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Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children

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Abstract

Background

Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections).

Methods

Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term.

Results

Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95 % confidence interval (CI) 0.35–0.71 (p = 0.004); rs7089424, OR 2.12, 95 % CI 1.70–2.65 (p = 1.16 × 10−9); rs4982731, OR 1.69, 95 % CI 1.37–2.08 (p = 2.35 × 10−6), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed.

Conclusions

Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.

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References

  1. Kaatsch P (2010) Epidemiology of childhood cancer. Cancer Treat Rev 36(4):277–285

    Article  PubMed  Google Scholar 

  2. Pui CH, Relling MV, Downing JR (2004) Acute lymphoblastic leukemia. N Engl J Med 350(15):1535–1548

    Article  CAS  PubMed  Google Scholar 

  3. Eden T (2010) Aetiology of childhood leukaemia. Cancer Treat Rev 36(4):286–297

    Article  CAS  PubMed  Google Scholar 

  4. Urayama KY, Chokkalingam AP, Manabe A, Mizutani S (2013) Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia. Int J Hematol 97(1):3–19

    Article  PubMed  Google Scholar 

  5. Vijayakrishnan J, Houlston RS (2010) Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica 95(8):1405–1414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E 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  CAS  PubMed  Google Scholar 

  7. Orsi L, Rudant J, Bonaventure A, Goujon-Bellec S, Corda E, Evans TJ et al (2012) Genetic polymorphisms and childhood acute lymphoblastic leukemia: GWAS of the ESCALE study (SFCE). Leukemia 26(12):2561–2564

    Article  CAS  PubMed  Google Scholar 

  8. Trevino LR, Yang W, French D, Hunger SP, Carroll WL, Devidas M et al (2009) Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41(9):1001–1005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Xu H, Yang W, Perez-Andreu V, Devidas M, Fan Y, Cheng C, et al (2013) Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst

  10. Greaves M (2006) Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer 6(3):193–203

    Article  CAS  PubMed  Google Scholar 

  11. Ma X, Buffler PA, Wiemels JL, Selvin S, Metayer C, Loh M et al (2005) Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomark Prev 14(8):1928–1934

    Article  Google Scholar 

  12. Hochberg Y, Benjamini Y (1990) More powerful procedures for multiple significance testing. Stat Med 9(7):811–818

    Article  CAS  PubMed  Google Scholar 

  13. Urayama KY, Buffler PA, Gallagher ER, Ayoob JM, Ma X (2010) A meta-analysis of the association between day-care attendance and childhood acute lymphoblastic leukaemia. Int J Epidemiol 39(3):718–732

    Article  PubMed Central  PubMed  Google Scholar 

  14. Urayama KY, Ma X, Selvin S, Metayer C, Chokkalingam AP, Wiemels JL et al (2011) Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. Int J Cancer 128(7):1632–1643

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Westergaard T, Andersen PK, Pedersen JB, Olsen JH, Frisch M, Sorensen HT et al (1997) Birth characteristics, sibling patterns, and acute leukemia risk in childhood: a population-based cohort study. J Natl Cancer Inst 89(13):939–947

    Article  CAS  PubMed  Google Scholar 

  16. Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ (2001) Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol 30(6):1428–1437

    Article  CAS  PubMed  Google Scholar 

  17. Roman E, Simpson J, Ansell P, Kinsey S, Mitchell CD, McKinney PA et al (2007) Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol 165(5):496–504

    Article  CAS  PubMed  Google Scholar 

  18. Rudant J, Orsi L, Menegaux F, Petit A, Baruchel A, Bertrand Y et al (2010) Childhood acute leukemia, early common infections, and allergy: the ESCALE study. Am J Epidemiol 172(9):1015–1027

    Article  PubMed  Google Scholar 

  19. O’Connor SM, Boneva RS (2007) Infectious etiologies of childhood leukemia: plausibility and challenges to proof. Environ Health Perspect 115(1):146–150

