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Intron 3 of the ARID5B gene: a hot spot for acute lymphoblastic leukemia susceptibility

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Abstract

Purpose

Single-nucleotide polymorphisms (SNPs) in AT-rich interactive domain 5B (ARID5B) have been associated with risk for pediatric acute lymphoblastic leukemia (ALL). After reviewing previous studies, we realized that the most significant associations were restricted to intron 3, but the mechanism(s) by which those SNPs affect ALL risk remain to be elucidated. Therefore, the aim of this study was to analyze the association between genetic variants of the intron 3 region of ARID5B and the incidence of B-ALL in a Spanish population. We also aimed to find a functional explanation for the association, searching for copy number variations (CNVs), and changes in ARID5B expression associated with the genotypes of the SNPs.

Methods

We analyzed 10 SNPs in intron 3 of ARID5B in a Spanish population of 219 B-ALL patients and 397 unrelated controls with the Taqman Open Array platform. CNVs were analyzed in 23 patients and 17 controls using the Cytogenetics Whole-genome 2.7 M platform. Expression of ARID5B transcript 1 was quantified by qPCR and related to SNPs genotype in seven ALL cell lines.

Results

Association between intron 3 and B-ALL risk was confirmed for all of the SNPs evaluated in our Spanish population. We could not explain this association by the presence of CNVs. We neither detected changes in the expression of ARID5B isoform associated with the genotype of the SNPs.

Conclusions

The intron 3 of ARID5B gene was found to be strongly associated with B-ALL risk in the Spanish population examined. However, neither CNVs nor changes in mRNA expression were found to be responsible for this association.

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References

  • Bourquin JP, Subramanian A et al (2006) Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci USA 103(9):3339–3344

    Article  PubMed  CAS  Google Scholar 

  • Chang LW, Payton JE et al (2008) Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia. Genome Biol 9(2):R38

    Article  PubMed  Google Scholar 

  • Ellinghaus E, Stanulla M et al (2012) Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia. Leukemia 26(5):902–909

    Article  PubMed  CAS  Google Scholar 

  • Gusev A, Lowe JK et al (2009) Whole population, genome-wide mapping of hidden relatedness. Genome Res 19(2):318–326

    Article  PubMed  CAS  Google Scholar 

  • Han S, Lee KM et al (2010) Genome-wide association study of childhood acute lymphoblastic leukemia in Korea. Leuk Res 34(10):1271–1274

    Article  PubMed  CAS  Google Scholar 

  • Healy J, Richer C et al (2010) Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia. Haematologica 95(9):1608–1611

    Article  PubMed  CAS  Google Scholar 

  • Huang L, Yu D et al (2012) Copy number variation at 6q13 functions as a long-range regulator and is associated with pancreatic cancer risk. Carcinogenesis 33(1):94–100

    Article  PubMed  CAS  Google Scholar 

  • Johnston WT, Lightfoot TJ et al (2010) Childhood cancer survival: a report from the United Kingdom Childhood Cancer Study. Cancer Epidemiol 34(6):659–666

    Article  PubMed  Google Scholar 

  • Klipper-Aurbach Y, Wasserman M et al (1995) Mathematical formulae for the prediction of the residual beta cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus. Med Hypotheses 45(5):486–490

    Article  PubMed  CAS  Google Scholar 

  • Lahoud MH, Ristevski S et al (2001) Gene targeting of Desrt, a novel ARID class DNA-binding protein, causes growth retardation and abnormal development of reproductive organs. Genome Res 11(8):1327–1334

    Article  PubMed  CAS  Google Scholar 

  • Lautner-Csorba O, Gézsi A et al (2012) Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by Bayesian network based Bayesian multilevel analysis of relevance. BMC Med Genomics 5:42

    Article  PubMed  CAS  Google Scholar 

  • Lee PH, Shatkay H (2008) F-SNP: computationally predicted functional SNPs for disease association studies. Nucleic Acids Res 36(Database issue): D820–D824

    Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408

    Google Scholar 

  • Lopez-Lopez E, Martin-Guerrero I et al (2011) Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 57(4):612–619

    Article  PubMed  Google Scholar 

  • Orsi L, Rudant J et al (2012) Genetic polymorphisms and childhood acute lymphoblastic leukemia: GWAS of the ESCALE study (SFCE). Leukemia 26(12):2561–2564

