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Familial Acute Myeloid Leukemia and Myelodysplasia in Hungary

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Pathology & Oncology Research

Abstract

Although genetic predisposition to haematological malignancies has long been known, genetic testing is not yet the part of the routine diagnostics. In the last ten years, next generation sequencing based studies identified novel germline mutations in the background of familial aggregation of certain haematologic disorders including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is supported by the fact that the myeloid neoplasms with genetic predisposition represent a new category in the revised 2016 World Health Organization classification. According to the new classification, these disorders are subdivided based on the clinical and genetic features, including myeloid neoplasms with germline predisposition alone, or with pre-existing platelet disorder, cytopaenias or other organ failures. The predisposing genetic factors include mutations in the RUNX1, CEBPA, GATA2, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 genes. The genes affected in these syndromes are important regulators of haemopoiesis and are frequently implicated in leukaemogenesis, providing deeper insight into the understanding of normal and malignant haemopoiesis. Despite the growing knowledge of germline predisposing events in the background of familial myeloid malignancies, the germline genetic component is still unknown in a subset of these pedigrees. Here, we present the first study of inherited myeloid malignancies in Hungary. We identified three families with apparent clustering of myeloid malignancies with nine affected individuals across these pedigrees. All tested individuals were negative for CEBPA, GATA2, RUNX1, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 mutations, suggesting the presence of so far unidentified predisposing mutations.

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References

  1. Porter CC (2016) Germ line mutations associated with leukemias. Hematol Am Soc Hematol Educ Prog 2016(1):302–308

    Google Scholar 

  2. West AH, Godley LA, Churpek JE (2014) Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. Ann N Y Acad Sci 1310:111–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC et al (2011) Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43(10):1012–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kirwan M, Walne AJ, Plagnol V, Velangi M, Ho A, Hossain U et al (2012) Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am J Hum Genet 90(5):888–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pippucci T, Savoia A, Perrotta S, Pujol-Moix N, Noris P, Castegnaro G et al (2011) Mutations in the 5′ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet 88(1):115–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N et al (2015) Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27(5):658–670

    Article  CAS  PubMed  Google Scholar 

  7. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405

    Article  CAS  PubMed  Google Scholar 

  8. Duployez N, Lejeune S, Renneville A, Preudhomme C (2016) Myelodysplastic syndromes and acute leukemia with genetic predispositions: a new challenge for hematologists. Expert Rev Hematol 9(12):1189–1202

    Article  CAS  PubMed  Google Scholar 

  9. Churpek JE (2016) Godley LA. How I diagnose and manage individuals at risk for inherited myeloid malignancies, Blood

    Google Scholar 

  10. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S et al (2001) Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 27(3):263–270

    Article  CAS  PubMed  Google Scholar 

  11. Li R, Sobreira N, Witmer PD, Pratz KW, Braunstein EM (2016) Two novel germline DDX41 mutations in a family with inherited myelodysplasia/acute myeloid leukemia. Haematologica 101(6):e228–e231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cardoso SR, Ryan G, Walne AJ, Ellison A, Lowe R, Tummala H et al (2016) Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia. Leukemia 30(10):2083–2086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J (2004) Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med 351(23):2403–2407

    Article  CAS  PubMed  Google Scholar 

  14. Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M et al (2011) Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 118(10):2656–2658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY et al (2011) Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118(10):2653–2655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Armanios M (2009) Syndromes of telomere shortening. Annu Rev Genomics Hum Genet 10:45–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23(2):166–175

    Article  CAS  PubMed  Google Scholar 

  18. Zhang MY, Churpek JE, Keel SB, Walsh T, Lee MK, Loeb KR et al (2015) Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet 47(2):180–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Haslam K, Langabeer SE, Hayat A, Conneally E, Vandenberghe E (2016) Targeted next-generation sequencing of familial platelet disorder with predisposition to acute myeloid leukaemia. Br J Haematol 175(1):161–163

    Article  PubMed  Google Scholar 

  20. Preudhomme C, Renneville A, Bourdon V, Philippe N, Roche-Lestienne C, Boissel N et al (2009) High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder. Blood 113(22):5583–5587

