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Genetic susceptibility in childhood acute lymphoblastic leukemia

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Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading cause of death due to disease in children. The genetic basis of ALL susceptibility has been supported by its association with certain congenital disorders and, more recently, by several genome-wide association studies (GWAS). These GWAS identified common variants in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 influencing ALL risk. However, the risk variants of these SNPs were not validated in all populations, suggesting that some of the loci could be population specific. On the other hand, the currently identified risk SNPs in these genes only account for 19% of the additive heritable risk. This estimation indicates that additional susceptibility variants could be discovered. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL in all GWAS and subsequent studies and we will also point to future directions that could be explored in the near future.

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References

  1. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166–78.

    Article  CAS  PubMed  Google Scholar 

  2. Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer. 2006;6:193–203.

    Article  CAS  PubMed  Google Scholar 

  3. Greaves M. In utero origins of childhood leukaemia. Early Hum Dev. 2005;81:123–9.

    Article  PubMed  Google Scholar 

  4. Zuna J, Madzo J, Krejci O, Zemanova Z, Kalinova M, Muzikova K, Zapotocky M, Starkova J, Hrusak O, Horak J, Trka J. ETV6/RUNX1 (TEL/AML1) is a frequent prenatal first hit in childhood leukemia. Blood. 2011;117:368–9.

    Article  CAS  PubMed  Google Scholar 

  5. Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact. 2012;196:59–67.

    Article  CAS  PubMed  Google Scholar 

  6. Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J, Alexandrov LB, Van Loo P, Cooke SL, Marshall J, Martincorena I, Hinton J, Gundem G, van Delft FW, Nik-Zainal S, Jones DR, Ramakrishna M, Titley I, Stebbings L, Leroy C, Menzies A, Gamble J, Robinson B, Mudie L, Raine K, O’Meara S, Teague JW, Butler AP, Cazzaniga G, Biondi A, Zuna J, Kempski H, Muschen M, Ford AM, Stratton MR, Greaves M, Campbell PJ. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet. 2014;46:116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hsu LI, Chokkalingam AP, Briggs FB, Walsh K, Crouse V, Fu C, Metayer C, Wiemels JL, Barcellos LF, Buffler PA. 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. 2015;26:609–19.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, Yang W, Cheng C, Cao X, Quinn E, Raimondi S, Gastier-Foster JM, Raetz E, Larsen E, Martin PL, Bowman WP, Winick N, Komada Y, Wang S, Edmonson M, Xu H, Mardis E, Fulton R, Pui CH, Mullighan C, Evans WE, Zhang J, Hunger SP, Relling MV, Nichols KE, Loh ML, Yang JJ. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 2015;16:1659–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shah S, Schrader KA, Waanders E, Timms AE, Vijai J, Miething C, Wechsler J, Yang J, Hayes J, Klein RJ, Zhang J, Wei L, Wu G, Rusch M, Nagahawatte P, Ma J, Chen SC, Song G, Cheng J, Meyers P, Bhojwani D, Jhanwar S, Maslak P, Fleisher M, Littman J, Offit L, Rau-Murthy R, Fleischut MH, Corines M, Murali R, Gao X, Manschreck C, Kitzing T, Murty VV, Raimondi SC, Kuiper RP, Simons A, Schiffman JD, Onel K, Plon SE, Wheeler DA, Ritter D, Ziegler DS, Tucker K, Sutton R, Chenevix-Trench G, Li J, Huntsman DG, Hansford S, Senz J, Walsh T, Lee M, Hahn CN, Roberts KG, King MC, Lo SM, Levine RL, Viale A, Socci ND, Nathanson KL, Scott HS, Daly M, Lipkin SM, Lowe SW, Downing JR, Altshuler D, Sandlund JT, Horwitz MS, Mullighan CG, Offit K. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 2013;45:1226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, Rigo I, LeDuc CA, Kelly K, Jalas C, Paietta E, Racevskis J, Rowe JM, Tallman MS, Paganin M, Basso G, Tong W, Chung WK, Ferrando AA. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood. 2013;122:2425–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS. 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 

  12. Vijayakrishnan J, Houlston RS. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica. 2010;95:1405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381:1943–55.

