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Association between MYCN gene polymorphisms and neuroblastoma susceptibility: a case-control study in Chinese children from Jiangsu Province

BMC Cancer volume 25, Article number: 892 (2025) Cite this article

Abstract

Background

Neuroblastoma, developed from the sympathetic nervous system, is a deadly childhood malignancy. There is an urgent need to elucidate its intricated etiology. MYCN amplification leads to aggressive neuroblastoma and represents a powerful marker of poor prognosis. However, the correlation between MYCN gene polymorphisms and neuroblastoma susceptibility remains largely unknown in Chinese Han children.

Methods

We conducted a case-control study to evaluate the associations between MYCN gene polymorphisms and neuroblastoma susceptibility, involving 402 cases and 473 controls from Jiangsu Province, China. The association strength between the studied polymorphisms and neuroblastoma susceptibility was quantified using odds ratios and 95% confidence intervals.

Results

Four studied polymorphisms (rs57961569 G > A, rs9653226 T > C, rs13034994 A > G, and rs60226897 G > A) were significantly associated with neuroblastoma susceptibility. Stratified analysis of two polymorphisms (rs13034994 A > G and rs60226897 G > A) demonstrated stronger associations with neuroblastoma susceptibility in specific subgroups. Moreover, survival analysis demonstrated elevated MYCN expression in high-risk patients, with reduced expression correlating to improved survival outcomes.

Conclusion

Our study indicated that MYCN gene polymorphisms are significantly associated with neuroblastoma susceptibility in the eastern Chinese population and that high expression of the MYCN gene may suggest a poor prognosis. Nevertheless, further verification should be conducted with large-scale and well-designed studies to confirm our findings.

Peer Review reports

Introduction

Neuroblastoma is the most common extracranial malignancy in childhood, with the mean age at diagnosis of approximately 17 months [1]. Its incidence ranks fourth among pediatric cancers in China and is approximately 7.7 per million [2]. Neuroblastoma comprises 8-10% of all pediatric neoplasms and contributes to 15% of cancer-associated childhood mortality [3]. This neoplasm exhibits high heterogeneity with a wide spectrum of clinical patterns, varying from spontaneous improvement without any clinical intervention or minimal chemotherapy to aggressive phenotypes and poor prognosis despite multiple intensive comprehensive therapies [4]. The survival rate of patients with neuroblastoma sharply decreases with the progression of the disease. The survival rate for early low-risk patients is over 95%, while for those in clinical stage III, it drops to only 60%, and for stage IV patients, it plummets to just 20% [5]. Advanced neuroblastoma patients typically present with aggressive and metastatic disease at the time of diagnosis, which poses a significant challenge in treating these high-risk individuals and contributes to their poor prognosis. Therefore, improving the assessment of risk factors and accurately identifying genetic markers is crucial for effectively screening high-risk populations and precisely predicting patient outcomes.

The pathology and etiology of neuroblastoma are rather complicated and remain poorly understood involving the interaction of environmental and genetic factors. Studies have shown that genetic variants of the PHOX2B [6] and ALK [7] genes are related to the risk of familial neuroblastoma. The genetic etiology of sporadic neuroblastoma is not fully known. Several environmental factors, such as hydrocarbons, wood dust, welding flux, and radiation sources, may predispose individuals to neuroblastoma [8, 9]. However, only a small fraction of individuals suffer from neuroblastoma after being exposed to the above environmental factors. Therefore, genetic factors have gradually been recognized as the main causes of the neuroblastoma. An increasing number of studies suggest that hereditary genetic polymorphisms are associated with neuroblastoma susceptibility and may predispose to neuroblastoma [10].

Single nucleotide polymorphisms (SNPs) are well-known to be involved in disease susceptibility, prognosis, and survival. SNPs are also extensively employed in the exploration of disease etiology, treatment optimization, and prognosis evaluation for various complex diseases, including neuroblastoma. Genome-wide association studies (GWASs) have been powerful tools to explore the genetic etiology of human disorders. Over the last decade, several GWASs in neuroblastoma have identified multiple independent susceptibility loci in the CASC15 [11], BARD1 [12], HSD17B12, DUSP12, IL31RA, DDX4 [13], LMO1 [14], LIN28B, HACE1 [15], CPZ and MLF1 [16]. In addition, neuroblastoma susceptibility loci in the CDKN1B [17], XPG [18], and NEFL [19] genes have also been found via the candidate gene method. The above findings highlight the importance of SNPs in neuroblastoma susceptibility. However, many disease-associated SNPs remain to be discovered. Therefore, extensive research is needed to further elucidate the genetic etiology of neuroblastoma.