    Article  PubMed Central  PubMed  Google Scholar 

  20. Campleman SLWW (1988) Childhood cancer in California, to 1999 Volume I: birth to age 14. Sacramento, CA: California department of health services. Cancer Surveill Sect 2004:16–17

    Google Scholar 

  21. Walsh KM, Chokkalingam AP, Hsu LI, Metayer C, de Smith AJ, Jacobs DI et al (2013) Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children. Leukemia 27(12):2416–2419

    Article  CAS  PubMed  Google Scholar 

  22. Ma X, Buffler PA, Layefsky M, Does MB, Reynolds P (2004) Control selection strategies in case-control studies of childhood diseases. Am J Epidemiol 159(10):915–921

    Article  PubMed  Google Scholar 

  23. Bartley K, Metayer C, Selvin S, Ducore J, Buffler P (2010) Diagnostic X-rays and risk of childhood leukaemia. Int J Epidemiol 39(6):1628–1637

    Article  PubMed Central  PubMed  Google Scholar 

  24. Aldrich MC, Zhang L, Wiemels JL, Ma X, Loh ML, Metayer C et al (2006) Cytogenetics of Hispanic and White children with acute lymphoblastic leukemia in California. Cancer Epidemiol Biomark Prev 15(3):578–581

    Article  Google Scholar 

  25. Ma X, Buffler PA, Selvin S, Matthay KK, Wiencke JK, Wiemels JL et al (2002) Daycare attendance and risk of childhood acute lymphoblastic leukaemia. Br J Cancer 86(9):1419–1424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38(8):904–909

    Article  CAS  PubMed  Google Scholar 

  28. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PI (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24(24):2938–2939

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Yang TP, Beazley C, Montgomery SB, Dimas AS, Gutierrez-Arcelus M, Stranger BE et al (2010) Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26(19):2474–2476

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, Beazley C et al (2007) Population genomics of human gene expression. Nat Genet 39(10):1217–1224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Jewell N (2004) Statistics for epidemiology. Chapman & Hall/CRC, Boca Raton

    Google Scholar 

  32. Baye TM, Wilke RA (2010) Mapping genes that predict treatment outcome in admixed populations. Pharmacogenomics J 10(6):465–477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Han S, Lee KM, Park SK, Lee JE, Ahn HS, Shin HY et al (2010) Genome-wide association study of childhood acute lymphoblastic leukemia in Korea. Leuk Res 34(10):1271–1274

    Article  CAS  PubMed  Google Scholar 

  34. Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M 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  CAS  PubMed  Google Scholar 

  35. Vijayakrishnan J, Sherborne AL, Sawangpanich R, Hongeng S, Houlston RS, Pakakasama S (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  CAS  PubMed  Google Scholar 

  36. Pastorczak A, Gorniak P, Sherborne A, Hosking F, Trelinska J, Lejman M 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  CAS  PubMed  Google Scholar 

  37. Healy J, Richer C, Bourgey M, Kritikou EA, Sinnett D (2010) Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia. Haematologica 95(9):1608–1611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Yang W, Trevino LR, Yang JJ, Scheet P, Pui CH, Evans WE 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  CAS  PubMed  Google Scholar 

  39. Chokkalingam AP, Hsu LI, Metayer C, Hansen HM, Month SR, Barcellos LF et al (2013) Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics. Cancer Causes Control 24(10):1789–1795

    Article  PubMed Central  PubMed  Google Scholar 

  40. John LB, Ward AC (2011) The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol 48(9–10):1272–1278

    Article  CAS  PubMed  Google Scholar 

  41. Schmitt C, Tonnelle C, Dalloul A, Chabannon C, Debre P, Rebollo A (2002) Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation. Apoptosis 7(3):277–284

    Article  CAS  PubMed  Google Scholar 

  42. Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, Scheijen B et al (2010) IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 24(7):1258–1264

    Article  CAS  PubMed  Google Scholar 

  43. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB et al (2009) Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 360(5):470–480

