroblastoma remains incompletely understood., Methods: We separately constructed the corresponding risk scores for each of the eight cell death pathways separately and assessed their predictive performance. Through Cox regression analysis, these eight risk scores were integrated to obtain final cell death risk scores (CDRS). We evaluated the predictive performance of CDRS in multiple datasets and compared its accuracy with the clinical characteristics of patients and some existing prognostic models for neuroblastoma. We then explored the differences in immune infiltration between the high and low CDRS groups, and the significance of CDRS on EFS and disease progression., Results: All eight risk scores have high predictive accuracy, with the Immunogenic-RS being the most accurate and the cuproptosis-RS the least accurate. Model genes are mainly enriched in a variety of cancer-related pathways and are closely related to the clinical characteristics. CDRS showed superior and robust predictive performance in multiple datasets and was more accurate than the clinical characteristics of patients and some existing prognostic models for neuroblastoma. High CDRS group featured distinct immune cold tumor profiles and may have poorer immune checkpoint inhibitor efficacy. CDRS had significance in predicting EFS and disease progression., Conclusion: We integrated risk scores associated with multiple cell death pathways to develop a high-performing and robust neuroblastoma signature. CDRS was a promising tool that may help with risk assessment and prediction of overall prognosis, and thus improve clinical outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neuroblastoma is a childhood malignancy with high morbidity and mortality. We identified key biomarkers associated with neuroblastoma risk and prognosis. The gene modules most associated with neuroblastoma risk were derived by WGCNA. Modular genes were intersected with differentially expressed genes between patients with high-risk (HR) and non-high-risk (NHR) to obtain risk genes, and enrichment analysis was performed. After incorporating risk genes into Cox regression analysis, LASSO algorithm, and K-M survival analysis, key genes were identified and introduced into four external datasets for validation. We performed short time-series expression miner analysis and single-sample genome enrichment analysis. Finally, we evaluated the difference in DNA methylation levels to identify meaningful methylation marks. We identified 5 key genes (ANO6, CPNE2, DST, PLXNC1, SCN3A) for neuroblastoma risk and prognosis, which correlated closely with known neuroblastoma biomarkers. All key genes showed a progressive downregulation trend with increasing risk levels of neuroblastoma. The immune infiltration of 14 immune cells was significantly different between HR-NB and NHR-NB, and most immune cells were negatively correlated with key genes. Furthermore, the expression of ANO6, CPNE2, DST, and PLXNC1 was modified by DNA methylation. This study identified 5 key genes for neuroblastoma risk and prognosis that were potential biomarkers., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuroblastoma (NB) is the most common extracranial tumor in children. YTHDC1, a member of RNA methylation modification binding proteins, plays critical roles in tumor occurrence and metastasis. However, it is unclear whether YTHDC1 gene polymorphisms are related to NB susceptibility. Herein, we aimed to evaluate the association between YTHDC1 gene polymorphisms (rs2293596 T>C, rs2293595 T>C, rs3813832 T>C) and susceptibility of NB by logistic regression models. In this eight-center case-control study, 898 patients with NB and 1734 healthy controls were genotyped by TaqMan assay. The results showed that rs3813832 TC genotype could significantly reduce the susceptibility of NB compared with the TT genotype [adjusted odds ratio (AOR) = 0.81, 95% confidence interval (CI) = 0.68-0.96, P = 0.018]. Combined genotype analysis revealed that individuals with 3 protective genotypes had a prominently lower NB risk than those with 0-2 protective genotypes (AOR = 0.80, 95% CI = 0.68-0.94, P = 0.006). The stratified analysis also demonstrated the protective effect of rs3813832 TC/CC and 3 protective genotypes in certain subgroups. Further functional experiments revealed that YTHDC1 siRNA-554, targeting the area near the rs3813832 T>C polymorphism site, could observably inhibit the proliferation and migration of NB cells. In conclusion, our findings highlight the involvement of YTHDC1 gene and its genetic variants in the etiology of NB.

Background: Neuroblastoma is one of the most common malignant tumors in childhood. Polymorphisms in proto-oncogene MYC are implicated in many cancers, although their role in neuroblastoma remains unclear. In the present study, we attempted to investigate the association between MYC gene polymorphisms and neuroblastoma susceptibility in Chinese children., Methods: We included two MYC polymorphisms (rs4645943 and rs2070583) and assessed their effects on neuroblastoma risk in 505 cases and 1070 controls via the Taqman method., Results: In single and combined locus analysis, no significant association was found between the two selected polymorphisms and neuroblastoma susceptibility. In stratification analysis, the rs4645943 CT/TT genotypes were significantly associated with a decreased neuroblastoma risk in subjects with tumors originating from other sites [adjusted odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.21-0.84, p = 0.013]. Meanwhile, the presence of one or two protective genotypes was significantly associated with a decreased neuroblastoma risk in subjects with tumors arising from other sites (adjusted OR = 0.50, 95% CI = 0.26-0.96, p = 0.036)., Conclusions: The present study indicates that MYC gene polymorphisms may have a weak effect on the neuroblastoma risk, which neeeds to be verified further., (© 2020 John Wiley & Sons, Ltd.)