MYCN is an important member of the MYC oncogene family, which was first discovered in neuroblastoma cell lines [20]. MYCN functions by assembling a heterodimer with MYC-associated protein X and then binding to the E-box regulatory motif at the promoters of target genes to regulate transcriptions [21]. MYCN plays key roles in numerous cytophysiological processes, including mainly cell growth [22], differentiation [23], proliferation [24], and apoptosis [25]. Its dysregulation has been reported to be involved in the initiation and progression of malignancy [26, 27]. Furthermore, MYCN amplification is a common and crucial genetic event in neuroblastoma, occurring in 20–25% of neuroblastoma cases and leading to aggressive behaviors and malignant progression. The amplification of MYCN is generally considered a reliable genetic marker of poor prognosis in neuroblastoma patients [28, 29]. However, few studies have reported associations between MYCN gene variants and neuroblastoma susceptibility. In this current study, four potentially functional SNPs (rs57961569 G > A, rs9653226 T > C, rs13034994 A > G, and rs60226897 G > A) in the MYCN gene were chose for analysis, all of them were located in the transcription factor binding sites, a key region for regulation of gene transcription. SNPs in this region may affect the binding of transcription factor then modifying gene expression. Considering the crucial roles of MYCN in neuroblastoma progression and the potential regulation of SNPs in the MYCN gene, it is biologically plausible to propose that functional SNPs in the MYCN gene may change its protein expression or structure. This alteration could subsequently disrupt the normal transcriptional regulation of downstream target genes, leading to cell dysfunction and eventually contributing to carcinogenesis and neuroblastoma susceptibility.

Therefore, we performed the current case-control study to assess the association between the MYCN gene SNPs and neuroblastoma susceptibility. These findings may help identify novel genetic markers for high-risk neuroblastoma population screening.

Materials and methods

Study subjects

In this case-control study, 402 neuroblastoma patients and 473 control subjects were enrolled from Jiangsu Province, China [30, 31]. All patients were newly clinically diagnosed and histopathologically confirmed without previous treatments. The healthy control participants were randomly selected from children visiting for routine medical examinations in the same area during the same period. Age, sex, and race were matched between the cases and controls. The exclusion criteria for the participants were described in detail in our previous publications [18]. The demographic features of the study subjects are displayed in Table S1. Medical informed consent documents were acquired from the included subjects or their guardians before the study. The study followed the Declaration of Helsinki guidelines and the research protocol was approved by the ethics committee of the Children’s Hospital of Nanjing Medical University (Approval No: 202112141-1).

Polymorphism selection and genotyping

Four potentially functional genetic variants in the MYCN gene (rs13034994 A > G, rs60226897 G > A, rs57961569 G > A, and rs9653226 T > C) were selected for analysis [32]. For genotyping, the extraction and purification of genomic DNA from peripheral blood were conducted with a TIANamp Blood DNA Kit (TianGen Biotech, Beijing, China). The genotyping of the selected SNPs in the diluted DNA samples was performed via the TaqMan PCR method (Figure S1) [33,34,35]. A second analysis was conducted on 10% of the randomly selected DNA samples and 100% consistency was obtained between the two genotyping results.

Statistical analysis

The Hardy‒Weinberg equilibrium (HWE) status of the SNPs was tested using a goodness-of-fit χ2 test in the controls. The two-sided χ2 test was applied to compare the differences in demographic characteristics and genotype frequency distributions between the case and control groups. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via the logistic regression model to evaluate the associations between the SNPs and neuroblastoma susceptibility. The adjusted ORs and counterpart 95% CIs adjusted for age and sex were determined through unconditional multivariate logistic regression analysis. In addition, we performed stratified analysis regarding age, sex, tumor site of origin, and clinical stage. We applied SAS software (version 9.4 SAS Institute, NC, USA) to carry out the statistical analysis. The results were considered statistically significant when the corresponding P value was < 0.005.

Survival analysis

A public microarray dataset (GSE49710) was obtained from the NCBI Gene Expression Omnibus (GEO) database. Information on MYCN expression was extracted from the database, and the differences between the high-risk group and the group with no high risk were analyzed [36]. Based on this dataset, the level of MYCN was dichotomized into low- and high-expression subgroups according to the median. The Kaplan‒Meier method with the R2 database server was used for survival analysis and statistical difference in survival between the subgroups was assessed using a log-rank test.

