Tumor Biology

, Volume 37, Issue 7, pp 9579–9586 | Cite as

IKZF1 gene polymorphisms increased the risk of childhood acute lymphoblastic leukemia in an Iranian population

  • Gholamreza Bahari
  • Mohammad Hashemi
  • Majid Naderi
  • Mohsen Taheri
Original Article

Abstract

Genome-wide association studies (GWAS) have proved the association of IKZF1 polymorphisms with childhood acute lymphoblastic leukemia (ALL). In the present study, we aimed to inspect the impact of IKZF1 gene polymorphisms and childhood ALL in a sample of Iranian population who live in south east of Iran. This case-control study was done on 110 children diagnosed with ALL and 120 healthy children. The IKZF1 (rs4132601 T > G, rs11978267 A > G, rs11980379 T > C, and rs10272724 T > C) polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The results showed that rs4132601 T > G polymorphism increased the risk of ALL in the codominant (OR = 2.96, 95 % CI = 1.58–5.54, p = 0.0008, TG vs TT; and OR = 2.75, 95 % CI = 1.31–5.76, p = 0.0094, GG vs TT) and dominant (OR = 2.89, 95 % CI = 1.61–5.19, p = 0.0004, TG + GG vs TT) inheritance models. On the other hand, the rs4132601 G allele increased the risk of ALL (OR = 1.86, 95 % CI = 1.28–2.96; p = 0.0011) in comparison with the T allele. We have also showed that rs11980379 T > C variant increased the risk of ALL in codominant (OR = 2.43, 95 % CI = 1.28–4.60, p = 0.0076, TC vs TT; and OR = 2.35, 95 % CI = 1.14–4.85, p = 0.0291, CC vs TT) and dominant (OR = 2.40, 95 % CI = 1.32–4.36, p = 0.0038, TC + CC vs TT) inheritance models. The rs11980379 C allele increased the risk of ALL (OR = 1.59, 95 % CI = 1.10–2.31, p = 0.0151) compared with T allele. Our study also revealed that the rs10272724 T > C polymorphism increased the risk of ALL in codominant (OR = 2.18, 95 % CI = 1.19–3.99, p = 0.0115, TC vs TT; and OR = 2.67, 95 % CI = 1.24–5.77, p = 0.0131, CC vs TT) and dominant (OR = 2.31, 95 % CI = 1.30–4.08, p = 0.0049, TC + CC vs TT) inheritance models. On the one hand, the rs11980379 C allele increased the risk of ALL (OR = 1.70, 95 % CI = 1.17–2.46, p = 0.0062) compared with T allele, while the rs11978267 A/G polymorphism was not associated with ALL risk. In conclusion, our findings confirm the impact of IKZF1 polymorphisms on childhood ALL risk in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are needed to confirm our findings.