Dysregulation of long non-coding RNAs (lncRNAs) has been known to be relevant to the progression of human cancers, including neuroblastoma (NB). Small nucleolar RNA host gene 7 (SNHG7) has been identified as an oncogene in a series of human cancers. The purpose of the present study was to investigate the function and underlying mechanism of SNHG7 in NB progression. qRT-PCR was used to determine the levels of SNHG7, cyclin D1 (CCND1), miR-323a-5p and miR-342-5p. Cell migration and invasion abilities were detected by transwell assays. Glucose consumption and lactate production were assessed using the corresponding assay kits. The targeted interaction between SNHG7 and miR-323a-5p or miR-342-5p was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft tumor assays were performed to observe the effect of SNHG7 silencing on tumor growth in vivo. We found that SNHG7 was upregulated in NB tissues and cell lines, and high SNHG7 level was relevant to poor prognosis of NB patients. SNHG7 silencing resulted in the repression of NB cell migration, invasion and glycolysis. SNHG7 directly targeted miR-323a-5p and miR-342-5p and negatively modulated their expression in NB cells. The overexpression of miR-323a-5p or miR-342-5p weakened NB cell migration, invasion and glycolysis. Moreover, miR-323a-5p or miR-342-5p mediated the suppressive effect of SNHG7 silencing on NB cell progression. CCND1 was a direct target of miR-323a-5p and miR-342-5p. Additionally, SNHG7 knockdown repressed tumor growth in vivo. In conclusion, our study suggested that SNHG7 silencing hindered NB progression at least partly though sponging miR-323a-5p and miR-342-5p, illuminating its potential value as a therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Neuroblastoma is an extracranial solid tumor that mainly occurs in childhood. Mutations of NRAS gene have been described in several cancers. However, whether NRAS gene polymorphisms can predict the risk of neuroblastoma have not been investigated. We hypothesized that variations of NRAS gene contribute to neuroblastoma predisposition. Therefore, we conducted a multi-center case-control study using 263 cases and 715 controls to examine the association of NRAS gene rs2273267 A>T polymorphism and neuroblastoma risk. We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the strength of the associations. Relative to those with AA genotype, subjects with AT/TT genotype had reduced neuroblastoma risk (adjusted OR = 0.72, 95% CI = 0.54-0.96, P = 0.024). Stratified analysis revealed that rs2273267 AT/TT carriers were less likely to develop neuroblastoma for patients with tumor originating from the adrenal gland (adjusted OR = 0.67, 95% CI = 0.45-0.99, P = 0.047) and clinical stages III + IV (adjusted OR = 0.57, 95% CI = 0.36-0.90, P = 0.015). Our findings underline the likely importance of NRAS gene rs2273267 A>T in the risk of neuroblastoma. Further independent case-control studies with functional analysis are needed to verify the role of NRAS gene rs2273267 A>T polymorphism in the risk of neuroblastoma., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Neuroblastoma ranks the most common seen solid tumour in childhood. Overexpression of LIN28A gene has been linked to the development of multiple human malignancies, but the relationship between LIN28A single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility is still under debate. Herein, we evaluated the correlation of four potentially functional LIN28A SNPs (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) and neuroblastoma susceptibility in 505 neuroblastoma patients and 1070 controls from four independent hospitals in China. The correlation strengths were determined by using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Among these SNPs, rs34787247 G>A exhibited a significant association with increased susceptibility in neuroblastoma (GA vs GG: adjusted OR = 1.30, 95% CI = 1.03-1.64; AA vs GG: adjusted OR = 2.51, 95% CI = 1.36-4.64, AA/GA vs GG: adjusted OR = 1.42, 95% CI = 1.12-1.80, AA vs GG/GA: adjusted OR = 2.39, 95% CI = 1.29-4.42). Furthermore, the combined analysis of risk genotypes revealed that subjects carrying three risk genotypes (adjusted OR = 1.64, 95% CI = 1.02-2.63) are more inclined to develop neuroblastoma than those without risk genotype, and so do carriers of 1-4 risk genotypes (adjusted OR = 1.26, 95% CI = 1.01-1.56). Stratification analysis further revealed risk effect of rs3811464 G>A, rs34787247 G>A and 1-4 risk genotypes in some subgroups. Haplotype analysis of these four SNPs yields two haplotypes significantly correlated with increased neuroblastoma susceptibility. Overall, our finding indicated that LIN28A SNPs, especially rs34787247 G>A, may increase neuroblastoma risk., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Long non-coding RNAs (lncRNAs) have been confirmed to be aberrantly expressed and involved in the progression of neuroblastoma. This study aimed to explore the expression profile of lncRNA X-inactive specific transcript (XIST) and its functional involvement in neuroblastoma. In this study, the relative level of XIST in neuroblastoma tissues and cell lines was detected by qPCR, and DKK1 protein expression was determined using western blot. The effect of XIST on cell growth, invasion and migration in vitro and in tumorigenesis of neuroblastoma was assessed. The level of H3K27me3 in DKK1 promoter was analyzed with ChIP-qPCR. Interaction between XIST and EZH2 was verified by RNA immunoprecipitation (RIP) and RNA pull-down assay. XIST was significantly upregulated in neuroblastoma tissues ( n = 30) and cells lines, and it was statistically associated with the age and International Neuroblastoma Staging System (INSS) staging in neuroblastoma patients. Downregulation of XIST suppressed the growth, migration and invasion of neuroblastoma cells. EZH2 inhibited DKK1 expression through inducing H3 histone methylation in its promoter. XIST increased the level of H3K27me3 in DKK1 promoter via interacting with EZH2. Downregulation of XIST increased DKK1 expression to suppress neuroblastoma cell growth, invasion, and migration, which markedly restrained the tumor progression. In conclusion, XIST downregulated DKK1 by inducing H3 histone methylation via EZH2, thereby facilitating the growth, migration and invasion of neuroblastoma cells and retarding tumor progression.