Results

Associations between MYCN gene polymorphisms and neuroblastoma susceptibility

In the present study, 402 neuroblastoma patients and 473 cancer-free controls were included and successfully genotyped to analyze the relationship between MYCN gene polymorphisms and neuroblastoma susceptibility. As indicated in Table 1. The genotype frequencies of rs13034994 A > G (P = 0.772) and rs60226897 G > A (P = 0.664) were in HWE among the controls, while those of the other two SNPs, rs57961569 G > A (P = 0.036) and rs9653226 T > C (P = 0.028) did not follow HWE. All four candidate SNPs were significantly associated with neuroblastoma susceptibility via single-locus analysis. More specifically, we found that carriers with the rs57961569 GA genotype had a decreased neuroblastoma susceptibility compared with children harboring the GG genotype (AOR = 0.72, 95% CI = 0.54–0.95, P = 0.022). The rs9653226 TC genotype was also associated with a decreased neuroblastoma susceptibility against the reference TT genotype (AOR = 0.66, 95% CI = 0.49–0.88, P = 0.005); however, the rs9653226 CC genotype increased the neuroblastoma susceptibility under the dominant model (AOR = 1.53, 95% CI = 1.07–2.18, P = 0.019). Subjects with the rs13034994 GG genotype also had a greater neuroblastoma susceptibility than those with the AA or AA/AG genotype (GG vs. AA: AOR = 1.76, 95% CI = 1.04–2.97, P = 0.036, GG vs. AA/AG: AOR = 1.85, 95% CI = 1.10–3.10, P = 0.019); and the rs60226897 GA genotype had a reduced neuroblastoma susceptibility compared with the GG genotype (AOR = 0.72, 95% CI = 0.54–0.96, P = 0.025). In addition, compared with children without the risk genotype, those carrying the 1–4 risk genotypes had an increased neuroblastoma susceptibility (AOR = 1.46, 95% CI = 1.11–1.92; P = 0.006).

Table 1 Association between MYCN gene polymorphisms and neuroblastoma susceptibility in children from Jiangsu Province
Full size table

Stratification analysis

To assess the protective or risk effects of significant SNPs on neuroblastoma susceptibility among various subgroups, stratification analysis was further performed for rs13034994 A > G and rs60226897 G > A by age, sex, site of tumor origin, and clinical stage. As shown in Table 2, the risk effect of rs13034994 A > G and the protective effect of rs60226897 G > A were more evident in different subgroups. Specifically, the association of the rs13034994 GG genotype with increased neuroblastoma susceptibility was more obvious among the following subgroups: age > 18 months (AOR = 2.31, 95% CI = 1.24–4.30, P = 0.008), girls (AOR = 2.55, 95% CI = 1.24–5.26, P = 0.011), neuroblastoma of mediastinum origin (AOR = 2.10, 95% CI = 1.04–4.22, P = 0.038), and advanced stage (AOR = 2.42, 95% CI = 1.31–4.47, P = 0.005). Compared with the GG genotype, the rs60226897 GA/AA genotype significantly decreased neuroblastoma susceptibility in the following subgroups: males (AOR = 0.64, 95% CI = 0.44–0.93, P = 0.020), retroperitoneal origin (AOR = 0.65, 95% CI = 0.46–0.93, P = 0.017), and late-stage disease (AOR = 0.64, 95% CI = 0.45–0.91, P = 0.014). In addition, the combined analysis revealed that carriers harboring 1–4 risk genotypes had significantly greater neuroblastoma susceptibility than those with no risk genotype in subgroups aged > 18 months (AOR = 1.44, 95% CI = 1.03-2.00, P = 0.032), males (AOR = 1.51, 95% CI = 1.04–2.20, P = 0.032), retroperitoneal origin (AOR = 1.61, 95% CI = 1.11–2.32, P = 0.011), and stages III + IV disease (AOR = 2.00, 95% CI = 1.36–2.93, P = 0.0004).

Table 2 Stratification analysis of risk genotypes with neuroblastoma susceptibility
Full size table

Expression and prognostic analysis

Expression analysis revealed that MYCN was more highly expressed in high-risk neuroblastoma patients than in no-high-risk patients, and patients with no high risk had lower expression of MYCN (Fig. 1). Prognostic analysis revealed that high MYCN expression was associated with decreased overall survival (OS) (Fig. 2) and event-free survival (EFS) (Fig. 3) of neuroblastoma patients. However, the association with EFS was only marginally significant (P = 0.060). These results indicate a carcinogenic effect of MYCN on neuroblastoma.