Keywords

IKZF1 Polymorphism Acute lymphocytic leukemia 

Notes

Acknowledgments

This work was supported by a dissertation grant (PhD thesis of GB) from Zahedan University of Medical Sciences.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Eden T, Pieters R, Richards S, Childhood Acute Lymphoblastic Leukaemia Collaborative G. Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia - an individual patient data meta-analysis involving 5,659 children. Br J Haematol. 2010;149:722–33.CrossRefPubMedGoogle Scholar
  2. 2.
    Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007;115:138–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36:277–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Guo LM, Xi JS, Ma Y, Shao L, Nie CL, Wang GJ. Arid5b gene rs10821936 polymorphism is associated with childhood acute lymphoblastic leukemia: a meta-analysis based on 39,116 subjects. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35:709–13.CrossRefGoogle Scholar
  5. 5.
    Ma Y, Sui Y, Wang L, Li H. Effect of gstm1 null genotype on risk of childhood acute leukemia: a meta-analysis. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35:397–402.CrossRefGoogle Scholar
  6. 6.
    Harker N, Naito T, Cortes M, Hostert A, Hirschberg S, Tolaini M, et al. The cd8alpha gene locus is regulated by the ikaros family of proteins. Mol Cell. 2002;10:1403–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, et al. The ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79:143–56.CrossRefPubMedGoogle Scholar
  8. 8.
    Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. Bcr-abl1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–4.CrossRefPubMedGoogle Scholar
  9. 9.
    Yang YL, Hung CC, Chen JS, Lin KH, Jou ST, Hsiao CC, et al. Ikzf1 deletions predict a poor prognosis in children with b-cell progenitor acute lymphoblastic leukemia: a multicenter analysis in Taiwan. Cancer Sci. 2011;102:1874–81.CrossRefPubMedGoogle Scholar
  10. 10.
    Martinelli G, Lacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. Foa R: Ikzf1 (ikaros) deletions in bcr-abl1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a gimema al wp report. J Clin Oncol: Off J Am Soc Clin Oncol. 2009;27:5202–7.CrossRefGoogle Scholar
  11. 11.
    Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of ikzf1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470–80.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Olsson L, Johansson B. Ikaros and leukaemia. Br J Haematol. 2015;169:479–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Molnar A, Georgopoulos K. The ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol. 1994;14:8292–303.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Molnar A, Wu P, Largespada DA, Vortkamp A, Scherer S, Copeland NG, et al. The ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J Immunol. 1996;156:585–92.PubMedGoogle Scholar
  15. 15.
    Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758–64.CrossRefPubMedGoogle Scholar
  16. 16.
    Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet. 2009;41:1006–10.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Trevino LR, Yang W, French D, Hunger SP, Carroll WL, Devidas M, et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. 2009;41:1001–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M, et al. Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor b-cell acute lymphoblastic leukemia of childhood. Blood. 2010;115:1765–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Dai YE, Tang L, Healy J, Sinnett D. Contribution of polymorphisms in ikzf1 gene to childhood acute leukemia: a meta-analysis of 33 case-control studies. PLoS One. 2014;9, e113748.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rudant J, Orsi L, Bonaventure A, Goujon-Bellec S, Baruchel A, Petit A, et al. Arid5b, ikzf1 and non-genetic factors in the etiology of childhood acute lymphoblastic leukemia: the escale study. PLoS One. 2015;10, e0121348.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Li S, Ren L, Fan L, Wang G. Ikzf1 rs4132601 polymorphism and acute lymphoblastic leukemia susceptibility: a meta-analysis. Leuk Lymphoma. 2015;56:978–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Lin CY, Li MJ, Chang JG, Liu SC, Weng T, Wu KH, et al. High-resolution melting analyses for genetic variants in arid5b and ikzf1 with childhood acute lymphoblastic leukemia susceptibility loci in taiwan. Blood Cells Mol Dis. 2014;52:140–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Gorniak P, Pastorczak A, Zalewska-Szewczyk B, Lejman M, Trelinska J, Chmielewska M, et al. Polish pediatric leukemia/lymphoma study G: polymorphism in ikzf1 gene affects age at onset of childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2014;55:2174–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Orsi L, Rudant J, Bonaventure A, Goujon-Bellec S, Corda E, Evans TJ, et al. Genetic polymorphisms and childhood acute lymphoblastic leukemia: Gwas of the escale study (sfce). Leukemia. 2012;26:2561–4.CrossRefPubMedGoogle Scholar
  25. 25.
    Evans TJ, Milne E, Anderson D, de Klerk NH, Jamieson SE, Talseth-Palmer BA, et al. Confirmation of childhood acute lymphoblastic leukemia variants, arid5b and ikzf1, and interaction with parental environmental exposures. PLoS One. 2014;9, e110255.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hashemi M, Sheybani-Nasab M, Naderi M, Roodbari F, Taheri M. Association of functional polymorphism at the mir-502-binding site in the 3′ untranslated region of the setd8 gene with risk of childhood acute lymphoblastic leukemia, a preliminary report. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35:10375–9.CrossRefGoogle Scholar
  27. 27.
    Hasani SS, Hashemi M, Eskandari-Nasab E, Naderi M, Omrani M, Sheybani-Nasab M. A functional polymorphism in the mir-146a gene is associated with the risk of childhood acute lymphoblastic leukemia: a preliminary report. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35:219–25.CrossRefGoogle Scholar
  28. 28.
    Hashemi M, Ebrahimi M, Amininia S, Naderi M, Eskanadri-Nasab E, Taheri M. Evaluation of osteoprotegerin gene polymorphisms and the risk of childhood acute lymphocytic leukemia in zahedan southeast iran. Int J Hematol Oncol Stem Cell Res. 2014;8:39–44.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Hashemi M, Moazeni-Roodi AK, Fazaeli A, Sandoughi M, Bardestani GR, Kordi-Tamandani DM, et al. Lack of association between paraoxonase-1 q192r polymorphism and rheumatoid arthritis in southeast Iran. Genet Mol Res. 2010;9:333–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Sole X, Guino E, Valls J, Iniesta R, Moreno V. Snpstats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Klug CA, Morrison SJ, Masek M, Hahm K, Smale ST, Weissman IL. Hematopoietic stem cells and lymphoid progenitors express different ikaros isoforms, and ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci U S A. 1998;95:657–62.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Olsson L, Ivanov Ofverholm I, Noren-Nystrom U, Zachariadis V, Nordlund J, Sjogren H, Golovleva I, Nordgren A, Paulsson K, Heyman M, Barbany G, Johansson B: The clinical impact of ikzf1 deletions in paediatric b-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in nordic society for paediatric haematology and oncology treatment protocols used between 1992 and 2013. Br J Haematol 2015.Google Scholar
  33. 33.
    Olsson L, Castor A, Behrendtz M, Biloglav A, Forestier E, Paulsson K, et al. Deletions of ikzf1 and spred1 are associated with poor prognosis in a population-based series of pediatric b-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia. 2014;28:302–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Walsh KM, de Smith AJ, Welch TC, Smirnov I, Cunningham MJ, Ma X, et al. Genomic ancestry and somatic alterations correlate with age at diagnosis in hispanic children with b-cell acute lymphoblastic leukemia. Am J Hematol. 2014;89:721–5.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Xu H, Yang W, Perez-Andreu V, Devidas M, Fan Y, Cheng C, et al. Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst. 2013;105:733–42.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lautner-Csorba O, Gezsi A, Semsei AF, Antal P, Erdelyi DJ, Schermann G, et al. Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by bayesian network based bayesian multilevel analysis of relevance. BMC Med Genet. 2012;5:42.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Gholamreza Bahari
    • 1
    • 2
  • Mohammad Hashemi
    • 1
    • 2
  • Majid Naderi
    • 3
  • Mohsen Taheri
    • 3
  1. 1.Cellular and Molecular Research CenterZahedan University of Medical SciencesZahedanIran
  2. 2.Department of Clinical Biochemistry, School of MedicineZahedan University of Medical SciencesZahedanIran
  3. 3.Genetics of Non Communicable Disease Research CenterZahedan University of Medical SciencesZahedanIran

Personalised recommendations