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Annals of Hematology

, Volume 95, Issue 7, pp 1043–1050 | Cite as

Mutational analysis of JAK2, CBL, RUNX1, and NPM1 genes in familial aggregation of hematological malignancies

  • Walid S. HamadouEmail author
  • Violaine Bourdon
  • Pascaline Gaildrat
  • Sawsen Besbes
  • Aurélie Fabre
  • Yosra B. Youssef
  • Haifa Regaieg
  • Mohamed A. Laatiri
  • François Eisinger
  • Véronique Mari
  • Paul Gesta
  • Hélène Dreyfus
  • Valérie Bonadona
  • Catherine Dugast
  • Hélène Zattara
  • Laurence Faivre
  • Saloua Yacoub Jemni
  • Testsuro Noguchi
  • Abderrahim Khélif
  • Hagay Sobol
  • Zohra Soua
Original Article

Abstract

Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a prominent function in hematological process and CBL and NPM1 as proto-oncogenes. Their disruption was described in several sporadic hematological malignancies. The aim of this study is to determine whether JAK2, CBL, RUNX1, and NPM1 germline genes mutations are involved in familial hematological malignancies. Using direct sequencing, we analyzed JAK2 (exons 12 and 14); CBL (exons 7, 8 and 9); NPM1 (exon 12) and the entire RUNX1 in 88 independent families belonging to Tunisian and French populations. Twenty-one sporadic acute leukemias were included in this study. We reported a heterozygous intronic c.1641 + 6 T > C JAK2 variant (rs182123615) found in two independent familial cases diagnosed with gastric lymphoma and Hodgkin lymphoma. The in silico analysis suggested a potential impact on splicing, but the functional splicing minigene reporter assay on rs182123615 variant showed no aberrant transcripts. In one sporadic acute myeloblastic leukemia, we reported an insertion 846 in. TGTT in exon 12 of NPM1 gene that may impact the normal reading frame. The rs182123615 JAK2 variant was described in several contexts including myeloproliferative neoplasms and congenital erythrocytosis and was supposed to be pathogenic. Through this current study, we established the assessment of pathogenicity of rs182123615 and we classified it rather as rare polymorphism.

Keywords

JAK2 CBL RUNX1 NPM1 Familial hematological malignancies 

Notes

Acknowledgments

This work was supported by la Société Française d’Hématologie, le groupe Génétique et Cancer and Institut National du Cancer (INCa) and the Ministère de l’Enseignement Supérieur et de la Recherche Scientifique Tunisie. It is a part of the GenHem INSERM/DGRS project. We are grateful for the English correction and assistance provided by Mouna Bouali.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Walid S. Hamadou
    • 1
    Email author
  • Violaine Bourdon
    • 2
  • Pascaline Gaildrat
    • 3
  • Sawsen Besbes
    • 1
  • Aurélie Fabre
    • 2
  • Yosra B. Youssef
    • 1
    • 4
  • Haifa Regaieg
    • 1
    • 4
  • Mohamed A. Laatiri
    • 5
  • François Eisinger
    • 6
  • Véronique Mari
    • 7
  • Paul Gesta
    • 8
  • Hélène Dreyfus
    • 9
  • Valérie Bonadona
    • 10
  • Catherine Dugast
    • 11
  • Hélène Zattara
    • 12
  • Laurence Faivre
    • 13
  • Saloua Yacoub Jemni
    • 14
  • Testsuro Noguchi
    • 2
  • Abderrahim Khélif
    • 1
    • 4
  • Hagay Sobol
    • 2
  • Zohra Soua
    • 1
  1. 1.UR “Biologie moléculaire des leucémies et lymphomes”, Laboratoire de Biochimie, Faculté de Médecine de SousseUniversité de SousseSousseTunisia
  2. 2.Département d’Oncologie Génétique, de Prévention et DépistageInstitut Paoli-CalmettesMarseilleFrance
  3. 3.Inserm U1079, Institut de Recherche et d’Innovation Biomédicale (IRIB)Université de RouenRouenFrance
  4. 4.Service d’Hématologie cliniqueCHU Farhat HachedSousseTunisia
  5. 5.Service d’Hématologie cliniqueCHU Fattouma BourguibaMonastirTunisia
  6. 6.Département d’Anticipation et de Suivi du Cancer, Centre de Lutte Contre le CancerInstitut Paoli CalmettesMarseilleFrance
  7. 7.Service d’Oncologie Génétique, Centre de Lutte Contre le CancerCentre Antoine LacassagneNiceFrance
  8. 8.Service d’Oncologie GénétiqueCentre HospitalierNiortFrance
  9. 9.Institut Sainte CatherineAvignonFrance
  10. 10.Unité de génétique EpidémiologiqueCentre Léon BérardLyonFrance
  11. 11.Centre Eugène MarquisRennesFrance
  12. 12.Département de GénétiqueHôpital de la TimoneMarseilleFrance
  13. 13.Hôpital d’EnfantsCHU de DijonDijonFrance
  14. 14.Centre régional de transfusion sanguineCHU F. HachedSousseTunisia

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