Advertisement

Familial Cancer

, Volume 13, Issue 4, pp 659–663 | Cite as

Molecular heterogeneity of familial myeloproliferative neoplasms revealed by analysis of the commonly acquired JAK2, CALR and MPL mutations

  • Stephen E. Langabeer
  • Karl Haslam
  • Jennifer Linders
  • Melanie J. Percy
  • Eibhlin Conneally
  • Amjad Hayat
  • Brian Hennessy
  • Maeve Leahy
  • Karen Murphy
  • Margaret Murray
  • Fionnuala Ni Ainle
  • Patrick Thornton
  • Jeremy Sargent
Original Article

Abstract

The myeloproliferative neoplasms (MPN) are clonal, hematological malignancies that include polycythemia vera, essential thrombocythemia and primary myelofibrosis. While most cases of MPN are sporadic in nature, a familial pattern of inheritance is well recognised. The phenotype and status of the commonly acquired JAK2 V617F, CALR exon 9 and MPL W515L/K mutations in affected individuals from a consecutive series of ten familial MPN (FMPN) kindred are described. Affected individuals display the classical MPN phenotypes together with one kindred identified suggestive of hereditary thrombocytosis. In affected patients the JAK2 V617F mutation is the most commonly acquired followed by CALR exon nine mutations with no MPL W515L/K mutations detected. The JAK2 V617F and CALR exon 9 mutations appear to occur at approximately the same frequency in FMPN as in the sporadic forms of these diseases. The familial nature of MPN may often be overlooked and accordingly more common than previously considered. Characterisation of these FMPN kindred may allow for the investigation of molecular events that contribute to this inheritance.