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Virely C, Moulin S, Cobaleda C, Lasgi C, Alberdi A, Soulier J et al (2010) Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia. Leukemia 24(6):1200–1204

    Article  CAS  PubMed  Google Scholar 

  45. Greaves MF, Wiemels J (2003) Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 3(9):639–649

    Article  CAS  PubMed  Google Scholar 

  46. Walsh KM, de Smith AJ, Chokkalingam AP, Metayer C, Dahl GV, Hsu LI et al (2013) Novel childhood ALL susceptibility locus BMI1-PIP4K2A is specifically associated with the hyperdiploid subtype. Blood 121(23):4808–4809

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Paulsson K, Forestier E, Lilljebjorn H, Heldrup J, Behrendtz M, Young BD et al (2010) Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 107(50):21719–21724

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Sherborne AL, Houlston RS (2010) What are genome-wide association studies telling us about B-cell tumor development? Oncotarget 1(5):367–372

    PubMed Central  PubMed  Google Scholar 

  49. Akagi T, Thoennissen NH, George A, Crooks G, Song JH, Okamoto R et al (2010) In vivo deficiency of both C/EBPbeta and C/EBPepsilon results in highly defective myeloid differentiation and lack of cytokine response. PLoS ONE 5(11):e15419

    Article  PubMed Central  PubMed  Google Scholar 

  50. Bedi R, Du J, Sharma AK, Gomes I, Ackerman SJ (2009) Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 113(2):317–327

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R et al (2007) Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 109(8):3451–3461

    Article  CAS  PubMed  Google Scholar 

  52. Chokkalingam APAM, Bartley K, Hsu LI, Metayer C et al (2011) Matching on race and ethnicity in case–control studies as a means of control for population stratification. Epidemiology 1:101

    Article  Google Scholar 

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Acknowledgments

We thank the participated hospitals and clinical collaborators including University of California Davis Medical Center (Dr. Jonathan Ducore); University of California, San Francisco (Dr. Mignon Loh and Dr. Katherine Matthay); Children’s Hospital of Central California (Dr. Vonda Crouse); Lucile Packard Children’s Hospital (Dr. Gary Dahl); Children’s Hospital Oakland (Dr. James Feusner); Kaiser Permanente Sacramento (Dr. Vincent Kiley); Kaiser Permanente Santa Clara (Dr. Carolyn Russo and Dr. Alan Wong); Kaiser Permanente, San Francisco (Dr. Kenneth Leung); Children’s Hospital of Los Angeles (Dr. Cecilia Fu); and Kaiser Permanente, Oakland (Dr. Stacy Month). We also acknowledge our collaborators at the Northern California Cancer Center and the entire California Childhood Leukemia Study staff for their effort and dedication. This study was supported by grants from the National Institute of Environmental Health Sciences (PS42 ES04705 and R01 ES09137), the National Cancer Institute (R25CA112355), and Children with Cancer, United Kingdom.

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Authors and Affiliations

  1. School of Public Health, University of California, Berkeley, Berkeley, CA, 94720, USA

    Ling-I. Hsu, Anand P. Chokkalingam, Catherine Metayer & Patricia A. Buffler

  2. Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, Berkeley, CA, 94720-7356, USA

    Lisa F. Barcellos

  3. Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA

    Kyle Walsh

  4. Children’s Hospital Central California, Madera, CA, 93636, USA

    Vonda Crouse

  5. Children’s Hospital Los Angeles, Los Angeles, CA, 90027, USA

    Cecilia Fu

  6. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94143, USA

    Joseph L. Wiemels

  7. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, 44106, USA

    Farren B. S. Briggs

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  1. Ling-I. Hsu
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  2. Anand P. Chokkalingam
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Correspondence to Ling-I. Hsu.

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Hsu, LI., Chokkalingam, A.P., Briggs, F.B. et al. Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children. Cancer Causes Control 26, 609–619 (2015). https://doi.org/10.1007/s10552-015-0550-3

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  • DOI: https://doi.org/10.1007/s10552-015-0550-3

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