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Neuroblastoma susceptibility and association of N7-methylguanosine modification gene polymorphisms: multi-center case-control study

Pediatric Research (2024)Cite this article

Abstract

Background

Neuroblastoma (NB) is a common extracranial solid malignancy in children. The N7-methylguanosine (m7G) modification gene METTL1/WDR4 polymorphisms may serve as promising molecular markers for identifying populations susceptible to NB.

Methods

TaqMan probes was usded to genotype METTL1/WDR4 single nucleotide polymorphisms (SNPs) in 898 NB patients and 1734 healthy controls. A logistic regression model was utilized to calculate the odds ratio (OR) and 95% confidence interval (CI), evaluating the association between genotype polymorphisms and NB susceptibility. The analysis was also stratified by age, sex, tumor origin site, and clinical stage.

Results

Individual polymorphism of the METTL1/WDR4 gene investigated in this study did not show significant associations with NB susceptibility. However, combined genotype analysis revealed that carrying all 5 WDR4 protective genotypes was associated with a significantly lower NB risk compared to having 0–4 protective genotypes (AOR = 0.82, 95% CI = 0.69–0.96, P = 0.014). Further stratified analyses revealed that carrying 1–3 METTL1 risk genotypes, the WDR4 rs2156316 CG/GG genotype, the WDR4 rs2248490 CG/GG genotype, and having all five WDR4 protective genotypes were all significantly correlated with NB susceptibility in distinct subpopulations.

Conclusions

In conclusion, our findings suggest significant associations between m7G modification gene METTL1/WDR4 SNPs and NB susceptibility in specific populations.

Impact

  • Genetic variation in m7G modification gene is associated with susceptibility to NB.

  • Single nucleotide polymorphisms in METTL1/WDR4 are associated with susceptibility to NB.

  • Single nucleotide polymorphisms of METTL1/WDR4 can be used as a biomarker for screening NB susceptible populations.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Cheung, N. K. & Dyer, M. A. Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat. Rev. Cancer 13, 397–411 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu, Z. & Thiele, C. J. Unraveling the enigmatic origin of neuroblastoma. Cancer Cell 38, 618–620 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, T. et al. Rtel1 gene polymorphisms and neuroblastoma risk in Chinese children. BMC Cancer 23, 1145 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mlakar, V. et al. 11q deletion in neuroblastoma: A review of biological and clinical implications. Mol. Cancer 16, 114 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gatta, G. et al. Childhood cancer survival in Europe 1999–2007: Results of Eurocare-5–a population-based study. Lancet Oncol. 15, 35–47 (2014).

    Article  PubMed  Google Scholar 

  6. Tonini, G. P. & Capasso, M. Genetic predisposition and chromosome instability in neuroblastoma. Cancer Metastasis Rev. 39, 275–285 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Matthay, K. K. et al. Neuroblastoma. Nat. Rev. Dis. Prim. 2, 16078 (2016).

    Article  PubMed  Google Scholar 

  8. Park, J. R. et al. Effect of tandem autologous stem cell transplant vs single transplant on event-free survival in patients with high-risk neuroblastoma: A randomized clinical trial. JAMA 322, 746–755 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Matthay, K. K. et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-Cis-retinoic acid: A Children’s oncology group study. J. Clin. Oncol. 27, 1007–1013 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Patton, T., Olshan, A. F., Neglia, J. P., Castleberry, R. P. & Smith, J. Parental exposure to medical radiation and neuroblastoma in offspring. Paediatr. Perinat. Epidemiol. 18, 178–185 (2004).