    Article  CAS  PubMed  Google Scholar 

  21. Ding LW, Ikezoe T, Tan KT, Mori M, Mayakonda A, Chien W, et al. (2016) Mutational profiling of a MonoMAC syndrome family with GATA2 deficiency. Leukemia

  22. Godley LA (2014) Inherited predisposition to acute myeloid leukemia. Semin Hematol 51(4):306–321

    Article  PubMed  Google Scholar 

  23. DiNardo CD, Bannon SA, Routbort M, Franklin A, Mork M, Armanios M et al (2016) Evaluation of patients and families with concern for predispositions to hematologic malignancies within the hereditary hematologic malignancy clinic (HHMC). Clin Lymphoma, Myeloma Leuk 16(7):417–28.e2

    Article  Google Scholar 

  24. Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A et al (2015) Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet 47(5):535–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vulliamy T, Marrone A, Dokal I, Mason PJ (2002) Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359(9324):2168–2170

    Article  CAS  PubMed  Google Scholar 

  26. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ et al (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 352(14):1413–1424

    Article  CAS  PubMed  Google Scholar 

  27. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447

    Article  PubMed  PubMed Central  Google Scholar 

  28. Churpek JE, Lorenz R, Nedumgottil S, Onel K, Olopade OI, Sorrell A et al (2013) Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leuk Lymphoma 54(1):28–35

    Article  PubMed  Google Scholar 

  29. Green CL, Tawana K, Hills RK, Bodor C, Fitzgibbon J, Inglott S et al (2013) GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 161(5):701–705

    Article  CAS  PubMed  Google Scholar 

  30. Greif PA, Dufour A, Konstandin NP, Ksienzyk B, Zellmeier E, Tizazu B et al (2012) GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood 120(2):395–403

    Article  CAS  PubMed  Google Scholar 

  31. Osato M, Yanagida M, Shigesada K, Ito Y (2001) Point mutations of the RUNx1/AML1 gene in sporadic and familial myeloid leukemias. Int J Hematol 74(3):245–251

    Article  CAS  PubMed  Google Scholar 

  32. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S et al (2002) Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the acute leukemia French association (ALFA). Blood 100(8):2717–2723

    Article  CAS  PubMed  Google Scholar 

  33. Galili NT, Trifonov, V., Ewalt, M., Mukherjee, S., Rabadan, R., Raza, A. (2012) Identification of Dido1 Mutation Associated with Familial Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) Blood. 120:169

  34. Yang F, Gong Q, Shi W, Zou Y, Shi J, Wei F et al (2016) Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation. Tumour Biol 37(9):12609–12618

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by the Momentum grant of the Hungarian Academy of Sciences and NVKP_16-1-2016-0004 and NVKP_16-1-2016-0005 grants of the Hungarian National Research, Development and Innovation Office (NFKIH).

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Authors and Affiliations

  1. MTA-SE Lendület Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    Attila Péter Király, Ambrus Gángó, Richárd Kiss, Judit Csomor, András Matolcsy & Csaba Bödör

  2. Pediatric Hematology and Stem Cell Transplantation Unit, United St. István and St. László Hospital, Budapest, Hungary

    Krisztián Kállay

  3. Department of Hematology, Kaposi Mor Teaching Hospital, Kaposvár, Hungary

    Ádám Kellner & Miklós Egyed

  4. 2nd Department of Medicine and Cardiology Centre, Medical Faculty, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary

    Anita Szőke

  5. United St. István and St. László Hospital, Budapest, Hungary

    István Vályi-Nagy

Authors
  1. Attila Péter Király
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  2. Krisztián Kállay
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  3. Ambrus Gángó
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  4. Ádám Kellner
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  9. Judit Csomor
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  10. András Matolcsy
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Correspondence to Csaba Bödör.

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Király, A.P., Kállay, K., Gángó, A. et al. Familial Acute Myeloid Leukemia and Myelodysplasia in Hungary. Pathol. Oncol. Res. 24, 83–88 (2018). https://doi.org/10.1007/s12253-017-0216-4

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  • DOI: https://doi.org/10.1007/s12253-017-0216-4

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