Tumor Biology

, Volume 36, Issue 3, pp 1579–1588 | Cite as

Genetic variants in N-myc (and STAT) interactor and susceptibility to glioma in a Chinese Han population

  • Delong Meng
  • Xiaoying Li
  • Shuo Zhang
  • Yingjie Zhao
  • Xiao Song
  • Yuanyuan Chen
  • Shiming Wang
  • Ying Mao
  • Hongyan Chen
  • Daru Lu
Research Article

Abstract

Glioma is one of the most common and lethal brain tumors. N-myc (and STAT) interactor (NMI) gene has been reported in tumorigenesis, and our previous study further showed its implication in glioma progression. To elucidate its involvement in the etiology of glioma, we conducted a case–control study of 875 patients and 1040 controls in a Chinese Han population by genotyping 7 representative single nucleotide polymorphisms (SNPs) in NMI. Allele and genotype frequency distribution of five loci (rs2278089, rs2194492, rs6734376, rs3854012, and rs11730) were significantly different between the cases and controls. Unconditional logistic regression showed that the variant genotypes of rs2278089 [adjusted odds ratio (OR) = 1.57, P = 4.23 × 10−6], rs2194492 (adjusted OR = 1.49, P = 1.20 × 10−4), and rs6734376 (adjusted OR = 0.06, P = 8.65 × 10−13) significantly affected glioma risk compared with the major homozygotes, while the minor homozygotes of rs3854012 (adjusted OR = 0.54, P = 4.64 × 10−6) and rs11730 (adjusted OR = 0.60, P = 1.50 × 10−4) showed significant protective effects. Further stratified analyses indicated that these associations remained significant in subgroups of low-grade glioma (LGG) and high-grade glioma (HGG). Additionally, haplotype and diplotype analyses showed consistent results. The Bonferroni correction was applied for all these analyses. Moreover, luciferase reporter gene assays revealed enhanced promoter activity of the C risk allele of rs2194492 in several cell lines compared with the G major allele, suggesting its potential function in transcriptional activation of NMI. Taken together, these results revealed that NMI polymorphisms may contribute to genetic susceptibility to glioma.

Keywords

NMI Glioma Single nucleotide polymorphism Susceptibility Case–control study 

Notes

Acknowledgments

We thank all staff of the Department of Neurosurgery of Huashan Hospital for their help of sample and epidemiology data collection. We also thank all volunteers recruited in this study for their help of DNA preparing. This work was supported by the National Natural Science Foundation of China (grants 81372706, 81372235, 81170786, and 81071739).