    Article  PubMed  Google Scholar 

  11. Han, W. et al. Functional polymorphisms in Fas/Fasl system increase the risk of neuroblastoma in Chinese population. PLoS One 8, e71656 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mosse, Y. P. et al. Identification of Alk as a major familial neuroblastoma predisposition gene. Nature 455, 930–935 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Janoueix-Lerosey, I. et al. Somatic and germline activating mutations of the Alk kinase receptor in neuroblastoma. Nature 455, 967–970 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Trochet, D. et al. Germline mutations of the paired-like homeobox 2b (Phox2b) gene in neuroblastoma. Am. J. Hum. Genet 74, 761–764 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mosse, Y. P. et al. Germline Phox2b mutation in hereditary neuroblastoma. Am. J. Hum. Genet 75, 727–730 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maris, J. M. et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N. Engl. J. Med. 358, 2585–2593 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Capasso, M. et al. Common variations in Bard1 influence susceptibility to high-risk neuroblastoma. Nat. Genet 41, 718–723 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, K. et al. Integrative genomics identifies Lmo1 as a neuroblastoma oncogene. Nature 469, 216–220 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Nguyen le, B. et al. Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility loci. PLoS Genet 7, e1002026 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Diskin, S. J. et al. Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459, 987–991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Malbec, L. et al. Dynamic methylome of internal Mrna N(7)-methylguanosine and its regulatory role in translation. Cell Res 29, 927–941 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kouzarides, T., Pandolfini, L., Barbieri, I., Bannister, A. J. & Andrews, B. Further evidence supporting N7-methylation of guanosine (M(7)G) in human micrornas. Mol. Cell 79, 201–202 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Varshney, D. et al. Molecular basis of rna guanine-7 methyltransferase (Rnmt) activation by ram. Nucleic Acids Res 44, 10423–10436 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Galloway, A. et al. Upregulation of Rna cap methyltransferase rnmt drives ribosome biogenesis during T cell activation. Nucleic Acids Res 49, 6722–6738 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen, Z. et al. Mettl1 promotes hepatocarcinogenesis Via M(7) G Trna modification-dependent translation control. Clin. Transl. Med. 11, e661 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ma, J. et al. Mettl1/Wdr4-mediated M(7)G Trna modifications and M(7)G codon usage promote Mrna translation and lung cancer progression. Mol. Ther. 29, 3422–3435 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ying, X. et al. Mettl1-M(7) G-Egfr/Efemp1 axis promotes the bladder cancer development. Clin. Transl. Med. 11, e675 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Katsara, O. & Schneider, R. J. M(7)G Trna modification reveals new secrets in the translational regulation of cancer development. Mol. Cell 81, 3243–3245 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhuo, Z. et al. Mettl14 gene polymorphisms confer neuroblastoma susceptibility: An eight-center case-control study. Mol. Ther. Nucleic Acids 22, 17–26 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Alexandrov, A., Martzen, M. R. & Phizicky, E. M. Two proteins that form a complex are required for 7-methylguanosine modification of yeast Trna. RNA 8, 1253–1266 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ratner, N., Brodeur, G. M., Dale, R. C. & Schor, N. F. The “Neuro” of neuroblastoma: neuroblastoma as a neurodevelopmental disorder. Ann. Neurol. 80, 13–23 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Norsker, F. N. et al. Neurologic disorders in long-term survivors of neuroblastoma - a population-based cohort study within the adult life after childhood cancer in scandinavia (Aliccs) research program. Acta Oncol. 59, 134–140 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Ma, J. et al. M(7)Gdisai: N7-Methylguanosine (M(7)G) sites and diseases associations inference based on heterogeneous network. BMC Bioinforma. 22, 152 (2021).

    Article  CAS  Google Scholar 

  34. Bull, M. J. Down syndrome. N. Engl. J. Med. 382, 2344–2352 (2020).

    Article  PubMed  Google Scholar 

  35. Li, W., Li, X., Ma, X., Xiao, W. & Zhang, J. Mapping the M1a, M5c, M6a and M7g Methylation Atlas in Zebrafish Brain under Hypoxic Conditions by Merip-Seq. BMC Genomics 23, 105 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jiang, J., Wang, C., Qi, R., Fu, H. & Ma, Q. Scread: A single-cell Rna-Seq database for Alzheimer’s disease. iScience 23, 101769 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao, Y. et al. M7g methyltransferase Mettl1 promotes post-ischemic angiogenesis via promoting Vegfa Mrna translation. Front Cell Dev. Biol. 9, 642080 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Australia & New Zealand Multiple Sclerosis Genetics, C Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat. Genet 41, 824–828 (2009).