Neuroblastoma is a life-threatening extracranial solid tumor, preferentially occurring in children. However, its etiology remains unclear. APEX1 is a critical gene in the base excision repair (BER) system responsible for maintaining genome stability. Given the potential effects of APEX1 polymorphisms on the ability of the DNA damage repair, many studies have investigated the association between these variants and susceptibility to several types of cancer but not neuroblastoma. Here, we conducted a three-center case-control study to evaluate the association between APEX1 polymorphisms (rs1130409 T>G, rs1760944 T>G, and rs3136817 T>C) and neuroblastoma risk in Chinese children, consisting of 469 cases and 998 controls. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the associations. No significant association with neuroblastoma risk was found for the studied APEX1 polymorphisms in the single locus or combination analysis. Interestingly, stratified analysis showed that rs1130409 GG genotype significantly reduced the risk of tumor in males. Furthermore, we found that carriers with 1-3 protective genotypes had a lower neuroblastoma risk in the children older than18 months and male, when compared to those without protective genotypes. In summary, our data indicate that APEX1 gene polymorphisms may have a weak effect on neuroblastoma susceptibility. These findings should be further validated by well-designed studies with larger sample size.

Neuroblastoma is the most frequently diagnosed neural tumor of childhood. Abnormal function of the long intergenic non-coding RNA (lincRNA) LINC00673 has been implicated in various human malignancies. Genome-wide association studies revealed the LINC00673 rs11655237 C>T polymorphism to be associated with the risk of neuroblastoma, though the effect was not well defined, in part due to the small sample size in our earlier study. Herein, we verified the impact of LINC00673 rs11655237 C>T on the risk of neuroblastoma in 700 cases and 1516 controls from six centers in China. After pooling all enrolled patients, we observed a significant association between LINC00673 rs11655237 C>T and risk of neuroblastoma (TT vs. CC: adjusted odds ratio [OR]=1.58, 95% confidence interval [CI]=1.06-2.35, P =0.024; additive model: adjusted OR=1.20, 95% CI=1.03-1.39, P =0.020; recessive model: adjusted OR=1.50, 95% CI=1.02-2.22, P =0.040). Stratification analysis revealed a significant relationship between rs11655237 CT/TT and neuroblastoma risk in subgroups of males, patients whose tumor originated in the adrenal gland, and patients with clinical stage IV disease. These findings add new evidence of the importance of LINC00673 rs11655237 C>T to the risk of developing neuroblastoma.

Background polymorphisms have been reported to correlate with an increased susceptibility to a few types of cancers, although their role in neuroblastoma has not yet been clarified. H19 We investigated the association between three single polymorphisms (rs2839698 G>A, rs3024270 C>G, and rs217727 G>A) and neuroblastoma susceptibility in Chinese Han populations. Three hundred ninety-three neuroblastoma patients and 812 healthy controls were enrolled from the Henan and Guangdong provinces. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to determine the strength of the association of interest. Materials and methods Separated and combined analyses revealed no associations of the rs2839698 G>A, rs3024270 C>G or rs217727 G>A polymorphisms and neuroblastoma susceptibility. In the stratification analysis, female children with rs3024270 GG genotypes had an increased neuroblastoma risk (adjusted OR = 1.61, 95% CI = 1.04-2.50, Results Separated and combined analyses revealed no associations of the rs2839698 G>A, rs3024270 C>G or rs217727 G>A polymorphisms and neuroblastoma susceptibility. In the stratification analysis, female children with rs3024270 GG genotypes had an increased neuroblastoma risk (adjusted OR = 1.61, 95% CI = 1.04-2.50, P The rs3024270 GG genotype might contribute to an increased neuroblastoma susceptibility in female Chinese children.Conclusion The rs3024270 GG genotype might contribute to an increased neuroblastoma susceptibility in female Chinese children., (© 2019 The Author(s).)