    Article  PubMed  Google Scholar 

  14. Sherborne AL, Hemminki K, Kumar R, Bartram CR, Stanulla M, Schrappe M, Petridou E, Semsei AF, Szalai C, Sinnett D, Krajinovic M, Healy J, Lanciotti M, Dufour C, Indaco S, El-Ghouroury EA, Sawangpanich R, Hongeng S, Pakakasama S, Gonzalez-Neira A, Ugarte EL, Leal VP, Espinoza JP, Kamel AM, Ebid GT, Radwan ER, Yalin S, Yalin E, Berkoz M, Simpson J, Roman E, Lightfoot T, Hosking FJ, Vijayakrishnan J, Greaves M, Houlston RS. Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia. Haematologica. 2011;96:1049–54.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Treviño LR, Yang W, French D, Hunger SP, Carroll WL, Devidas M, Willman C, Neale G, Downing J, Raimondi SC, Pui CH, Evans WE, Relling MV. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. 2009;41:1001–5.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lahoud MH, Ristevski S, Venter DJ, Jermiin LS, Bertoncello I, Zavarsek S, Hasthorpe S, Drago J, de Kretser D, Hertzog PJ, Kola I. Gene targeting of Desrt, a novel ARID class DNA-binding protein, causes growth retardation and abnormal development of reproductive organs. Genome Res. 2001;11:1327–34.

    Article  CAS  PubMed  Google Scholar 

  17. Paulsson K, Forestier E, Lilljebjörn H, Heldrup J, Behrendtz M, Young BD, Johansson B. Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2010;107:21719–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chang LW, Payton JE, Yuan W, Ley TJ, Nagarajan R, Stormo GD. Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia. Genome Biol. 2008;9:R38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bourquin JP, Subramanian A, Langebrake C, Reinhardt D, Bernard O, Ballerini P, Baruchel A, Cavé H, Dastugue N, Hasle H, Kaspers GL, Lessard M, Michaux L, Vyas P, van Wering E, Zwaan CM, Golub TR, Orkin SH. Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci USA. 2006;103:3339–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Han S, Lee KM, Park SK, Lee JE, Ahn HS, Shin HY, Kang HJ, Koo HH, Seo JJ, Choi JE, Ahn YO, Kang D. Genome-wide association study of childhood acute lymphoblastic leukemia in Korea. Leuk Res. 2010;34:1271–4.

    Article  CAS  PubMed  Google Scholar 

  21. Healy J, Richer C, Bourgey M, Kritikou EA, Sinnett D. Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia. Haematologica. 2010;95:1608–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vijayakrishnan J, Sherborne AL, Sawangpanich R, Hongeng S, Houlston RS, Pakakasama S. 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. 2010;51:1870–4.

    Article  CAS  PubMed  Google Scholar 

  23. Yang W, Treviño LR, Yang JJ, Scheet P, Pui CH, Evans WE, Relling MV. ARID5B SNP rs10821936 is associated with risk of childhood acute lymphoblastic leukemia in blacks and contributes to racial differences in leukemia incidence. Leukemia. 2010;24:894–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gutiérrez-Camino Á, López-López E, Martín-Guerrero I, Sánchez-Toledo J, García de Andoin N, Carboné Bañeres A, García-Miguel P, Navajas A, García-Orad Á. Intron 3 of the ARID5B gene: a hot spot for acute lymphoblastic leukemia susceptibility. J Cancer Res Clin Oncol. 2013;139:1879–86.

    Article  PubMed  Google Scholar 

  25. Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M, Sheridan E, Gast A, Kinsey SE, Lightfoot T, Roman E, Taylor M, Pritchard-Jones K, Stanulla M, Schrappe M, Bartram CR, Houlston RS, Kumar R, Hemminki K. 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 

  26. Pastorczak A, Górniak P, Sherborne A, Hosking F, Trelińska J, Lejman M, Szczepański T, Borowiec M, Fendler W, Kowalczyk J, Houlston RS, Młynarski W. 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. 2011;35:1534–6.