    Article  Google Scholar 

  39. Hadjigeorgiou, G. M. et al. Replication study of gwas risk loci in greek multiple sclerosis patients. Neurol. Sci. 40, 253–260 (2019).

    Article  PubMed  Google Scholar 

  40. Alcina, A. et al. Identification of a functional variant in the Kif5a-Cyp27b1-Mettl1-Fam119b locus associated with multiple sclerosis. J. Med Genet 50, 25–33 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Gil-Varea, E. et al. A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of Cxcr5+ circulating regulatory T cells. J. Clin. Med. 9, 625 (2020).

  42. Cheng, Y. et al. Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials. Signal Transduct. Target Ther. 4, 62 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kentsis, A., Topisirovic, I., Culjkovic, B., Shao, L. & Borden, K. L. Ribavirin suppresses eif4e-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine Mrna cap. Proc. Natl. Acad. Sci. USA 101, 18105–18110 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhu, J. et al. Association of Rna M(7)G modification gene polymorphisms with pediatric glioma risk. Biomed. Res Int 2023, 3678327 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  45. He, S. et al. Wdr4 gene polymorphisms increase hepatoblastoma susceptibility in girls. J. Cancer 13, 3342–3347 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pandolfini, L. et al. Mettl1 promotes Let-7 microrna processing Via M7g methylation. Mol. Cell 74, 1278–1290.e1279 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xia, P. et al. Myc-targeted Wdr4 promotes proliferation, metastasis, and sorafenib resistance by inducing Ccnb1 translation in hepatocellular carcinoma. Cell Death Dis. 12, 691 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Deng, Y., Zhou, Z., Ji, W., Lin, S. & Wang, M. Mettl1-mediated M(7)G methylation maintains pluripotency in human stem cells and limits mesoderm differentiation and vascular development. Stem Cell Res. Ther. 11, 306 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Funding

This work was supported by grants from the National Natural Science Foundation of China (82173593, 82002636), Guangzhou Science and Technology Project (No: 202201020622), The Science, Technology, and Innovation Commission of Shenzhen (JCYJ20220531093213030), the Major Science and Technology Special Project of Wenzhou (No. ZY2020021).

Author information

Authors and Affiliations

  1. 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, Guangzhou, 510623, Guangdong, China

    Huiran Lin, Fan Liao, Jiabin Liu & Jing He

  2. Faculty of Medicine, Macau University of Science and Technology, Macau, 999078, China

    Huiran Lin & Jing He

  3. Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China

    Zhonghua Yang

  4. Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Jiao Zhang

  5. Department of Pediatric Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, Shaanxi, China

    Jiwen Cheng

  6. Department of Hematology, The Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China

    Haixia Zhou

  7. Department of Pathology, Children Hospital and Women Health Center of Shanxi, Taiyuan, 030013, Shannxi, China

    Suhong Li

  8. Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Yunnan Medical Center for Pediatric Diseases, Kunming Children’s Hospital, Kunming, 650228, Yunnan, China

    Li Li

  9. Department of Pediatric Surgery, Hunan Children’s Hospital, Changsha, 410004, Hunan, China

    Yong Li

  10. Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China

    Zhenjian Zhuo

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  1. Huiran Lin
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Contributions

Study concept and design (HL, FL, JL, ZY, JZ), acquisition of data (HL, FL, JL, ZY, JZ), analysis and interpretation of data (HL, FL, JL, ZY, JZ, JC), drafting of the manuscript (HL, FL, JL, ZY, JZ, JC), critical revision of the manuscript for important intellectual content (HZ, SL, LL, YL, ZZ, JH), administrative, technical, or material support, study supervision (HZ, SL, LL, YL, ZZ, JH).

Corresponding authors

Correspondence to Zhenjian Zhuo or Jing He.

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Lin, H., Liao, F., Liu, J. et al. Neuroblastoma susceptibility and association of N7-methylguanosine modification gene polymorphisms: multi-center case-control study. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03318-w

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  • DOI: https://doi.org/10.1038/s41390-024-03318-w

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