Fig. 1
figure 1

Expression analysis of MYCN in neuroblastoma patients at high risk and not at high risk from a public GEO dataset

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Fig. 2
figure 2

Prognostic analysis between the expression of MYCN and the overall survival probability of neuroblastoma patients

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Fig. 3
figure 3

Prognostic analysis between the expression of MYCN and the event-free survival probability of neuroblastoma patients

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Discussion

SNP is the most common type of genetic variant among individuals, referring to congenital mutations with a frequency of ≥ 1% in the population. The research results of the Human Genome Project showed that the genome differences among human individuals were only 0.1%, and SNPs is the main form of these differences. Researches showed that it is these numerous SNP sites that combine together to determine the differences in traits amongst individuals, including differences in disease susceptibility and drug sensitivity. Therefore, SNP has been widely included in the research scope of disease etiology exploration, disease diagnosis and treatment research, and disease prognosis evaluation, etc. Considering the pivotal roles of MYCN in neuroblastoma progression and the regulatory potential of SNPs, we conducted this case-control study to evaluate the relationship between potential functional MYCN gene polymorphisms and neuroblastoma susceptibility. In this study, we identified four MYCN gene susceptibility loci (rs57961569, rs9653226, rs13034994, and rs60226897) that significantly modify neuroblastoma susceptibility. Our study contributes to the understanding of the genetic predisposition of neuroblastoma patients, and further analysis of multiple loci may improve the early diagnosis and screening of high-risk populations.

The MYCN gene is mapped to chromosome 2p24.3 and encodes a transcriptional nuclear phosphoprotein of the MYC family. It is crucial in processes associated with neoplasm initiation and progression, such as proliferation, differentiation, and survival [37]. Many studies have revealed abnormal expression of the MYCN gene in various tumors, such as astrocytoma, small cell lung carcinomas, Wilms’ tumor, and neuroblastoma [38]. Moreover, numerous studies have shown that MYCN amplification commonly occurs in neuroblastoma and is closely associated with aggressive phenotypes and poor survival. MYCN amplification is the most important molecular marker indicating advanced-stage disease and poor outcomes in neuroblastoma patients [39,40,41,42]. One study conducted by Tanaka et al. demonstrated that MYCN amplification enhances the migration and invasion of neuroblastoma cells by downregulating integrin α1 [43]. Rouah et al. reported that a decreased level of MYCN was related to neuron terminal differentiation [44]. Janardhanan et al. reported that silencing MYCN induced the differentiation and apoptosis of neuroblastoma cells [45]. Zaatiti et al. also revealed that the knockout of the MYCN gene reduced the migration and proliferation of a neuroblastoma cell line [46]. In addition, MYCN is involved in immune evasion by dampening the expression of ligands on the neuroblastoma cell surface, which bind to NK-cell-activating receptors for NK cell activation [47]. These studies revealed the important roles of MYCN in neuroblastoma progression; however, few studies have investigated the associations between MYCN genetic variants and neuroblastoma susceptibility. One study involving 243 cases and 247 controls performed by Dahlin et al. revealed no significant association between MYCN rs922 G > A variant and medulloblastoma susceptibility in Swedish and Danish individuals, which was the first study to explore the association between MYCN gene polymorphisms and cancer susceptibility [48]. Our recent study also revealed no significant relationship between MYCN polymorphisms and Wilms tumor risk in Chinese children [49]. However, our other research revealed that one of the MYCN genetic variants, rs57961569 G > A, was significantly associated with neuroblastoma susceptibility in a three-center case-control study, whereas other variants (rs9653226 T > C, rs13034994 A > G, and rs60226897 G > A) were not [32].

Herein, we carried out a case-control study to assess the associations between four SNPs of the MYCN gene and neuroblastoma susceptibility in a population from Jiangsu Province, China. All the studied SNPs were located at the promoter region of the MYCN gene. Our results revealed that all four selected SNPs were significantly associated with neuroblastoma susceptibility. Specifically, we found that subjects with the rs57961569 GA, rs9653226 TC, or rs60226897 GA genotypes had a lower neuroblastoma susceptibility than those with the reference genotype and that carriers with the rs13034994 GG genotype had a greater neuroblastoma susceptibility than those with the AA genotype. More prominent associations were observed among the different subgroups in the stratification analysis. The effects of MYCN gene polymorphisms on neuroblastoma susceptibility may be age-, sex-, site- and origin-, and clinical stage dependent. These contradictory results may result from differences in the study population, tumor type, or other factors. It is possible that these significant SNPs maybe just a chance discovery owing to the relatively small sample size. Well-designed research with larger samples should be conducted to confirm our findings.

Moreover, the expression analysis revealed that MYCN was expressed at higher levels in the high-risk cohort than in the low-risk cohort. Survival analysis revealed better OS and EFS in neuroblastoma patients with low MYCN expression than in those with high MYCN expression. Although not statistically significant for EFS, these findings suggest a protumor role of MYCN in neuroblastoma progression. The candidate SNPs (especially those located at the promoter region of MYCN) may modify the expression of the MYCN gene, therefore affecting neuroblastoma susceptibility. This may also be one of the potential mechanisms by which associated SNPs modify neuroblastoma susceptibility. However, in-depth mechanistic studies on how significant SNPs affect the expression of MYCN and modify neuroblastoma susceptibility are needed in the future.

Several shortcomings should be noted in the present study. First, the sample size was small, especially in the stratification analysis, which inevitably led to decreased statistical power. Second, other potentially effective SNPs located at the MYCN gene should be assessed. Third, this case-control study was a single-center study, and the subjects included in the research were of Chinese origin; hence, the conclusions of this study may not be applicable to other regions and ethnicities. Fourth, environmental factors should be evaluated, as the complicated etiology of neuroblastoma involves interactions between multiple environmental and genetic factors. Fifth, mechanistic studies should be conducted to elucidate the underlying mechanisms by which MYCN genetic polymorphisms affect neuroblastoma susceptibility. Sixth, the unavailableness of complete sample information, such as environmental exposure and MYCN status of the investigate subjects.

Conclusion

In summary, our current study suggests that genetic variants of the MYCN gene could significantly modify neuroblastoma susceptibility in eastern China. These findings support the exploitation of new diagnostic genetic markers of neuroblastoma from MYCN genetic variants. Nevertheless, our findings should be confirmed by well-designed and multi-center studies involving larger samples. Moreover, future studies should elucidate the mechanisms through which MYCN variants contribute to neuroblastoma pathogenesis.

Data availability

The original contributions presented in the study are provided in the article/Supplementary Materials; all the data are available upon request from the correspondence authors (Jing He or Xinxin Zhang).

Abbreviations

SNP:

Single nucleotide polymorphism

GWAS:

Genome-wide association study

HWE:

Hardy‒Weinberg equilibrium

OR:

Odds ratio

CI:

Confidence interval

GEO:

Gene expression omnibus

OS:

Overall survival

EFS:

Event-free survival

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Acknowledgements

None.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No: 32300473), Guangdong Basic and Applied Basic Research Foundation (No: 2023A1515220053), and Guangzhou Science and Technology Project (No: 202201020622).

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Author notes

  1. Jiabin Liu, Mengzhen Zhang and Yu Ouyang contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Surgery, Liuzhou Key Laboratory of Birth Defect Prevention and Control, Guangzhou Women and Children’s Medical Center Liuzhou Hospital, Liuzhou, 545616, Guangxi, China

    Jiabin Liu, Yu Ouyang, Jing He & Xinxin Zhang

  2. Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, 510623, Guangdong, China

    Jiabin Liu, Mengzhen Zhang, Jiaming Chang, Wenli Zhang, Jing He & Xinxin Zhang

  3. Department of Pathology, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, Jiangsu, China

    Chunlei Zhou

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  1. Jiabin Liu
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Contributions

All the authors contributed significantly to this work. C.Z. collected the samples and data; J.L., M.Z., Y.O., J.C., W.Z., X.Z. and J.H. performed the research study; W.Z. and J.H. analyzed the data and prepared all the figures and tables; J.H. and X.Z. designed the research study; and J. L., M.Z., Y.O. and J.H. wrote the paper. All authors have read and approved the final manuscript to be published.

Corresponding authors

Correspondence to Jing He or Xinxin Zhang.

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Ethics approval and consent to participate

The study followed the Declaration of Helsinki guidelines. All participants’ guardians have signed informed written consent. Before conducting the research, the study obtained approval from the Children’s Hospital of Nanjing Medical University’s Institutional Review Committee (approval number No: 202112141-1).

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Liu, J., Zhang, M., Ouyang, Y. et al. Association between MYCN gene polymorphisms and neuroblastoma susceptibility: a case-control study in Chinese children from Jiangsu Province. BMC Cancer 25, 892 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14310-w

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Keywords

BMC Cancer

ISSN: 1471-2407

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