    Article  CAS  PubMed  Google Scholar 

  27. Ross JA, Linabery AM, Blommer CN, Langer EK, Spector LG, Hilden JM, Heerema NA, Radloff GA, Tower RL, Davies SM. Genetic variants modify susceptibility to leukemia in infants: a children’s oncology group report. Pediatr Blood Cancer. 2013;60:31–4.

    Article  PubMed  Google Scholar 

  28. Lautner-Csorba O, Gézsi A, Semsei AF, Antal P, Erdélyi DJ, Schermann G, Kutszegi N, Csordás K, Hegyi M, Kovács G, Falus A, Szalai C. Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by Bayesian network based Bayesian multilevel analysis of relevance. BMC Med Genomics. 2012;5:42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Emerenciano M, Barbosa TC, Lopes BA, Blunck CB, Faro A, Andrade C, Meyer C, Marschalek R, Pombo-de-Oliveira MS. Leukemia BCSGoIA: ARID5B polymorphism confers an increased risk to acquire specific MLL rearrangements in early childhood leukemia. BMC Cancer. 2014;14:127.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kreile M, Piekuse L, Rots D, Dobele Z, Kovalova Z, Lace B. Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population. Arch Med Sci. 2016;12:479–85.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gharbi H, Ben Hassine I, Soltani I, Safra I, Ouerhani S, Bel Haj Othmen H, Teber M, Farah A, Amouri H, Toumi NH, Abdennebi S, Abbes S, Menif S. Association of genetic variation in IKZF1, ARID5B, CDKN2A, and CEBPE with the risk of acute lymphoblastic leukemia in Tunisian children and their contribution to racial differences in leukemia incidence. Pediatr Hematol Oncol. 2016;33:157–67.

    Article  CAS  PubMed  Google Scholar 

  32. Bhandari P, Ahmad F, Mandava S, Das BR. Association of genetic variants in ARID5B, IKZF1 and CEBPE with risk of childhood de novo B-Lineage Acute lymphoblastic leukemia in India. Asian Pac J Cancer Prev. 2016;17:3989–95.

    PubMed  Google Scholar 

  33. 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 

  34. Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79:143–56.

    Article  CAS  PubMed  Google Scholar 

  35. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–4.

    Article  CAS  PubMed  Google Scholar 

  36. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, Ma J, Liu W, Cheng C, Schulman BA, Harvey RC, Chen IM, Clifford RJ, Carroll WL, Reaman G, Bowman WP, Devidas M, Gerhard DS, Yang W, Relling MV, Shurtleff SA, Campana D, Borowitz MJ, Pui CH, Smith M, Hunger SP, Willman CL, Downing JR. Group CsO: deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Bahari G, Hashemi M, Naderi M, Taheri M. IKZF1 gene polymorphisms increased the risk of childhood acute lymphoblastic leukemia in an Iranian population. Tumour Biol. 2016;37:9579–86.

    Article  CAS  PubMed  Google Scholar 

  39. Wang C, Chen J, Sun H, Sun L, Liu Y. CEBPE polymorphism confers an increased risk of childhood acute lymphoblastic leukemia: a meta-analysis of 11 case-control studies with 5,639 cases and 10,036 controls. Ann Hematol. 2015;94:181–5.

    Article  CAS  PubMed  Google Scholar 

  40. Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk S, Martin-Subero JI, Atherton MG, Brüggemann M, Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer MJ. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood. 2007;109:3451–61.

    Article  CAS  PubMed  Google Scholar 

  41. Orsi L, Rudant J, Bonaventure A, Goujon-Bellec S, Corda E, Evans TJ, Petit A, Bertrand Y, Nelken B, Robert A, Michel G, Sirvent N, Chastagner P, Ducassou S, Rialland X, Hémon D, Milne E, Scott RJ, Baruchel A, Clavel J. Genetic polymorphisms and childhood acute lymphoblastic leukemia: GWAS of the ESCALE study (SFCE). Leukemia. 2012;26:2561–4.

