Cancer Res Treat.  2020 Oct;52(4):1251-1261. 10.4143/crt.2020.140.

Genome-Wide Association Study for the Identification of Novel Genetic Variants Associated with the Risk of Neuroblastoma in Korean Children

Affiliations
  • 1Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 2Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 3Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 4Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Abstract

Purpose
Neuroblastoma (NB) is the most common extracranial solid tumor found in children. To identify significant genetic factors for the risk of NB, several genetic studies was conducted mainly for Caucasians and Europeans. However, considering racial differences, there is a possibility that genetic predispositions that contribute to the development of NB are different, and GWAS study has not yet been conducted on Korean NB patients.
Materials and Methods
To identify the genetic variations associated with the risk of pediatric NB in Korean children, we performed a genome-wide association analysis with 296 NB patients and 1000 unaffected controls (total n = 1,296) after data cleaning and filtering as well as imputation of non-genotyped SNPs using IMPUTE v2.3.2.
Results
After adjusting for multiple comparisons, we found 21 statistically significant SNPs associated with the risk of NB (Pcorr < 0.05) within 12 genes (RPTN, MRPS18B, LRRC45, KANSL1L, ARHGEF40, IL15RA, L1TD1, ANO7, LAMA5, OR7G2, SALL4, and NEUROG2). Interestingly, out of these, 12 markers were nonsynonymous SNPs. The SNP rs76015112 was most significantly associated with the risk of NB (p = 8.1E-23, Pcorr = 2.3E-17) and was located in the RPTN gene. In addition, significant nonsynonymous SNPs in ADGRE1 were found in patients with MYCN amplification (rs7256147, p = 2.6E-05). In high-risk group, rs7256147 was observed as a significant SNP (p = 5.9E-06).
Conclusion
Our findings might facilitate improved understanding of the mechanism of pediatric NB pathogenesis. However, functional evaluation and replication of these results in other populations are still needed.

Keyword

Neuroblastoma; Genetic variation; Genome wide association study; amplification; high risk; Korean children

Figure

  • Fig. 1. (A) The p-values of genome-wide association study. The Manhattan plot shows the p-values for the risk of neuroblastoma using logistic regression analysis. x-axis represents the single nucleotide polymorphism (SNP) markers on each chromosome. The highest p-value (p=8.1E-23, pcorr=2.3E-17) was observed in rs76015112 on 1q21.3. (B) Regional association plots at the RPTN. Regional association plots including both genotyped and SNPs for the RPTN was generated by LocusZoom within 400 kb. The significance of association (−log10-transformed p-values) and the recombination rate are plotted. SNPs are colored to reflect pairwise linkage disequilibrium (r2) with the most significantly associated genotyped SNP in the 1000 Genomes Project Phase 1 interim release Asian (ASN) population genotypes. The most significant genotyped SNPs are labeled and shown in purple.


Reference

References

1. Latimer E, Anderson G, Sebire NJ. Ultrastructural features of neuroblastic tumors in relation to morphological, and molecular findings; a retrospective review study. BMC Clin Pathol. 2014; 14:13.
Article
2. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009; 27:289–97.
Article
3. Lee JW, Son MH, Cho HW, Ma YE, Yoo KH, Sung KW, et al. Clinical significance of MYCN amplification in patients with high-risk neuroblastoma. Pediatr Blood Cancer. 2018; 65:e27257.
Article
4. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015; 33:3008–17.
Article
5. Barr EK, Applebaum MA. Genetic predisposition to neuroblastoma. Children (Basel). 2018; 5:119.
Article
6. Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, Scott RH, et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008; 358:2585–93.
Article
7. Capasso M, Devoto M, Hou C, Asgharzadeh S, Glessner JT, Attiyeh EF, et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet. 2009; 41:718–23.
Article
8. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010; 7:248–9.
Article
9. Chang X, Zhao Y, Hou C, Glessner J, McDaniel L, Diamond MA, et al. Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk. Nat Commun. 2017; 8:569.
Article
10. Hungate EA, Applebaum MA, Skol AD, Vaksman Z, Diamond M, McDaniel L, et al. Evaluation of genetic predisposition for MYCN-amplified neuroblastoma. J Natl Cancer Inst. 2017; 109:djx093.
Article
11. Capasso M, McDaniel LD, Cimmino F, Cirino A, Formicola D, Russell MR, et al. The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma. J Cell Mol Med. 2017; 21:3224–30.
Article
12. McDaniel LD, Conkrite KL, Chang X, Capasso M, Vaksman Z, Oldridge DA, et al. Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma. PLoS Genet. 2017; 13:e1006787.
Article
13. Diskin SJ, Capasso M, Diamond M, Oldridge DA, Conkrite K, Bosse KR, et al. Rare variants in TP53 and susceptibility to neuroblastoma. J Natl Cancer Inst. 2014; 106:dju047.
Article
14. Capasso M, Diskin S, Cimmino F, Acierno G, Totaro F, Petrosino G, et al. Common genetic variants in NEFL influence gene expression and neuroblastoma risk. Cancer Res. 2014; 74:6913–24.
Article
15. Latorre V, Diskin SJ, Diamond MA, Zhang H, Hakonarson H, Maris JM, et al. Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiol Biomarkers Prev. 2012; 21:658–63.
16. Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet. 2012; 44:1126–30.
Article
17. Nguyen le B, Diskin SJ, Capasso M, Wang K, Diamond MA, Glessner J, et al. Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility loci. PLoS Genet. 2011; 7:e1002026.
Article
18. Matthews JM, Lester K, Joseph S, Curtis DJ. LIM-domain-only proteins in cancer. Nat Rev Cancer. 2013; 13:111–22.
Article
19. Wang K, Diskin SJ, Zhang H, Attiyeh EF, Winter C, Hou C, et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature. 2011; 469:216–20.
Article
20. Capasso M, Diskin SJ, Totaro F, Longo L, De Mariano M, Russo R, et al. Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility. Carcinogenesis. 2013; 34:605–11.
Article
21. Huber M, Siegenthaler G, Mirancea N, Marenholz I, Nizetic D, Breitkreutz D, et al. Isolation and characterization of human repetin, a member of the fused gene family of the epidermal differentiation complex. J Invest Dermatol. 2005; 124:998–1007.
Article
22. Baud V, Chissoe SL, Viegas-Pequignot E, Diriong S, N’Guyen VC, Roe BA, et al. EMR1, an unusual member in the family of hormone receptors with seven transmembrane segments. Genomics. 1995; 26:334–44.
Article
Full Text Links
  • CRT
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr