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ACUTE LYMPHOBLASTIC LEUKEMIA

Overt and covert genetic causes of pediatric acute lymphoblastic leukemia

Leukemia volume 39, pages 1031–1045 (2025)Cite this article

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Abstract

Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy, yet its etiology remains incompletely understood. However, over the course of three waves of germline genetic research, several non-environmental causes have been identified. Beginning with trisomy 21, seven overt cancer predisposition syndromes (CPSs)—characterized by broad clinical phenotypes that include an elevated risk of pALL—were first described. More recently, newly described CPSs conferring high risk of pALL are increasingly covert, with six exhibiting only minimal or no non-cancer features. These 13 CPSs now represent the principal known hereditary causes of pALL, and human pangenomic data indicates a strong negative selection against mutations in the genes associated with these conditions. Collectively they affect approximately 1 in 450 newborns, of which just a minority will develop the disease. As evidenced by tailored leukemia care protocols for children with trisomy 21, there is growing recognition that CPSs warrant specialized diagnostic, therapeutic, and long-term management strategies. In this review, we investigate the evidence that the 12 other CPSs associated with high risk of pALL may also see benefits from specialized care — even if these needs are often incompletely mapped or addressed in the clinic. Given the rarity of each syndrome, collaborative international research and shared data initiatives will be crucial for advancing knowledge and improving outcomes for these patients.

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Fig. 1: A timeline of pediatric acute lymphoblastic leukemia predisposition.
Fig. 2: Pediatric acute lymphoblastic leukemia predisposition in molecular and evolutionary context.
Fig. 3: Phenotypes of pediatric acute lymphoblastic leukemia predisposition syndromes.

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References

  1. Hjalgrim LL, Rostgaard K, Schmiegelow K, Söderhäll S, Kolmannskog S, Vettenranta K, et al. Age- and sex-specific incidence of childhood leukemia by immunophenotype in the Nordic countries. J Natl Cancer Inst. 2003;95:1539–1544.

    PubMed  Google Scholar 

  2. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet Lond Engl. 2020;395:1146–62.

    CAS  Google Scholar 

  3. Tulstrup M, Stoltze UK, Schmiegelow K, Yang JJ. Epidemiology and Etiology of Childhood ALL. In: Vora A (ed). Childhood Acute Lymphoblastic Leukemia. Springer International Publishing: Cham, 2017, pp 1–27.

  4. Kamper-Jørgensen M, Woodward A, Wohlfahrt J, Benn CS, Simonsen J, Hjalgrim H, et al. Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia. Leukemia. 2008;22:189–93.

    PubMed  Google Scholar 

  5. Søegaard SH, Rostgaard K, Kamper-Jørgensen M, Schmiegelow K, Hjalgrim H. Childcare attendance and risk of childhood acute lymphoblastic leukaemia: A register study based on the Danish childcare database. Int J Cancer. 2023;152:1817–26.

    PubMed  Google Scholar 

  6. Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, et al. Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. J Clin Oncol J Am Soc Clin Oncol. 2019;37:3377–91.

    CAS  Google Scholar 

  7. Pui C-H, Yang JJ, Bhakta N, Rodriguez-Galindo C. Global efforts toward the cure of childhood acute lymphoblastic leukaemia. Lancet Child Adolesc Health. 2018;2:440–54.

    PubMed  PubMed Central  Google Scholar 

  8. Oskarsson T, Söderhäll S, Arvidson J, Forestier E, Frandsen TL, Hellebostad M et al. Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2018; 65. https://doi.org/10.1002/pbc.26909.

  9. Ehrlich BS, McNeil MJ, Pham LTD, Chen Y, Rivera J, Acuna C, et al. Treatment-related mortality in children with cancer in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Oncol. 2023;24:967–77.

    PubMed  PubMed Central  Google Scholar 

  10. Schmiegelow K, Müller K, Mogensen SS, Mogensen PR, Wolthers BO, Stoltze UK, et al. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Research. 2017;6:444. https://doi.org/10.12688/f1000research.10768.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Björk-Eriksson T, Boström M, Bryngelsson I-L, Lähteenmäki PM, Jarfelt M, Kalm M, et al. Mortality Among Pediatric Patients With Acute Lymphoblastic Leukemia in Sweden From 1988 to 2017. JAMA Netw Open. 2022;5:e2243857.

    PubMed  PubMed Central  Google Scholar 

  12. Klco JM, Mullighan CG. Advances in germline predisposition to acute leukemias and myeloid neoplasms. Nat Rev Cancer. 2021;21:122–37.

    CAS  PubMed  Google Scholar 

  13. Shendure J, Balasubramanian S, Church GM, Gilbert W, Rogers J, Schloss JA, et al. DNA sequencing at 40: past, present and future. Nature. 2017;550:345–53.

    CAS  PubMed  Google Scholar 

  14. Down JL. Observations on an ethnic classification of idiots. 1866. Ment Retard. 1995;33:54–56.

    CAS  PubMed  Google Scholar 

  15. Krivit W, Good RA. Simultaneous occurrence of mongolism and leukemia; report of a nationwide survey. AMA J Dis Child. 1957;94:289–93.

    CAS  PubMed  Google Scholar 

  16. Lampert F. [Acute lymphoblastic leukemia in sibblings with progressive cerebellar ataxia (Louis-Bar syndrome)]. Dtsch Med Wochenschr. 1969;94:217–20.

    CAS  PubMed  Google Scholar 

  17. McEvoy MW, Mann JR. Neurofibromatosis with leukaemia. Br Med J. 1971;3:641.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Fraumeni JF, Manning MD, Mitus WJ. Acute childhood leukemia: epidemiologic study by cell type of 1263 cases at the Children’s Cancer Research Foundation in Boston, 1947-65. J Natl Cancer Inst. 1971;46:461–70.

    PubMed  Google Scholar 

  19. 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.

    CAS  PubMed  Google Scholar 

  20. Moriyama T, Relling MV, Yang JJ. Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood. 2015;125:3988–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Jeon S, de Smith AJ, Li S, Chen M, Chan TF, Muskens IS, et al. Genome-wide trans-ethnic meta-analysis identifies novel susceptibility loci for childhood acute lymphoblastic leukemia. Leukemia. 2022;36:865–8.

    CAS  PubMed  Google Scholar 

  22. Kullo IJ, Lewis CM, Inouye M, Martin AR, Ripatti S, Chatterjee N. Polygenic scores in biomedical research. Nat Rev Genet. 2022;23:524–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet. 2000;355:165–9.

    CAS  PubMed  Google Scholar 

  24. Buitenkamp TD, Izraeli S, Zimmermann M, Forestier E, Heerema NA, Heuvel-eibrink MMVD, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. 2015;123:70–78.

    Google Scholar 

  25. Izraeli S. The acute lymphoblastic leukemia of Down Syndrome – Genetics and Pathogenesis. Eur J Med Genet. 2015;59:10–13.

    Google Scholar 

  26. Brown AL, de Smith AJ, Gant VU, Yang W, Scheurer ME, Walsh KM, et al. Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome. Blood. 2019;134:1227–37.

    PubMed  PubMed Central  Google Scholar 

  27. Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalová K, et al. Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood. 2008;111:1575–83.

    CAS  PubMed  Google Scholar 

  28. Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood. 2010;115:1006–17.

    CAS  PubMed  Google Scholar 

  29. Tal N, Shochat C, Geron I, Bercovich D, Izraeli S. Interleukin 7 and thymic stromal lymphopoietin: from immunity to leukemia. Cell Mol Life Sci CMLS. 2014;71:365–78.

    CAS  PubMed  Google Scholar 

  30. Shochat C, Tal N, Gryshkova V, Birger Y, Bandapalli OR, Cazzaniga G, et al. Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia. Blood. 2014;124:106–10.

    CAS  PubMed  Google Scholar 

  31. Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G, et al. Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med. 2011;208:901–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome. Lancet Lond Engl. 2008;372:1484–92.

    CAS  Google Scholar 

  33. Schwartzman O, Savino AM, Gombert M, Palmi C, Cario G, Schrappe M, et al. Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome. Proc Natl Acad Sci USA. 2017;114:E4030–E4039.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang Y-L, Pei D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371:1005–15.

    PubMed  PubMed Central  Google Scholar 

  35. Ensor HM, Schwab C, Russell LJ, Richards SM, Morrison H, Masic D, et al. Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood. 2011;117:2129–36.

    CAS  PubMed  Google Scholar 

  36. Rand V, Parker H, Russell LJ, Schwab C, Ensor H, Irving J, et al. Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia. Blood. 2011;117:6848–55.

    CAS  PubMed  Google Scholar 

  37. Li Z, Chang T-C, Junco JJ, Devidas M, Li Y, Yang W, et al. Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia. Blood. 2023;142:172–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Geron I, Savino AM, Fishman H, Tal N, Brown J, Turati VA, et al. An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia. Nat Commun. 2022;13:659.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Jardine L, Webb S, Goh I, Quiroga Londoño M, Reynolds G, Mather M, et al. Blood and immune development in human fetal bone marrow and Down syndrome. Nature. 2021;598:327–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rabin KR, Devidas M, Chen Z, Ji L, Kairalla J, Hitzler JK, et al. Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children’s Oncology Group. J Clin Oncol J Am Soc Clin Oncol. 2024;42:218–27.