Hirschsprung disease (HSCR) is a heterogeneous congenital disorder that affects the enteric nervous system, while neuroblastoma is an embryonal tumor of the sympathetic nervous system. Familial cases of both HSCR and neuroblastoma appear to be functionally linked to PHOX2B , which plays a key role in the development of neural crest derivatives. However, the association between common PHOX2B variants and disease risk is contested. Additionally, large-scale examination for pleiotropy or shared genetic susceptibility in sporadic HSCR and neuroblastoma cases lacks theoretical support. Here, we report the first examination of PHOX2B in 1470 HSCR and 469 neuroblastoma patients with matched healthy controls. The PHOX2B rs28647582 polymorphism was found to be associated with HSCR (P = 2.21E-03, OR = 1.26), and each subtype of the ailment (3.22E-03 ≤ P ≤ 0.43, 1.11 ≤ OR ≤ 2.32). The association between rs28647582 and NB risk was consistent with HSCR in a recessive model, though the P value was marginal (P = 0.06). These new genetic findings indicate the potential pleiotropic effects of PHOX2B in both HSCR and neuroblastoma, which could guide the development of therapeutic targets for the treatment of related neurodevelopmental disorders.

Background: Neuroblastoma is the commonest malignancy in neonates. Long non-coding RNA (lncRNA) RNA component of mitochondrial RNA processing endoribonuclease (RMRP) has been reported to be an oncogenic factor in some malignancies. However, its roles and molecular mechanisms in neuroblastoma progression are poor defined., Methods: The expression of RMRP, microRNA-206 (miR-206), and tachykinin-1 receptor (TACR1) mRNA was measured by RT-qPCR assay. Protein levels of TACR1, phosphorylated extracellular signal-regulated kinases (ERK) 1/2 (p-ERK1/2) and ERK1/2 were detected by western blot assay. Cell proliferation was assessed by CCK-8 and colony formation assays. Cell migratory and invasive capacities were determined using Transwell migration and invasion assays. The interaction between miR-206 and RMRP or TACR1 was verified by luciferase assay. The roles and molecular mechanisms of RMRP knockdown on the growth of neuroblastoma xenografts were examined in vivo., Results: RMRP was highly expressed in neuroblastoma tissues. RMRP knockdown inhibited proliferation, migration and invasion in neuroblastoma cells. Moreover, TACR1 was a target of miR-206 and RMRP performed as a molecular sponge of miR-206 to sequester miR-206 from TACR1 in neuroblastoma cells. TACR1 overexpression abrogated the inhibitory effect of RMRP downregulation on neuroblastoma cell progression by activating ERK1/2 pathway. Inhibition of TACR1 and ERK1/2 pathway abated RMRP-mediated pro-proliferation effect in neuroblastoma cells. RMRP knockdown hindered neuroblastoma xenograft growth by regulating miR-206/TACR1 axis via inactivating ERK1/2 pathway in vivo., Conclusion: RMRP knockdown hindered the tumorigenesis and progression of neuroblastoma by regulating miR-206/TACR1 axis via inactivating ERK1/2 pathway, hinting a potential therapeutic target for neuroblastoma.

Neuroblastoma is a common pediatric extra-cranial tumor of the sympathetic nervous system. XRCC1 is a scaffold protein that participates in DNA single-strand break repair by complexing with other proteins. XRCC1 gene polymorphisms are being increasingly explored in cancer epidemiology studies. However, the contribution of XRCC1 gene polymorphisms to neuroblastoma risk remains unclarified. Herein, we conducted a case-control study with 393 neuroblastoma patients and 812 controls to explore the association of XRCC1 gene polymorphisms (rs1799782 G>A, rs25487 C>T, rs25489 C>T and rs915927 T>C) with neuroblastoma risk. Results showed that none of the studied polymorphisms was associated with neuroblastoma risk. However, individuals with 2 risk genotypes seemed to be at significantly higher risk for neuroblastoma compared with those without risk genotype (adjusted odds ratio=1.69; 95% confidence interval=1.06-2.69). Stratified analysis revealed that the XRCC1 rs25489 CT/TT was strongly associated with reduced risk of neuroblastoma in the children ≤ 18 months of age and subgroup with clinical stage I+II+4s diseases, compared with CC genotypes. We also identified an increased neuroblastoma risk for carrier of 2-3 risk genotypes among children ≤ 18 months of age and subgroup with clinical stage I+II+4s. More evidence of the association between XRCC1 gene polymorphisms and neuroblastoma risk is needed.