    Article  CAS  PubMed  Google Scholar 

  42. Hungate EA, Vora SR, Gamazon ER, Moriyama T, Best T, Hulur I, Lee Y, Evans TJ, Ellinghaus E, Stanulla M, Rudant J, Orsi L, Clavel J, Milne E, Scott RJ, Pui CH, Cox NJ, Loh ML, Yang JJ, Skol AD, Onel K. A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. Nat Commun. 2016;7:10635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ellinghaus E, Stanulla M, Richter G, Ellinghaus D, te Kronnie G, Cario G, Cazzaniga G, Horstmann M, Panzer Grümayer R, Cavé H, Trka J, Cinek O, Teigler-Schlegel A, ElSharawy A, Häsler R, Nebel A, Meissner B, Bartram T, Lescai F, Franceschi C, Giordan M, Nürnberg P, Heinzow B, Zimmermann M, Schreiber S, Schrappe M, Franke A. Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia. Leukemia. 2012;26:902–9.

    Article  CAS  PubMed  Google Scholar 

  44. Wiemels JL, de Smith AJ, Xiao J, Lee ST, Muench MO, Fomin ME, Zhou M, Hansen HM, Termuhlen A, Metayer C, Walsh KM. A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros. Leukemia. 2016;30:1194–7.

    CAS  PubMed  Google Scholar 

  45. Yamanaka R, Barlow C, Lekstrom-Himes J, Castilla LH, Liu PP, Eckhaus M, Decker T, Wynshaw-Boris A, Xanthopoulos KG. Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice. Proc Natl Acad Sci USA. 1997;94:13187–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Houlston RS. Low-penetrance susceptibility to hematological malignancy. Curr Opin Genet Dev. 2010;20:245–50.

    Article  CAS  PubMed  Google Scholar 

  47. Sherborne AL, Hosking FJ, Prasad RB, Kumar R, Koehler R, Vijayakrishnan J, Papaemmanuil E, Bartram CR, Stanulla M, Schrappe M, Gast A, Dobbins SE, Ma Y, Sheridan E, Taylor M, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Moorman AV, Harrison CJ, Tomlinson IP, Richards S, Zimmermann M, Szalai C, Semsei AF, Erdelyi DJ, Krajinovic M, Sinnett D, Healy J, Gonzalez Neira A, Kawamata N, Ogawa S, Koeffler HP, Hemminki K, Greaves M, Houlston RS. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat Genet. 2010;42:492–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Iacobucci I, Sazzini M, Garagnani P, Ferrari A, Boattini A, Lonetti A, Papayannidis C, Mantovani V, Marasco E, Ottaviani E, Soverini S, Girelli D, Luiselli D, Vignetti M, Baccarani M, Martinelli G. A polymorphism in the chromosome 9p21 ANRIL locus is associated to Philadelphia positive acute lymphoblastic leukemia. Leuk Res. 2011;35:1052–9.

    Article  CAS  PubMed  Google Scholar 

  49. Congrains A, Kamide K, Ohishi M, Rakugi H. ANRIL: molecular mechanisms and implications in human health. Int J Mol Sci. 2013;14:1278–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chokkalingam AP, Hsu LI, Metayer C, Hansen HM, Month SR, Barcellos LF, Wiemels JL, Buffler PA. Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in hispanics. Cancer Causes Control. 2013;24:1789–95.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Xu H, Zhang H, Yang W, Yadav R, Morrison AC, Qian M, Devidas M, Liu Y, Perez-Andreu V, Zhao X, Gastier-Foster JM, Lupo PJ, Neale G, Raetz E, Larsen E, Bowman WP, Carroll WL, Winick N, Williams R, Hansen T, Holm JC, Mardis E, Fulton R, Pui CH, Zhang J, Mullighan CG, Evans WE, Hunger SP, Gupta R, Schmiegelow K, Loh ML, Relling MV, Yang JJ. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. Nat Commun. 2015;6:7553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Walsh KM, de Smith AJ, Hansen HM, Smirnov IV, Gonseth S, Endicott AA, Xiao J, Rice T, Fu CH, McCoy LS, Lachance DH, Eckel-Passow JE, Wiencke JK, Jenkins RB, Wrensch MR, Ma X, Metayer C, Wiemels JL. A heritable missense polymorphism in CDKN2A confers strong risk of childhood acute lymphoblastic leukemia and is preferentially selected during clonal evolution. Cancer Res. 2015;75:4884–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vijayakrishnan J, Henrion M, Moorman AV, Fiege B, Kumar R, da Silva Filho MI, Holroyd A, Koehler R, Thomsen H, Irving JA, Allan JM, Lightfoot T, Roman E, Kinsey SE, Sheridan E, Thompson PD, Hoffmann P, Nöthen MM, Mühleisen TW, Eisele L, Bartram CR, Schrappe M, Greaves M, Hemminki K, Harrison CJ, Stanulla M, Houlston RS. The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Sci Rep. 2015;5:15065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gutierrez-Camino A, Martin-Guerrero I, Garcia de Andoin N, Sastre A, Carbone Bañeres A, Astigarraga I, Navajas A, Garcia-Orad A. Confirmation of involvement of new variants at CDKN2A/B in pediatric acute lymphoblastic leukemia susceptibility in the Spanish population. PLoS ONE. 2017;12:e0177421.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Gong J, Tong Y, Zhang HM, Wang K, Hu T, Shan G, Sun J, Guo AY. Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis. Hum Mutat. 2012;33:254–63.