    CAS  Google Scholar 

  41. Bohnstedt C, Taskinen M, Zeller B, Björgvinsdóttir H, Hafsteinsdottir S, Schmiegelow K. Poor treatment compliance in children with down syndrome and acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2009;31:79–80.

    PubMed  Google Scholar 

  42. Rav ES, Wahba A, Patnaik A, Toruner G, Hittle A, Toepfer L, et al. A balancing act: Blinatumomab use in a rare occurrence of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia in an adolescent patient with Down syndrome. Pediatr Blood Cancer. 2023;70:e30191.

    CAS  PubMed  Google Scholar 

  43. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11:159.

    PubMed  PubMed Central  Google Scholar 

  44. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749–53.

    CAS  PubMed  Google Scholar 

  45. Lee J-H, Paull TT. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat Rev Mol Cell Biol. 2021;22:796–814.

    CAS  PubMed  Google Scholar 

  46. Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, et al. Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet. 1998;62:551–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Verhagen MMM, Abdo WF, Willemsen M, Hogervorst FBL, Smeets DFCM, Hiel JAP, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology. 2009;73:430–7.

    CAS  PubMed  Google Scholar 

  48. Micol R, Slama LB, Suarez F, Mignot LL, Beauté J, Mahlaoui N, et al. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol. 2011;128:382.

    PubMed  Google Scholar 

  49. Verhagen MMM, Last JI, Hogervorst FBL, Smeets DFCM, Roeleveld N, Verheijen F, et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat. 2012;33:561–71.

    CAS  PubMed  Google Scholar 

  50. Fiévet A, Bellanger D, Rieunier G, Dubois d’Enghien C, Sophie J, Calvas P, et al. Functional classification of ATM variants in ataxia-telangiectasia patients. Hum Mutat. 2019;40:1713–30.

    PubMed  Google Scholar 

  51. Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d’Enghien C, Brousse N, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol J Am Soc Clin Oncol. 2015;33:202–8.

    Google Scholar 

  52. Pastorczak A, Attarbaschi A, Bomken S, Borkhardt A, van der Werff Ten Bosch J, Elitzur S, et al. Consensus Recommendations for the Clinical Management of Hematological Malignancies in Patients with DNA Double Stranded Break Disorders. Cancers. 2022;14:2000.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Elitzur S, Shiloh R, Loeffen JLC, Pastorczak A, Takagi M, Bomken S et al. ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies. Blood. 2024; blood.2024024283.

  54. Varon R, Demuth I, Chrzanowska KH. Nijmegen Breakage Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ et al. (eds). GeneReviews®. University of Washington, Seattle: Seattle (WA), 1993 http://www.ncbi.nlm.nih.gov/books/NBK1176/ (accessed 8 Sep 2024).

  55. Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998;93:467–76.

    CAS  PubMed  Google Scholar 

  56. You Z, Chahwan C, Bailis J, Hunter T, Russell P. ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol Cell Biol. 2005;25:5363–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Stracker TH, Morales M, Couto SS, Hussein H, Petrini JHJ. The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex. Nature. 2007;447:218–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sharapova SO, Pashchenko OE, Bondarenko AV, Vakhlyarskaya SS, Prokofjeva T, Fedorova AS, et al. Geographical distribution, incidence, malignancies, and outcome of 136 eastern slavic patients with Nijmegen breakage syndrome and NBN Founder Variant c.657_661del5. Front Immunol. 2020;11:602482.

    CAS  PubMed  Google Scholar 

  59. Wolska-Kusnierz B, Pastorczak A, Fendler W, Wakulinska A, Dembowska-Baginska B, Heropolitanska-Pliszka E, et al. Hematopoietic stem cell transplantation positively affects the natural history of cancer in Nijmegen breakage syndrome. Clin Cancer Res J Am Assoc Cancer Res. 2021;27:575–84.

    Google Scholar 

  60. Taalman RD, Hustinx TW, Weemaes CM, Seemanová E, Schmidt A, Passarge E, et al. Further delineation of the Nijmegen breakage syndrome. Am J Med Genet. 1989;32:425–31.

    CAS  PubMed  Google Scholar 

  61. Jaspers NG, Taalman RD, Baan C. Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia. Am J Hum Genet. 1988;42:66–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M, Białecka M, Gutkowska A, Goryluk-Kozakiewicz B, et al. Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet. 1995;57:462–71.

    CAS  PubMed  Google Scholar 

  63. Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, et al. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. J Allergy Clin Immunol. 2018;141:322–.e10.