Background: The rs2147578 C > G polymorphism in the long non-coding RNA gene Lnc-LAMC2-1:1 is associated with increased susceptibility to a few types of cancers. However, its role in neuroblastoma has not been evaluated yet., Methods: We investigated the association between the lnc-LAMC2-1:1 rs2147578 C > G polymorphism and neuroblastoma susceptibility in Chinese Han populations. A total of 393 neuroblastoma cases and 812 healthy individuals from the Henan and Guangdong provinces were enrolled and subjected to genotyping. Odds ratio (OR) and 95% confidence interval (CI) were used to determine the strength of the association of interest., Results: Combined analysis revealed that the lnc-LAMC2-1:1 rs2147578 C > G polymorphism was associated with increased neuroblastoma susceptibility (CG vs. CC: adjusted OR = 1.33, 95% CI = 1.01-1.75, P = 0.045; CG/GG vs. CC: adjusted OR = 1.34, 95% CI = 1.03-1.74, P = 0.028). In stratification analysis, children under 18 months with rs2147578 CG/GG genotypes had an increased neuroblastoma risk (adjusted OR = 1.70, 95% CI = 1.08-2.67, P = 0.022). Females with rs2147578 CG/GG genotypes also had increased neuroblastoma susceptibility (adjusted OR = 2.08, 95% CI = 1.37-3.18, P = 0.0007). In addition, children with lnc-LAMC2-1:1 rs2147578 CG/GG genotypes were prone to develop earlier stages of neuroblastoma (adjusted OR = 1.46, 95% CI = 1.01-2.12, P = 0.046)., Conclusions: The Lnc-LAMC2-1:1 rs2147578 C > G polymorphism may contribute to increased neuroblastoma susceptibility in children of Henan province.

Neuroblastoma is a lethal tumor that commonly occurs in children. Polymorphisms in XPD reportedly influence risk for several types of cancer, though their roles in neuroblastoma remain unclear. Here we endeavored to determine the relevance of XPD gene polymorphisms and neuroblastoma susceptibility in Chinese children genotyping three XPD polymorphisms (rs3810366, rs13181 and rs238406) in 505 cases and 1070 controls and assessing their contributions to neuroblastoma risk. Overall, we detected no significant association between any single XPD genotype and neuroblastoma risk. When risk genotypes were combined, however, we found that patients with 2-3 risk genotypes were more likely to develop neuroblastoma (adjusted odds ratio =1.31; 95% confidence interval =1.06-1.62, P =0.013) than those with 0-1 risk genotypes. Stratification analysis of rs3810366 revealed significant relationships between the subgroups age ≤18 months and clinical stage I+II+4s and neuroblastoma risk. Moreover, the presence of 2-3 risk genotypes was significantly associated with increased neuroblastoma risk in the subgroups age ≤18 months, male, tumor originated from others, and clinical stage I+II+4s. Our findings provide novel insight into the genetic underpinnings of neuroblastoma and demonstrate that XPD polymorphisms may have a cumulative effect on neuroblastoma risk.

Two new neuroblastoma susceptibility loci at 3q25 (RSRC1 rs6441201 G > A) and 4p16 (CPZ rs3796725 T > C and rs3796727 A > G) were identified by a genome-wide association study (GWAS) involving Italians, African Americans and European Americans. In this case-control study with 393 neuroblastoma cases and 812 controls, we investigated the association between these three polymorphisms and neuroblastoma susceptibility in Chinese population. We found that participants harboring the RSRC1 rs6441201A allele were associated with an increased risk of neuroblastoma (AA vs. GG: adjusted OR = 1.55, 95% CI = 1.03-2.34, P = 0.036). No significant association between the CPZ polymorphisms (rs3796725 T > C and rs3796727A > G) and neuroblastoma susceptibility was observed. In conclusion, our results confirm that the RSRC1 rs6441201A allele is associated with neuroblastoma susceptibility in Chinese population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Neuroblastoma is the most frequently diagnosed extracranial solid tumor in children. Previous studies have shown that single-nucleotide polymorphisms in some genes are associated with the risk of multiple cancers, including neuroblastoma. Although Hox transcript antisense intergenic RNA (HOTAIR) gene polymorphisms have been investigated in a variety of cancers, to the authors' knowledge the relationships between HOTAIR gene polymorphisms and neuroblastoma susceptibility have not been reported to date. The objective of the current study was to evaluate the correlation between HOTAIR gene polymorphisms and neuroblastoma risk in Chinese children., Methods: The authors genotyped 6 polymorphisms (rs920778 A>G, rs12826786 C>T, rs4759314 A>G, rs7958904 G>C, rs874945 C>T, and rs1899663 C>A) of the HOTAIR gene in 2 Chinese populations including 393 neuroblastoma cases and 812 healthy controls. The strength of the associations was evaluated using odds ratios and 95% confidence intervals. Further stratification analyses were conducted to explore the association between the HOTAIR gene polymorphisms rs12826786 C>T, rs874945 C>T, and rs1899663 C>A with neuroblastoma susceptibility in terms of age, sex, clinical stage of disease, and sites of origin., Results: The authors found that the rs12826786 C>T (P =.013), rs874945 C>T (P =.020), and rs1899663 C>A (P =.029) polymorphisms were significantly associated with increased neuroblastoma risk. In stratification analyses, these associations were more predominant in females and among patients with tumor in the retroperitoneal region or mediastinum. The remaining 3 polymorphisms were not found to be related to neuroblastoma susceptibility., Conclusions: The results of the current study verified that HOTAIR gene polymorphisms are associated with increased neuroblastoma risk and suggest that HOTAIR gene polymorphisms might be a potential biomarker for neuroblastoma susceptibility. Cancer 2018;124:2599-606. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Previous studies have demonstrated that polymorphisms in the AURKA gene are associated with various types of cancer. In neuroblastoma, AURKA protein product regulates N-myc protein levels and plays a critical role in tumorigenesis. To investigate the association between three AURKA polymorphisms (rs1047972 C>T, rs2273535 T>A, and rs8173 G>C) and neuroblastoma susceptibility in Chinese populations, we performed this two-center case-control study including 393 neuroblastoma cases and 812 controls. Two study populations were recruited from two different regions in China. No significant associations were identified amongst any of the three AURKA polymorphisms and the risk of neuroblastoma. Similar observations were found in the stratified analysis. In conclusion, our results indicate that none of the AURKA polymorphisms are associated with neuroblastoma susceptibility in two distinct Chinese populations. Further studies with larger sample sizes and different ethnicities are warranted to validate our results., (© 2018 The Author(s).)