    Article  CAS  PubMed  Google Scholar 

  56. Xu H, Yang W, Perez-Andreu V, Devidas M, Fan Y, Cheng C, Pei D, Scheet P, Burchard EG, Eng C, Huntsman S, Torgerson DG, Dean M, Winick NJ, Martin PL, Camitta BM, Bowman WP, Willman CL, Carroll WL, Mullighan CG, Bhojwani D, Hunger SP, Pui CH, Evans WE, Relling MV, Loh ML, Yang JJ. 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 

  57. Migliorini G, Fiege B, Hosking FJ, Ma Y, Kumar R, Sherborne AL, da Silva Filho MI, Vijayakrishnan J, Koehler R, Thomsen H, Irving JA, Allan JM, Lightfoot T, Roman E, Kinsey SE, Sheridan E, Thompson P, Hoffmann P, Nöthen MM, Mühleisen TW, Eisele L, Zimmermann M, Bartram CR, Schrappe M, Greaves M, Stanulla M, Hemminki K, Houlston RS. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood. 2013;122:3298–307.

    Article  CAS  PubMed  Google Scholar 

  58. Lima K, Ribeiro DM, Campos PM, Costa FF, Traina F, Saad ST, Sonati MF, Machado-Neto JA. Differential profile of PIP4K2A expression in hematological malignancies. Blood Cells Mol Dis. 2015;55:228–35.

    Article  CAS  PubMed  Google Scholar 

  59. Liao F, Yin D, Zhang Y, Hou Q, Zheng Z, Yang L, Shu Y, Xu H, Li Y. Association Between PIP4K2A polymorphisms and acute lymphoblastic leukemia susceptibility. Medicine (Baltimore). 2016;95:e3542.

    Article  CAS  Google Scholar 

  60. Deng J, Xue Y, Wang Y, Chen J, Li J, Lu Q, Wang M, Tong N, Zhang Z, Fang Y. 10p12.31-12.2 variants and risk of childhood acute lymphoblastic leukemia in a Chinese population. Leuk Lymphoma. 2015;56:175–8.

    Article  PubMed  Google Scholar 

  61. Walsh KM, de Smith AJ, Chokkalingam AP, Metayer C, Dahl GV, Hsu LI, Barcellos LF, Wiemels JL, Buffler PA. Novel childhood ALL susceptibility locus BMI1-PIP4K2A is specifically associated with the hyperdiploid subtype. Blood. 2013;121:4808–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lopez-Lopez E, Gutierrez-Camino A, Martin-Guerrero I, Garcia-Orad A. Re: novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst. 2013;105:1512.