Keywords

Familial myeloproliferative neoplasms JAK2 CALR MPL 

Notes

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Tefferi A, Vainchenker W (2011) Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 29:573–582PubMedCrossRefGoogle Scholar
  2. 2.
    McMahon B, Stein BL (2013) Thrombotic and bleeding complications in classical myeloproliferative neoplasms. Semin Thromb Hemost 39:101–111PubMedGoogle Scholar
  3. 3.
    Levine RL, Pardanani A, Tefferi A, Gilliland DG (2007) Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7:673–683PubMedCrossRefGoogle Scholar
  4. 4.
    Santos FP, Verstovsek S (2012) Therapy with JAK2 inhibitors for myeloproliferative neoplasms. Hematol Oncol Clin North Am 26:1083–1099PubMedCrossRefGoogle Scholar
  5. 5.
    Scott LM, Tong W, Levine RL et al (2007) JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356:459–468PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Klampfl T, Gisslinger H, Harutyunyan AS et al (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369:2379–2390PubMedCrossRefGoogle Scholar
  7. 7.
    Nangalia J, Massie CE, Baxter EJ et al (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369:2391–2405PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Gong JZ, Cook JR, Greiner TC et al (2013) Laboratory practice guidelines for detecting and reporting JAK2 and MPL mutations in myeloproliferative neoplasms: a report from the Association for Molecular Pathology. J Mol Diagn 15:733–744PubMedCrossRefGoogle Scholar
  9. 9.
    Tefferi A (2010) Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 24:1128–1138PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Rumi E (2008) Familial chronic myeloproliferative disorders: the state of the art. Hematol Oncol 26:131–138PubMedCrossRefGoogle Scholar
  11. 11.
    Malak S, Labopin M, Saint-Martin C, Bellanne-Chantelot C, Najman A (2012) Long term follow up of 93 families with myeloproliferative neoplasms: life expectancy and implications of JAK2 V617F in the occurrence of complications. Blood Cells Mol Dis 49:170–176PubMedCrossRefGoogle Scholar
  12. 12.
    Ranjan A, Penninga E, Jelsig AM, Hasselbalch H, Bjerrum OW (2013) Inheritance of the chronic myeloproliferative neoplasms: a systematic review. Clin Genet 83:99–107PubMedCrossRefGoogle Scholar
  13. 13.
    Bento C, Percy MJ, Gardie B et al (2014) Genetic basis of congenital erythrocytosis: mutation update and online databases. Hum Mutat 35:15–26PubMedCrossRefGoogle Scholar
  14. 14.
    Skoda RC (2010) Hereditary myeloproliferative disorders. Haematologica 95:6–8PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Mead AJ, Rugless MJ, Jacobsen SE, Schuh A (2012) Germline JAK2 mutation in a family with hereditary thrombocytosis. N Engl J Med 366:967–969PubMedCrossRefGoogle Scholar
  16. 16.
    Jones AV, Chase A, Silver RT et al (2009) JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 41:446–449PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Olcaydu D, Harutyunyan A, Jäger R et al (2009) A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41:450–454PubMedCrossRefGoogle Scholar
  18. 18.
    Kilpivaara O, Mukherjee S, Schram AM et al (2009) A germline SNP is associated with predisposition to the development of JAK2 (V617F)-positive myeloproliferative neoplasms. Nat Genet 41:455–459PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Olcaydu D, Skoda RC, Looser R et al (2009) The GGCC haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera. Leukemia 23:1924–1926PubMedCrossRefGoogle Scholar
  20. 20.
    Jones AV, Campbell PJ, Beer PA et al (2010) The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms. Blood 115:4517–4523PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Swerdlow SH, Campo E, Harris NL et al (eds) (2008) WHO classification of tumours of haematopoietic and lymphoid tissue. International Agency for Research on Cancer, LyonGoogle Scholar
  22. 22.
    Baxter EJ, Scott LM, Campbell PJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061PubMedCrossRefGoogle Scholar
  23. 23.
    Daly S, Conneally E, Langabeer SE (2009) Identification of the MPL W515L/K mutations in patients with primary myelofibrosis and essential thrombocythaemia by allele-specific polymerase chain reaction. Acta Haematol 121:221–222PubMedCrossRefGoogle Scholar
  24. 24.
    Percy MJ, Scott LM, Erber WN et al (2007) The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Haematologica 92:1607–1614PubMedCrossRefGoogle Scholar
  25. 25.
    Martinez-Avilés L, Álvarez-Larrán A, Besses C et al (2012) Clinical significance of clonality assessment in JAK2 V617F-negative essential thrombocythemia. Ann Hematol 91:1555–1562PubMedCrossRefGoogle Scholar
  26. 26.
    Hussein K, Percy M, McMullin MF et al (2014) Clinical utility gene card for: hereditary thrombocythemia. Eur J Hum Genet. doi: 10.1038/ejhg.2013.117 PubMedGoogle Scholar
  27. 27.
    Maffioli M, Genoni A, Caramazza D et al (2014) Looking for CALR mutations in familial myeloproliferative disorders. Leukemia 28:1357–1360PubMedCrossRefGoogle Scholar
  28. 28.
    Rumi E, Harutyunyan AS, Pietra D et al (2014) CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis. Blood 123:2416–2419PubMedCrossRefGoogle Scholar
  29. 29.
    Rumi E, Harutyunyan AS, Casetti I et al (2014) A novel germline JAK2 mutation in familial myeloproliferative neoplasms. Am J Hematol 89:117–118PubMedCrossRefGoogle Scholar
  30. 30.
    Etheridge SL, Cosgrove ME, Sangkhae V et al (2014) A novel activating, germline JAK2 mutation, JAK2 R564Q, causes familial essential thrombocytosis. Blood 123:1059–1068PubMedCrossRefGoogle Scholar
  31. 31.
    Rumi E, Passamonti F, Della Porta MG et al (2007) Familial chronic myeloproliferative disorders: clinical phenotype and evidence of disease anticipation. J Clin Oncol 35:5630–5635CrossRefGoogle Scholar
  32. 32.
    Olcaydu D, Rumi E, Harutyunyan A et al (2011) The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms. Haematologica 96:367–374PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Scott LM, Rebel VI (2012) JAK2 and genomic instability in the myeloproliferative neoplasms: a case of the chicken or the egg? Am J Hematol 87:1028–1036PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Anderson LA, Duncombe AS, Hughes M et al (2012) Environmental, lifestyle, and familial/ethnic factors associated with myeloproliferative neoplasms. Am J Hematol 87:175–182PubMedCrossRefGoogle Scholar
  35. 35.
    Jones AV, Cross NCP (2013) Inherited predisposition to myeloproliferative neoplasms. Ther Adv Hematol 4:237–253PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Stephen E. Langabeer
    • 1
  • Karl Haslam
    • 1
  • Jennifer Linders
    • 2
  • Melanie J. Percy
    • 3
  • Eibhlin Conneally
    • 4
  • Amjad Hayat
    • 5
  • Brian Hennessy
    • 6
  • Maeve Leahy
    • 7
  • Karen Murphy
    • 8
  • Margaret Murray
    • 5
  • Fionnuala Ni Ainle
    • 9
  • Patrick Thornton
    • 10
  • Jeremy Sargent
    • 2
  1. 1.Cancer Molecular Diagnostics, Central Pathology LaboratorySt. James’s HospitalDublin 8Ireland
  2. 2.Department of HaematologyOur Lady of Lourdes HospitalDroghedaIreland
  3. 3.Department of HaematologyBelfast City HospitalBelfastUK
  4. 4.Department of HaematologySt. James’s HospitalDublinIreland
  5. 5.Department of HaematologyGalway University HospitalGalwayIreland
  6. 6.Department of HaematologyWaterford Regional HospitalWaterfordIreland
  7. 7.Department of HaematologyUniversity Hospital LimerickLimerickIreland
  8. 8.Department of HaematologySt Vincent’s University HospitalDublinIreland
  9. 9.Department of HaematologyMater Misericordiae University HospitalDublinIreland
  10. 10.Department of HaematologyBeaumont HospitalDublinIreland

Personalised recommendations