Skip to main content
Log in

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

  • Original Article
  • Published:
Tumor Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007;115:138–45.

    Article  CAS  PubMed  Google Scholar 

  3. Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36:277–85.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Olsson L, Johansson B. Ikaros and leukaemia. Br J Haematol. 2015;169:479–91.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohammad Hashemi.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bahari, G., Hashemi, M., Naderi, M. et al. IKZF1 gene polymorphisms increased the risk of childhood acute lymphoblastic leukemia in an Iranian population. Tumor Biol. 37, 9579–9586 (2016). https://doi.org/10.1007/s13277-016-4853-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-4853-0

Keywords

Navigation