    CAS  PubMed  Google Scholar 

  64. Ababou M. Bloom syndrome and the underlying causes of genetic instability. Mol Genet Metab. 2021;133:35–48.

    CAS  PubMed  Google Scholar 

  65. Chaganti RS, Schonberg S, German J. A manyfold increase in sister chromatid exchanges in Bloom’s syndrome lymphocytes. Proc Natl Acad Sci USA. 1974;71:4508–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hoover A, Turcotte LM, Phelan R, Barbus C, Rayannavar A, Miller BS et al. Longitudinal clinical manifestations of Fanconi anemia: a systematized review. Blood Rev. 2024;68:101225.

  67. Giardino S, Eikema D-J, Piepenbroek B, Algeri M, Ayas M, Faraci M et al. HLA-haploidentical stem cell transplantation in children with inherited bone marrow failure syndromes: a retrospective analysis on behalf of EBMT severe aplastic Anemia and pediatric diseases working parties. Am J Hematol. 2024;99:1066-76.

  68. Lum SH, Eikema D-J, Piepenbroek B, Wynn R, Samarasinghe S, Dalissier A et al. Outcome of hematopoietic stem cell transplantation in 813 pediatric patients with fanconi anemia. Blood. 2024;144:1329–42.

  69. Grant AR, Cushman BJ, Cavé H, Dillon MW, Gelb BD, Gripp KW, et al. Assessing the gene-disease association of 19 genes with the RASopathies using the ClinGen gene curation framework. Hum Mutat. 2018;39:1485–93.

    PubMed  Google Scholar 

  70. Landry JP, Schertz KL, Chiang Y-J, Bhalla AD, Yi M, Keung EZ, et al. Comparison of cancer prevalence in patients with neurofibromatosis type 1 at an academic cancer center vs in the general population from 1985 to 2020. JAMA Netw Open. 2021;4:e210945.

    PubMed  PubMed Central  Google Scholar 

  71. Kratz CP, Jongmans MC, Cavé H, Wimmer K, Behjati S, Guerrini-Rousseau L, et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc Health. 2021;5:142–54.

    PubMed  Google Scholar 

  72. Cavé H, Caye A, Strullu M, Aladjidi N, Vignal C, Ferster A, et al. Acute lymphoblastic leukemia in the context of RASopathies. Eur J Med Genet. 2016;59:173–8.

    PubMed  Google Scholar 

  73. Shearer P, Parham D, Kovnar E, Kun L, Rao B, Lobe T, et al. Neurofibromatosis type I and malignancy: review of 32 pediatric cases treated at a single institution. Med Pediatr Oncol. 1994;22:78–83.

    CAS  PubMed  Google Scholar 

  74. Galbiati M, Lettieri A, Micalizzi C, Songia S, Morerio C, Biondi A, et al. Natural history of acute lymphoblastic leukemia in neurofibromatosis type 1 monozygotic twins. Leukemia. 2013;27:1778–81.

    CAS  PubMed  Google Scholar 

  75. Bader JL, Miller RW. Neurofibromatosis and childhood leukemia. J Pediatr. 1978;92:925–9.

    CAS  PubMed  Google Scholar 

  76. Horigome H, Sumazaki R, Iwasaki N, Imoto N, Kinugasa H, Saito M, et al. Fatal eosinophilic heart disease in a child with neurofibromatosis-1 complicated by acute lymphoblastic leukemia. Heart Vessels. 2005;20:120–2.

    PubMed  Google Scholar 

  77. Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer. 1994;70:969–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Klopfenstein KJ, Sommer A, Ruymann FB. Neurofibromatosis-Noonan syndrome and acute lymphoblastic leukemia: a report of two cases. J Pediatr Hematol Oncol. 1999;21:158–60.

    CAS  PubMed  Google Scholar 

  79. Perilongo G, Felix CA, Meadows AT, Nowell P, Biegel J, Lange BJ. Sequential development of Wilms tumor, T-cell acute lymphoblastic leukemia, medulloblastoma and myeloid leukemia in a child with type 1 neurofibromatosis: a clinical and cytogenetic case report. Leukemia. 1993;7:912–5.

    CAS  PubMed  Google Scholar 

  80. Molteni CG, Te Kronnie G, Bicciato S, Villa T, Tartaglia M, Basso G, et al. PTPN11 mutations in childhood acute lymphoblastic leukemia occur as a secondary event associated with high hyperdiploidy. Leukemia. 2010;24:232–5.

    CAS  PubMed  Google Scholar 

  81. Zipper L, Wagener R, Fischer U, Hoffmann A, Yasin L, Brandes D, et al. Hyperdiploid acute lymphoblastic leukemia in children with LZTR1 germline variants. HemaSphere. 2024;8:e26.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Perrino MR, Das A, Scollon SR, Mitchell SG, Greer M-LC, Yohe ME et al. Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies. Clin Cancer Res Off J Am Assoc Cancer Res. 2024. https://doi.org/10.1158/1078-0432.CCR-24-1611.

  83. Wimmer K, Kratz CP, Vasen HFA, Caron O, Colas C, Entz-Werle N, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet. 2014;51:355–65.

    CAS  PubMed  Google Scholar 

  84. Suerink M, Ripperger T, Messiaen L, Menko FH, Bourdeaut F, Colas C, et al. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy. J Med Genet. 2019;56:53–62.

    PubMed  Google Scholar 

  85. Das A, MacFarland SP, Meade J, Hansford JR, Schneider KW, Kuiper RP, et al. Clinical updates and surveillance recommendations for DNA replication repair deficiency syndromes in children and young adults. Clin Cancer Res J Am Assoc Cancer Res. 2024;30:3378–87.

    CAS  Google Scholar 

  86. Wimmer K, Rosenbaum T, Messiaen L. Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1. Clin Genet. 2017;91:507–19.

    CAS  PubMed  Google Scholar 

  87. Ercan AB, Aronson M, Fernandez NR, Chang Y, Levine A, Liu ZA, et al. Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study. Lancet Oncol. 2024;25:668–82.

    CAS  PubMed  Google Scholar 

  88. Kroeze E, Weijers DD, Hagleitner MM, de Groot-Kruseman HA, Jongmans MCJ, Kuiper RP, et al. High prevalence of constitutional mismatch repair deficiency in a pediatric T-cell lymphoblastic lymphoma cohort. HemaSphere. 2022;6:e668.

    PubMed  Google Scholar 

  89. González-Acosta M, Marín F, Puliafito B, Bonifaci N, Fernández A, Navarro M, et al. High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers. J Med Genet. 2020;57:269–73.

    PubMed  Google Scholar 

  90. Gallon R, Phelps R, Hayes C, Brugieres L, Guerrini-Rousseau L, Colas C, et al. Constitutional microsatellite instability, genotype, and phenotype correlations in constitutional mismatch repair deficiency. Gastroenterology. 2023;164:579–.e8.

    CAS  PubMed  Google Scholar 

  91. Chung J, Negm L, Bianchi V, Stengs L, Das A, Liu ZA, et al. Genomic microsatellite signatures identify germline mismatch repair deficiency and risk of cancer onset. J Clin Oncol J Am Soc Clin Oncol. 2023;41:766–77.

    CAS  Google Scholar 

  92. Guerrini-Rousseau L, Gallon R, Pineda M, Brugières L, Baert-Desurmont S, Corsini C et al. Report of the sixth meeting of the European Consortium ‘Care for CMMRD’ (C4CMMRD), Paris, France, November 16th 2022. Fam Cancer. 2024. https://doi.org/10.1007/s10689-024-00403-1.

  93. Muir AW, Houston J, Marshall RJ, Bowman WC, Marshall IG. A comparison of the neuromuscular blocking and autonomic effects of two new short-acting muscle relaxants with those of succinylcholine in the anesthetized cat and pig. Anesthesiology. 1989;70:533–40.

    CAS  PubMed  Google Scholar 

  94. Westdorp H, Kolders S, Hoogerbrugge N, de Vries IJM, Jongmans MCJ, Schreibelt G. Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome. Cancer Lett. 2017;403:159–64.

    CAS  PubMed  Google Scholar 

  95. Das A, Sudhaman S, Morgenstern D, Coblentz A, Chung J, Stone SC, et al. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency. Nat Med. 2022;28:125–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Das A, Fernandez NR, Levine A, Bianchi V, Stengs LK, Chung J, et al. ComBined Immunotherapy Improves Outcome For Replication-repair-deficient (RRD) high-grade glioma failing anti-PD-1 monotherapy: a report from the international RRD Consortium. Cancer Discov. 2024;14:258–73.

    PubMed  Google Scholar 

  97. Yang F, Brady SW, Tang C, Sun H, Du L, Barz MJ, et al. Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse. Nat Cancer. 2021;2:819–34.

    CAS  PubMed  Google Scholar 

  98. van Engelen N, Roest M, van Dijk F, Sonneveld E, Bladergroen R, van Reijmersdal SV, et al. A novel germline PAX5 single exon deletion in a pediatric patient with precursor B-cell leukemia. Leukemia. 2023;37:1908–11.

    PubMed  PubMed Central  Google Scholar 

  99. Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature. 2020;580:517–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bougeard G, Renaux-Petel M, Flaman J-M, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni Syndrome from TP53 mutation carriers. J Clin Oncol J Am Soc Clin Oncol. 2015;33:2345–52.

    CAS  Google Scholar 

  101. Amadou A, Achatz MIW, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 2018;30:23–29.

    CAS  PubMed  Google Scholar 

  102. Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet. 2019;51:296–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Jongmans MC, Loeffen JL, Waanders E, Hoogerbrugge PM, Ligtenberg MJ, Kuiper RP, Hoogerbrugge N, et al. Recognition of genetic predisposition in pediatric cancer patients: An easy-to-use selection tool. Eur J Med Genet. 2016;59:116–25.

    PubMed  Google Scholar 

  105. Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G, et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A. 2017;173:1017–37.

    PubMed  Google Scholar 

  106. Goudie C, Witkowski L, Cullinan N, Reichman L, Schiller I, Tachdjian M, et al. Performance of the mcgill interactive pediatric oncogenetic guidelines for identifying cancer predisposition syndromes. JAMA Oncol. 2021;7:1806–14.

    PubMed  Google Scholar 

  107. Hebert R, Cullinan N, Armstrong L, Blood KA, Brossard J, Brunga L, et al. Performance of the eHealth decision support tool, MIPOGG, for recognising children with Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin syndromes. J Med Genet. 2023;60:1218–23.

    PubMed  Google Scholar 

  108. Valdez JM, Nichols KE, Kesserwan C. Li-Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition. Br J Haematol. 2017;176:539–52.

    PubMed  Google Scholar 

  109. Qian M, Cao X, Devidas M, Yang W, Cheng C, Dai Y, et al. TP53 Germline Variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol J Am Soc Clin Oncol. 2018;36:591–9.

    CAS  Google Scholar 

  110. Pinto EM, Ribeiro RC, Figueiredo BC, Zambetti GP. TP53-associated pediatric malignancies. Genes Cancer. 2011;2:485–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol J Am Soc Clin Oncol. 2009;27:1250–6.

    CAS  Google Scholar 

  112. Renaux-Petel M, Charbonnier F, Théry J-C, Fermey P, Lienard G, Bou J, et al. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet. 2018;55:173–80.

    CAS  PubMed  Google Scholar 

  113. Novel germline TP53 variant (p.(Phe109Ile)) confers high risk of cancer - PubMed. https://pubmed.ncbi.nlm.nih.gov/39317423/ (accessed 22 Oct 2024).

  114. Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47:535–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, et al. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet. 2015;11:e1005262.

    PubMed  PubMed Central  Google Scholar 

  116. Zhang MY, Churpek JE, Keel SB, Walsh T, Lee MK, Loeb KR, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47:180–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Di Paola J, Porter CC. ETV6-related thrombocytopenia and leukemia predisposition. Blood. 2019;134:663–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: A systematic genetic study. Lancet Oncol. 2015;16:1659–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Bloom M, Oak N, Baskin-Doerfler R, Feng R, Iacobucci I, Baviskar P, et al. ETV6 represses inflammatory response genes and regulates HSPC function during stress hematopoiesis in mice. Blood Adv. 2023;7:5608–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Nishii R, Baskin-Doerfler R, Yang W, Oak N, Zhao X, Yang W, et al. Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood. 2021;137:364–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Escudero A, Takagi M, Auer F, Friedrich UA, Miyamoto S, Ogawa A, et al. Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants. Leukemia. 2022;36:2338–42.

    CAS  PubMed  Google Scholar 

  122. Bettini LR, Fazio G, Saitta C, Piazza R, Palamini S, Buracchi C et al. Diverse mechanisms of leukemogenesis associated with PAX5 germline mutation. Leukemia. 2024;38:2479–82.

  123. 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.

    CAS  PubMed  Google Scholar 

  124. Georgopoulos K, Moore DD. Derfler B. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science. 1992;258:808–12.

    CAS  PubMed  Google Scholar 

  125. Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83:289–99.

    CAS  PubMed  Google Scholar 

  126. Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JGCAM, Peters STCJM, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10:125–34.

    Google Scholar 

  127. Boer JM, van der Veer A, Rizopoulos D, Fiocco M, Sonneveld E, de Groot-Kruseman HA, et al. Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study. Leukemia. 2016;30:32–38.

    CAS  PubMed  Google Scholar 

  128. Zhang J, McCastlain K, Yoshihara H, Xu B, Chang Y, Churchman ML, et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat Genet. 2016;48:1481–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Kuehn HS, Boast B, Rosenzweig SD. Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency. Clin Exp Immunol. 2023;212:129–36.

    PubMed  Google Scholar 

  130. Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, et al. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med. 2016;374:1032–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Boutboul D, Kuehn HS, Van de Wyngaert Z, Niemela JE, Callebaut I, Stoddard J, et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest. 2018;128:3071–87.

    PubMed  PubMed Central  Google Scholar 

  132. Kuehn HS, Niemela JE, Stoddard J, Mannurita SC, Shahin T, Goel S, et al. Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies. Blood. 2021;137:349–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Hoshino A, Boutboul D, Zhang Y, Kuehn HS, Hadjadj J, Özdemir N, et al. Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation. Sci Immunol. 2022;7:eabi7160.

    CAS  PubMed  Google Scholar 

  134. Churchman ML, Qian M, Kronnie TeG, Zhang R, Yang W, Zhang H, et al. Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell. 2018;33:937–.e8.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–75.

    CAS  PubMed  Google Scholar 

  136. Latger-Cannard V, Philippe C, Bouquet A, Baccini V, Alessi M-C, Ankri A, et al. Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders. Orphanet J Rare Dis. 2016;11:49.

    PubMed  PubMed Central  Google Scholar 

  137. Antony-Debré I, Duployez N, Bucci M, Geffroy S, Micol J-B, Renneville A, et al. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia. 2016;30:999–1002.

    PubMed  Google Scholar 

  138. Li Y, Yang W, Devidas M, Winter SS, Kesserwan C, Yang W, et al. Germline RUNX1 variation and predisposition to childhood acute lymphoblastic leukemia. J Clin Invest. 2021;131:e147898.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Schmiegelow K, Levinsen MF, Attarbaschi A, Baruchel A, Devidas M, Escherich G, et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol J Am Soc Clin Oncol. 2013;31:2469–76.

    CAS  Google Scholar 

  140. Turcotte LM, Neglia JP, Reulen RC, Ronckers CM, van Leeuwen FE, Morton LM, et al. Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review. J Clin Oncol J Am Soc Clin Oncol. 2018;36:2145–52.

    CAS  Google Scholar 

  141. Levinsen M, Rotevatn EØ, Rosthøj S, Nersting J, Abrahamsson J, Appell ML, et al. Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer. 2014;61:797–802.

    CAS  PubMed  Google Scholar 

  142. Inskip PD, Sigurdson AJ, Veiga L, Bhatti P, Ronckers C, Rajaraman P, et al. Radiation-related new primary solid cancers in the childhood cancer survivor study: comparative radiation dose response and modification of treatment effects. Int J Radiat Oncol Biol Phys. 2016;94:800–7.

    PubMed  Google Scholar 

  143. Yoshida M, Nakabayashi K, Yang W, Sato-Otsubo A, Tsujimoto S, Ogata-Kawata H, et al. NUDT15 variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia. Blood Adv. 2021;5:5420–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Junk SV, Förster A, Schmidt G, Zimmermann M, Fedders B, Haermeyer B, et al. Germline variants in patients developing second malignant neoplasms after therapy for pediatric acute lymphoblastic leukemia—a case-control study. Leukemia. 2024;38:887–92.

    PubMed  PubMed Central  Google Scholar 

  145. Zwaan CM, Kaspers GJL, Pieters R, Hählen K, Janka-Schaub GE, van Zantwijk CH, et al. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood. 2002;99:245–51.

    CAS  PubMed  Google Scholar 

  146. Maloney KW, Carroll WL, Carroll AJ, Devidas M, Borowitz MJ, Martin PL, et al. Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children’s Oncology Group. Blood. 2010;116:1045–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Szmyd B, Mlynarski W, Pastorczak A. Genetic predisposition to lymphomas: Overview of rare syndromes and inherited familial variants. Mutat Res Rev Mutat Res. 2021;788:108386.

    CAS  PubMed  Google Scholar 

  148. Junk SV, Klein N, Schreek S, Zimmermann M, Möricke A, Bleckmann K, et al. TP53, ETV6 and RUNX1 germline variants in a case series of patients developing secondary neoplasms after treatment for childhood acute lymphoblastic leukemia. Haematologica. 2019;104:e402–e405.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Ripperger T, Schlegelberger B. Acute lymphoblastic leukemia and lymphoma in the context of constitutional mismatch repair deficiency syndrome. Eur J Med Genet. 2016;59:133–42.

    PubMed  Google Scholar 

  150. Guha T, Malkin D. Inherited TP53 Mutations and the Li-Fraumeni Syndrome. Cold Spring Harb Perspect Med. 2017;7:a026187.

    PubMed  PubMed Central  Google Scholar 

  151. Hendrickson PG, Luo Y, Kohlmann W, Schiffman J, Maese L, Bishop AJ, et al. Radiation therapy and secondary malignancy in Li-Fraumeni syndrome: A hereditary cancer registry study. Cancer Med. 2020;9:7954–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ng AK, Kenney LB, Gilbert ES, Travis LB. Secondary malignancies across the age spectrum. Semin Radiat Oncol. 2010;20:67–78.