    Article  PubMed  CAS  Google Scholar 

  • Pal S, Gupta R et al (2012) Alternative transcription and alternative splicing in cancer. Pharmacol Ther 136(3):283–294

    Article  PubMed  CAS  Google Scholar 

  • Papaemmanuil E, Hosking FJ et al (2009) Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41(9):1006–1010

    Article  PubMed  CAS  Google Scholar 

  • Pastorczak A, Górniak P et al (2011) Role of 657del5 NBN mutation and 7p12.2 (IKZF1), 9p21 (CDKN2A), 10q21.2 (ARID5B) and 14q11.2 (CEBPE) variation and risk of childhood ALL in the Polish population. Leuk Res 35(11):1534–1536

    Article  PubMed  CAS  Google Scholar 

  • Paulsson K, Forestier E et al (2010) Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 107(50):21719–21724

    Article  PubMed  CAS  Google Scholar 

  • Perry GH, Ben-Dor A et al (2008) The fine-scale and complex architecture of human copy-number variation. Am J Hum Genet 82(3):685–695

    Article  PubMed  CAS  Google Scholar 

  • Prasad RB, Hosking FJ et al (2010) Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood 115(9):1765–1767

    Article  PubMed  CAS  Google Scholar 

  • Samuelsson J, Alonso S et al (2011) Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer. Int J Oncol 38(6):1575–1577

    PubMed  CAS  Google Scholar 

  • Treviño LR, Yang W et al (2009) Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41(9):1001–1005

    Article  PubMed  Google Scholar 

  • Vijayakrishnan J, Sherborne AL et al (2010) Variation at 7p12.2 and 10q21.2 influences childhood acute lymphoblastic leukemia risk in the Thai population and may contribute to racial differences in leukemia incidence. Leuk Lymphoma 51(10):1870–1874

    Article  PubMed  CAS  Google Scholar 

  • Xu H, Cheng C et al (2012) ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 30(7):751–757

    Article  PubMed  CAS  Google Scholar 

  • Yang W, Treviño LR et al (2010) ARID5B SNP rs10821936 is associated with risk of childhood acute lymphoblastic leukemia in blacks and contributes to racial differences in leukemia incidence. Leukemia 24(4):894–896

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Xabier Agirre for providing us the RNA of the seven cell lines of ALL and Nerea Bilbao for her contribution to this study. Support by SGIker (UPV/EHU) is gratefully acknowledged. This project was supported by RTICS (RD/06/0020/0048), Basque Government (GIC10/71), and UPV/EHU (UFI11/35). AGC was supported by a predoctoral grant from the Gangoiti Barrera Foundation. ELL was supported by a “Fellowship for recent Doctors until their integration in postdoctoral programs” by the Investigation Vice-rector’s office of the UPV/EHU.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940, Leioa, Spain

    Ángela Gutiérrez-Camino, Elixabet López-López, Idoia Martín-Guerrero & África García-Orad

  2. Service of Pediatric Oncology and Hematology, University Hospital Vall d’ Hebron, VHIR, Barcelona, Spain

    José Sánchez-Toledo

  3. Unit of Pediatric Oncohematology, University Hospital Donostia, San Sebastián, Spain

    Nagore García de Andoin

  4. Unit of Pediatric Oncohematology, University Hospital Miguel Servet, Zaragoza, Spain

    Ana Carboné Bañeres

  5. Service of Pediatric Oncohematology, University Hospital La Paz, Madrid, Spain

    Purificación García-Miguel

  6. Unit of Pediatric Hematology/Oncology, University Hospital Cruces, Bilbao, Spain

    Aurora Navajas

Authors
  1. Ángela Gutiérrez-Camino
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  2. Elixabet López-López
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  3. Idoia Martín-Guerrero
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  4. José Sánchez-Toledo
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  5. Nagore García de Andoin
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  6. Ana Carboné Bañeres
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  7. Purificación García-Miguel
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  8. Aurora Navajas
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  9. África García-Orad
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Corresponding author

Correspondence to África García-Orad.

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Gutiérrez-Camino, Á., López-López, E., Martín-Guerrero, I. et al. Intron 3 of the ARID5B gene: a hot spot for acute lymphoblastic leukemia susceptibility. J Cancer Res Clin Oncol 139, 1879–1886 (2013). https://doi.org/10.1007/s00432-013-1512-3

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  • DOI: https://doi.org/10.1007/s00432-013-1512-3

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