Conflicts of interest

None

References

  1. 1.
    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 2013;15 Suppl 2:ii1–56.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sadetzki S, Chetrit A, Freedman L, Stovall M, Modan B, Novikov I. Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat Res. 2005;163(4):424–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Liu Y, Shete S, Hosking FJ, Robertson LB, Bondy ML, Houlston RS. New insights into susceptibility to glioma. Arch Neurol. 2010;67(3):275–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Gu J, Liu Y, Kyritsis AP, Bondy ML. Molecular epidemiology of primary brain tumors. Neurotherapeutics. 2009;6(3):427–35.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bao J, Zervos AS. Isolation and characterization of Nmi, a novel partner of Myc proteins. Oncogene. 1996;12(10):2171–6.PubMedGoogle Scholar
  7. 7.
    Zhu M, John S, Berg M, Leonard WJ. Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Cell. 1999;96(1):121–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zhou X, Liao J, Meyerdierks A, Feng L, Naumovski L, Bottger EC, et al. Interferon-alpha induces nmi-IFP35 heterodimeric complex formation that is affected by the phosphorylation of IFP35. J Biol Chem. 2000;275(28):21364–71.CrossRefPubMedGoogle Scholar
  10. 10.
    Li H, Lee TH, Avraham H. A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer. J Biol Chem. 2002;277(23):20965–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Schlierf B, Lang S, Kosian T, Werner T, Wegner M. The high-mobility group transcription factor Sox10 interacts with the N-myc-interacting protein Nmi. J Mol Biol. 2005;353(5):1033–42.CrossRefPubMedGoogle Scholar
  12. 12.
    Li Z, Hou J, Sun L, Wen T, Wang L, Zhao X, et al. NMI mediates transcription-independent ARF regulation in response to cellular stresses. Mol Biol Cell. 2012;23(23):4635–46.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang J, Wang Y, Liu J, Ding L, Zhang Q, Li X, et al. A critical role of N-myc and STAT interactor (Nmi) in foot-and-mouth disease virus (FMDV) 2C-induced apoptosis. Virus Res. 2012;170(1–2):59–65.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang J, Yang B, Hu Y, Zheng Y, Zhou H, Wang Y, et al. Negative regulation of Nmi on virus-triggered type I IFN production by targeting IRF7. J Immunol. 2013;191(6):3393–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Lebrun SJ, Shpall RL, Naumovski L. Interferon-induced upregulation and cytoplasmic localization of Myc-interacting protein Nmi. J Interferon Cytokine Res. 1998;18(9):767–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Fillmore RA, Mitra A, Xi Y, Ju J, Scammell J, Shevde LA, et al. Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth. Int J Cancer. 2009;125(3):556–64.CrossRefPubMedGoogle Scholar
  17. 17.
    Devine DJ, Rostas JW, Metge BJ, Das S, Mulekar MS, Tucker JA, et al. Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-beta/SMAD signaling. Oncogene. 2014;33(20):2620–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Quaye L, Song H, Ramus SJ, Gentry-Maharaj A, Hogdall E, DiCioccio RA, et al. Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer. Br J Cancer. 2009;100(6):993–1001.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liu Y, Zhang H, Zhou K, Chen L, Xu Z, Zhong Y, et al. Tagging SNPs in non-homologous end-joining pathway genes and risk of glioma. Carcinogenesis. 2007;28(9):1906–13.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhou K, Liu Y, Zhang H, Liu H, Fan W, Zhong Y, et al. XRCC3 haplotypes and risk of gliomas in a Chinese population: a hospital-based case–control study. Int J Cancer. 2009;124(12):2948–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Chen H, Chen Y, Zhao Y, Fan W, Zhou K, Liu Y, et al. Association of sequence variants on chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) with glioma susceptibility in a Chinese population. Am J Epidemiol. 2011;173(8):915–22.CrossRefPubMedGoogle Scholar
  23. 23.
    Li R, Zhao Y, Fan W, Chen H, Chen Y, Liu Y, et al. Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population. Int J Cancer. 2011;128(1):166–75.CrossRefPubMedGoogle Scholar
  24. 24.
    Wu W, Liu H, Lei R, Chen D, Zhang S, Lv J, et al. Genetic variants in GTF2H1 and risk of lung cancer: a case–control analysis in a Chinese population. Lung Cancer. 2009;63(2):180–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Hu Z, Wang H, Shao M, Jin G, Sun W, Wang Y, et al. Genetic variants in MGMT and risk of lung cancer in Southeastern Chinese: a haplotype-based analysis. Hum Mutat. 2007;28(5):431–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang S, Chen H, Zhao X, Cao J, Tong J, Lu J, et al. REV3L 3'UTR 460T>C polymorphism in microRNA target sites contributes to lung cancer susceptibility. Oncogene. 2013;32(2):242–50.CrossRefPubMedGoogle Scholar
  27. 27.
    Dupont WD, Plummer Jr WD. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990;11(2):116–28.CrossRefPubMedGoogle Scholar
  28. 28.
    Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296(5576):2225–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002;70(2):425–34.CrossRefPubMedGoogle Scholar
  30. 30.
    Fan W, Zhou K, Hu D, Song X, Zhao Y, Chen H, et al. Single nucleotide polymorphisms of matrix metallopeptidase 3 and risk of gliomas in a Chinese Han population. Mol Carcinog. 2012;51(S1):E1–10.CrossRefPubMedGoogle Scholar
  31. 31.
    Fan S, Zhao Y, Li X, Du Y, Wang J, Song X, et al. Genetic variants in SLC7A7 are associated with risk of glioma in a Chinese population. Exp Biol Med. 2013;238(9):1075–81.CrossRefGoogle Scholar
  32. 32.
    de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, et al. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 2008;22(4):449–62.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Delong Meng
    • 1
  • Xiaoying Li
    • 1
  • Shuo Zhang
    • 1
  • Yingjie Zhao
    • 1
  • Xiao Song
    • 1
  • Yuanyuan Chen
    • 1
  • Shiming Wang
    • 1
  • Ying Mao
    • 2
  • Hongyan Chen
    • 1
  • Daru Lu
    • 1
  1. 1.State Key Laboratory of Genetic Engineering, Fudan-VARI Genetic Epidemiology Center and MOE Key Laboratory of Contemporary Anthropology, Institute of Genetics, School of Life SciencesFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Neurosurgery, Huashan HospitalFudan UniversityShanghaiPeople’s Republic of China

Personalised recommendations