    PubMed  Google Scholar 

  153. Lee JS, DuBois SG, Coccia PF, Bleyer A, Olin RL, Goldsby RE. Increased risk of second malignant neoplasms in adolescents and young adults with cancer. Cancer. 2016;122:116–23.

    PubMed  Google Scholar 

  154. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Stoltze UK, Foss-Skiftesvik J, Hansen T, van O, Rasmussen S, Karczewski KJ, et al. The evolutionary impact of childhood cancer on the human gene pool. Nat Commun. 2024;15:1881.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Amund Henriksen K, Van Overeem Hansen T, Wadt K, Schmiegelow K, Foss-Skiftesvik J, Stoltze UK. Evolutionary evidence precludes ELP1 as a high-penetrance pediatric cancer predisposition syndrome gene. Neuro-Oncol Adv. 2024;6:vdae165.

    Google Scholar 

  157. Zerella JR, Homan CC, Arts P, Lin X, Spinelli SJ, Venugopal P et al. Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition. Blood. 2024; blood.2024024607.

  158. Stanley KE, Giordano J, Thorsten V, Buchovecky C, Thomas A, Ganapathi M, et al. Causal Genetic Variants in Stillbirth. N Engl J Med. 2020;383:1107–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Stoltze UK, Hansen T, Foss-Skiftesvik J, Byrjalsen A, Henriksen K, Laspiur A et al. Causal germline variants in children with cancer. 2024. https://doi.org/10.2139/ssrn.4889581.

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Funding

This work is part of the Danish nation-wide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by the Danish Cancer Society (R-257-A14720 & R376-A22861) and the Danish Childhood Cancer Foundation (2019-5934, 2020-5769 & 2023-001063). GC is funded by the Italian Association for cancer Research (AIRC), IG 2023 grant #29175.

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Authors and Affiliations

  1. Department of Childhood and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark

    Ulrik Stoltze, Anna Byrjalsen, Lisa Lyngsie Hjalgrim, Louise Lundgren, Theis Mikkelsen & Kjeld Schmiegelow

  2. Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark

    Ulrik Stoltze, Anna Byrjalsen & Karin Wadt

  3. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Stefanie V. Junk, Melina Mescher & Arndt Borkhardt

  4. Department of Genetics, Robert Debré University Hospital, APHP, Paris, France

    Hélène Cavé

  5. University Paris Cité, Paris, France

    Hélène Cavé & Marion Strullu

  6. INSERM UMR_S1131 - Institut de Recherche Saint-Louis, Paris France, Paris, France

    Hélène Cavé & Marion Strullu

  7. Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

    Giovanni Cazzaniga

  8. School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy

    Giovanni Cazzaniga

  9. Department of Pediatric Hematology and Oncology, Schneider Children’s Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Sarah Elitzur & Shai Izraeli

  10. Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia

    Eva Fronkova & Jan Trka

  11. Department of Clinical Medicine, Faculty of Medicine, Copenhagen University, Copenhagen, Denmark

    Lisa Lyngsie Hjalgrim, Karin Wadt & Kjeld Schmiegelow

  12. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

    Roland P. Kuiper

  13. Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

    Roland P. Kuiper

  14. Department of Pediatrics, Oncology, and Hematology, Medical University of Lodz, Lodz, Poland

    Agata Pastorczak

  15. Department of Genetic Predisposition to Cancer, Medical University of Lodz, Lodz, Poland

    Agata Pastorczak

  16. Pediatric Hematology and Immunology Department, Robert Debré Academic Hospital, GHU AP-HP Nord Paris, Paris, France

    Marion Strullu

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  1. Ulrik Stoltze
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  2. Stefanie V. Junk
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Contributions

US editorialized all sections, and was primary writer for all sections not listed below. SI authored section on t21. SE and SJ co-wrote the “ATM & NBS” section. SJ also led the “FA & BSyn” section. HC and MS co-authored “NF1 & RAS”, with AB assisting. RK prepared the “CMMRD & LFS” section, and GC wrote “ETV6 & PAX5.” EF contributed the “IKFZ1 & RUNX1” section, with JT assisting. LL authored the “radio/chemosusceptibility” section, with TM and SJ assisting. LH, AP, KW assisted with structuring, editorializing, and literature review/checking. US generated graphical elements and associated code, with MM assisting. All authors reviewed and approved the final manuscript and contributed to revisions where applicable.

Corresponding authors

Correspondence to Ulrik Stoltze or Kjeld Schmiegelow.

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Stoltze, U., Junk, S.V., Byrjalsen, A. et al. Overt and covert genetic causes of pediatric acute lymphoblastic leukemia. Leukemia 39, 1031–1045 (2025). https://doi.org/10.1038/s41375-025-02535-4

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