The genetic etiology of sporadic neuroblastoma remains largely obscure. RAN and RANBP2 genes encode Ras-related nuclear protein and Ran-binding protein 2, respectively. These two proteins form Ran-RanBP2 complex that regulate various cellular activities including nuclear transport. Aberrant functions of the two proteins are implicated in carcinogenesis. Given the unknown role of RAN/RANBP2 single nucleotide polymorphisms (SNPs) in neuroblastoma risk, we performed a multi-center case-control study in Chinese children to assess the association of the RAN/RANBP2 SNPs with neuroblastoma risk. We analyzed three potentially functional SNPs in RAN gene (rs56109543 C>T, rs7132224 A>G, rs14035 C>T) and one in RANBP2 (rs2462788 C>T) in 429 cases and 884 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the association between these four polymorphisms and neuroblastoma risk. No single variant was found to statistically significantly associate with neuroblastoma risk. However, individuals with 3 protective genotypes were less likely to develop neuroblastoma, in comparison to non-carriers (adjusted OR=0.33; 95% CI=0.12-0.96; P =0.042), as well as those with 0-2 protective genotypes (adjusted OR=0.33; 95% CI=0.11-0.94; P =0.038). Stratified analysis revealed no significant association for any of the four polymorphisms. Further studies are warranted to validate the weak impact of RAN/RANBP2 SNPs on neuroblastoma risk.

Variations in nucleotide excision repair pathway genes may predispose to initiation of cancers. However, polymorphisms of ERCC1/XPF genes and neuroblastoma risk have not been investigated before. To evaluate the relevance of polymorphisms of ERCC1/XPF genes in influencing neuroblastoma susceptibility, we genotyped four polymorphisms in ERCC1/XPF genes using a Chinese population of 393 cases and 812 controls. The results showed that ERCC1 rs2298881 and rs11615 predisposed to enhanced neuroblastoma risk [CA vs. AA: adjusted odds ratio (OR)=1.94, 95% confidence interval (CI)=1.30-2.89, P=0.0012; CC vs. AA: adjusted OR=2.18, 95% CI=1.45-3.26, P=0.0002 for rs2298881, and AG vs. GG: adjusted OR=1.31, 95% CI=1.02-1.69, P=0.038 for rs11615]. Moreover, XPF rs2276466 was also associated with increased neuroblastoma risk (GG vs. CC: adjusted OR=1.66, 95% CI=1.02-2.71, P=0.043). In the combined analysis of ERCC1, we found that carriers with 2-3 risk genotypes were more likely to get risk of neuroblastoma, when compared to those with 0-1 risk genotype (adjusted OR=1.75; 95% CI=1.25-2.45, P=0.0012). Our study indicates that common genetic variations in ERCC1/XPF genes predispose to neuroblastoma risk, which needs to be further validated by ongoing efforts., (Copyright © 2018 German Center for Neurodegenerative Diseases (DZNE). Published by Elsevier B.V. All rights reserved.)

Neuroblastoma is the third most common childhood cancer after leukemias and cancer of the central nervous system. Long noncoding RNA MEG3 polymorphisms have been shown to confer cancer susceptibility; however, their roles in the genetic predisposition to neuroblastoma remain unclarified. To answer this question, we genotyped two MEG3 polymorphisms, rs7158663 G>A and rs4081134 G>A, in 392 neuroblastoma children and 783 controls by TaqMan method. The results showed that neither single locus nor the combination analysis supported an association between MEG3 polymorphism and neuroblastoma risk. Interestingly, we found that subjects carrying rs4081134 AG/AA genotypes significantly tended to develop neuroblastoma among subgroups with age >18 month (adjusted OR=1.36, 95% CI=1.01-1.84) and clinical stage III+IV disease (adjusted OR=1.47, 95% CI=1.08-1.99), when compared with reference group. In the combined analysis of MEG3 polymorphisms, we found that carriers of 2 risk genotypes were more likely to have higher risk of developing neuroblastoma than those with 0-1 risk genotype among children more than 18 months of age (adjusted OR=1.36, 95% CI=1.01-1.84, P =0.042), and with clinical stages III+IV disease (adjusted OR=1.47, 95% CI=1.08-2.00, P =0.014). Our data suggest MEG3 as a weak-effect neuroblastoma susceptibility gene. Well-designed studies with large sample studies are needed to further validate this finding.

Aims: Methylphenidate (MPH) is a dopamine-reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). Nonetheless, the cellular and molecular mechanisms of MPH are still unknown. We attempt to determine whether MPH protect neuron cells against oxidative stress by using human neuroblastoma SH-SY5Y cells., Main Methods: The SH-SY5Y cells were cultured in normoxic and hypoxic conditions in the presence of different doses of MPH. Then, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and adenosine triphosphate (ATP) production were quantitatively measured by using flow cytometry or spectrophotometry. The mitochondrial ultrastructure of the cells was observed by electron microscope, and the function of mitochondrial was evaluated by measuring mitochondrial membrane potential (MMP) using flow cytometry. The levels of SOD and heme oxygenase-1 (HO-1) proteins were detected by Western blot., Key Findings: We found that low doses of MPH treatment (50-500 ng/mL) led to decreased ROS and MDA production (P<0.05), increased GSH and SOD as well as ATP concentration (P<0.05) in hypoxic SH-SY5Y cells. Additionally, low doses of MPH significantly inhibited mitochondrial swelling and decreased the percentage of JC-1 monomer positive cells. However, we did not observe the same effects of MPH in normoxia., Significance: Our results show that low doses of MPH play protective roles in maintaining mitochondrial homeostasis in response to hypoxia-induced oxidative stress. Our findings may provide novel insight into the mechanisms of MPH in the treatment of ADHD, and shed light on the disease mechanisms of ADHD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neuroblastoma, which accounts for approximately 10% of all pediatric cancer-related deaths, has become a therapeutic challenge and global burden attributed to poor outcomes and mortality rates of its high-risk form. Previous genome-wide association studies (GWASs) identified the LINC00673 rs11655237 C>T polymorphism to be associated with the susceptibility of several malignant tumors. However, the association between this polymorphism and neuroblastoma susceptibility is not clear. We genotyped LINC00673 rs11655237 C>T in 393 neuroblastoma patients in comparison with 812 age-, gender-, and ethnicity-matched healthy controls. We found a significant association between the LINC00673 rs11655237 C>T polymorphism and neuroblastoma risk (TT compared with CC: adjusted odds ratio (OR) =1.80, 95% confidence interval (CI) =1.06-3.06, P =0.029; TT/CT compared with CC: adjusted OR =1.31, 95% CI =1.02-1.67, P =0.033; and T compared with C: adjusted OR =1.29, 95% CI =1.06-1.58, P =0.013). Furthermore, stratified analysis indicated that the rs11655237 T allele carriers were associated with increased neuroblastoma risk for patients with tumor originating from the adrenal gland (adjusted OR =1.51, 95% CI =1.06-2.14, P =0.021) and International Neuroblastoma Staging System (INSS) stage IV disease (adjusted OR =1.60, 95% CI =1.12-2.30, P =0.011). In conclusion, we verified that the LINC00673 rs11655237 C>T polymorphism might be associated with neuroblastoma susceptibility. Prospective studies with a large sample size and different ethnicities are needed to validate our findings., (© 2018 The Author(s).)