    Article  PubMed  Google Scholar 

  63. Vijayakrishnan J, Kumar R, Henrion MY, Moorman AV, Rachakonda PS, Hosen I, da Silva Filho MI, Holroyd A, Dobbins SE, Koehler R, Thomsen H, Irving JA, Allan JM, Lightfoot T, Roman E, Kinsey SE, Sheridan E, Thompson PD, Hoffmann P, Nöthen MM, Heilmann-Heimbach S, Jöckel KH, Greaves M, Harrison CJ, Bartram CR, Schrappe M, Stanulla M, Hemminki K, Houlston RS. A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1. Leukemia. 2016;31:573.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Perez-Andreu V, Roberts KG, Harvey RC, Yang W, Cheng C, Pei D, Xu H, Gastier-Foster JES, Lim JY, Chen IM, Fan Y, Devidas M, Borowitz MJ, Smith C, Neale G, Burchard EG, Torgerson DG, Klussmann FA, Villagran CR, Winick NJ, Camitta BM, Raetz E, Wood B, Yue F, Carroll WL, Larsen E, Bowman WP, Loh ML, Dean M, Bhojwani D, Pui CH, Evans WE, Relling MV, Hunger SP, Willman CL, Mullighan CG, Yang JJ. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013;45:1494–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Whitehead TP, Metayer C, Wiemels JL, Singer AW, Miller MD. Childhood leukemia and primary prevention. Curr Probl Pediatr Adolesc Health Care. 2016;46:317–52.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Moriyama T, Relling MV, Yang JJ. Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood. 2015;125:3988–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Khurana E, Fu Y, Chakravarty D, Demichelis F, Rubin MA, Gerstein M. Role of non-coding sequence variants in cancer. Nat Rev Genet. 2016;17:93–108.

    Article  CAS  PubMed  Google Scholar 

  68. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15:423–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ryan BM, Robles AI, Harris CC. Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer. 2010;10:389–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Slaby O, Bienertova-Vasku J, Svoboda M, Vyzula R. Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer. J Cell Mol Med. 2012;16:8–21.

    Article  CAS  PubMed  Google Scholar 

  71. 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. 2014;35:219–25.

    Article  CAS  PubMed  Google Scholar 

  72. Tong N, Xu B, Shi D, Du M, Li X, Sheng X, Wang M, Chu H, Fang Y, Li J, Wu D, Zhang Z. Hsa-miR-196a2 polymorphism increases the risk of acute lymphoblastic leukemia in Chinese children. Mutat Res. 2014;759:16–21.

    Article  CAS  PubMed  Google Scholar 

  73. Gutierrez-Camino A, Lopez-Lopez E, Martin-Guerrero I, Piñan MA, Garcia-Miguel P, Sanchez-Toledo J, Carbone Bañeres A, Uriz J, Navajas A, Garcia-Orad A. Noncoding RNA-related polymorphisms in pediatric acute lymphoblastic leukemia susceptibility. Pediatr Res. 2014;75:767–73.

    Article  CAS  PubMed  Google Scholar 

  74. Tong N, Chu H, Wang M, Xue Y, Du M, Lu L, Zhang H, Wang F, Fang Y, Li J, Wu D, Zhang Z, Sheng X. Pri-miR-34b/c rs4938723 polymorphism contributes to acute lymphoblastic leukemia susceptibility in Chinese children. Leuk Lymphoma. 2016;57:1436–41.

    Article  CAS  PubMed  Google Scholar 

  75. Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

    Article  Google Scholar 

  76. Lowe CB, Haussler D. 29 mammalian genomes reveal novel exaptations of mobile elements for likely regulatory functions in the human genome. PLoS ONE. 2012;7:e43128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR, Farnham PJ, Hirst M, Lander ES, Mikkelsen TS, Thomson JA. The NIH roadmap epigenomics mapping consortium. Nat Biotechnol. 2010;28:1045–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM, Network CGAR. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45:1113–20.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was funded by the Basque Government (IT989-16), UPV/EHU (UFI11/35). AGC 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.

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Authors and Affiliations

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

    Angela Gutierrez-Camino, Idoia Martin-Guerrero & Africa García-Orad

  2. BioCruces Health Research Institute, Barakaldo, Spain

    Africa García-Orad

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  1. Angela Gutierrez-Camino
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  2. Idoia Martin-Guerrero
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  3. Africa García-Orad
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Correspondence to Africa García-Orad.

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Gutierrez-Camino, A., Martin-Guerrero, I. & García-Orad, A. Genetic susceptibility in childhood acute lymphoblastic leukemia. Med Oncol 34, 179 (2017). https://doi.org/10.1007/s12032-017-1038-7

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