Neuroblastoma is the most common form of childhood extracranial tumor and almost half of neuroblastoma cases occur in infants under two years old. Neuroblastoma accounts for ~6‑10% of childhood cancers and 15% of cancer‑associated childhood mortality. However, an effective treatment remains to be developed. Honokiol exhibits long‑lasting central muscle relaxation, anti‑inflammatory, antibacterial, antimicrobial, antiulcer, antioxidation, antiaging and antitumor effects. Honokiol has been previously demonstrated to kill neuroblastoma cells, however, the underlying mechanism of action remains unclear. The present study reports that honokiol inhibits the growth of neuroblastoma cells via upregulation of reactive oxygen species (ROS). MTT assays demonstrated that treatment of Neuro‑2a neuroblastoma cells with honokiol resulted in time‑ and dose‑dependent inhibition of cell proliferation, which was associated with upregulation of the protein expression of receptor‑interacting protein kinase 3 (RIP3), as demonstrated by western blot analysis. Furthermore, knockdown of RIP3 by small interfering RNA, or pharmacological inhibition of RIP3 by the RIP3 specific inhibitor necrosulfonamide, reversed honokiol‑induced loss of cell viability in Neuro‑2a cells. Importantly, honokiol significantly increased the intracellular ROS levels as determined by a 2',7'‑dichlorofluorescin diacetate assay, while ROS scavenger N‑acetyl cysteine significantly prevented the induction of ROS and RIP3 by honokiol. The results of the present study indicate that honokiol may suppress the growth of neuroblastoma Neuro‑2a cells, at least partially, through ROS‑mediated upregulation of RIP3.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Glucose/regulated protein 78 (GRP78) is a stress-associated protein. It has been reported that overexpression of GRP78 occurs in various human cancers, and GRP78 polymorphisms have effect on the expression of GRP78 with possible function of predicting clinical outcome. Upregulation of GRP78 has been detected in NB. However, little is known about the relationship of GRP78 polymorphisms and the susceptibility of NB., Aim: To investigate whether GRP78 polymorphisms were associated with the risk and clinical characteristics of NB., Materials and Methods: Two GRP78 polymorphisms rs391957 (C>T) and rs430397 (G>A) were detected in 105 NB cases and 145 healthy controls using the polymerase chain reaction fragment length polymorphism technique., Results: Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of NB. In NB cases, the variant T allele was significantly associated with tumor International Neuroblastoma Staging System stage (P = 0.027), but not with MYCN amplification (P = 0.056). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of NB. The rs430397 polymorphism was not associated with the clinicopathological characteristics of NB., Conclusion: These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as the markers to predict the risk and poor prognosis of NB.

Neuroblastoma is the most common extracranial solid tumor in childhood and is associated with serious morbidity and mortality. The effective treatment of neuroblastoma remains one of the major challenges in pediatric oncology. The Wnt signaling pathway has been shown to play a significant role in the pathogenesis of adult and pediatric tumors. WIF-1 has been identified as an important Wnt antagonist which inhibits Wnt/β-catenin signaling by directly binding to Wnt proteins. However, the expression and function of WIF-1 in neuroblastoma remains unknown. The present study showed that WIF-1 was downregulated with high level promoter methylation in neuroblastoma cells, and was significantly upregulated after exposure to demethylating agent. This finding suggests that downregulation of WIF-1 was associated with its promoter methylation in neuroblastoma. To further study the potential function of WIF-1 in neuroblastoma, we constructed a plasmid that over-expressed WIF-1 and transfected the plasmid into one neuroblastoma cell line SK-N-SH. We found that restoration of WIF-1 inhibited the growth and proliferation of neuroblastoma cells in vitro. Moreover, Wnt/β-catenin signaling activity and target genes expression were reduced by WIF-1 restoration. These results provide support that WIF-1 is downregulated and functions as a tumor suppressor by antagonizing Wnt/β-catenin signaling in neuroblastoma, suggesting a potential role as a therapeutic target in neuroblastoma., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Neuroblastoma is the second most common malignant solid tumor in children, and often metastasizes to liver, most notably in patients with stage 4S tumors. Solid pseudopapillary tumor of the pancreas (SPT) is a pancreatic borderline tumor with low malignant potential. Coexistence of these two tumors in one patient has never been reported before. Hereby, we present a case of an 8-month-old infant with coexisting tumors of SPT and metastatic neuroblastoma of liver. Dysdifferentiation of neural crest might be responsible for histogenesis of the coexisting tumors.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Glucose/regulated protein 78 (GRP78) is a stress-associated protein. It has been reported that overexpression of GRP78 occurs in various human cancers, and GRP78 polymorphisms have effect on the expression of GRP78 with possible function of predicting clinical outcome. Upregulation of GRP78 has been detected in NB. However, little is known about the relationship of GRP78 polymorphisms and the susceptibility of NB.Aim: To investigate whether GRP78 polymorphisms were associated with the risk and clinical characteristics of NB.Materials and Methods: Two GRP78 polymorphisms rs391957 (C>T) and rs430397 (G>A) were detected in 105 NB cases and 145 healthy controls using the polymerase chain reaction fragment length polymorphism technique.Results: Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of NB. In NB cases, the variant T allele was significantly associated with tumor International Neuroblastoma Staging System stage (P = 0.027), but not with MYCN amplification (P = 0.056). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of NB. The rs430397 polymorphism was not associated with the clinicopathological characteristics of NB.Conclusion: These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as the markers to predict the risk and poor prognosis of NB. [ABSTRACT FROM AUTHOR]