ORIGINAL ARTICLE 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 Ó Springer Science+Business Media Dordrecht 2014 Abstract The myeloproliferative neoplasms (MPN) are clonal, hematological malignancies that include polycythe- mia vera, essential thrombocythemia and primary myelofi- brosis. While most cases of MPN are sporadic in nature, a familial pattern of inheritance is well recognised. The phe- notype 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 spo- radic 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 Á JAK2 Á CALR Á MPL Introduction The myeloproliferative neoplasms (MPN) are clonal, hematopoietic stem cell-derived diseases characterised by bone marrow proliferation of one or more of the myeloid cell lineages with the main classical subtypes of MPN being polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The primary goal of therapy in PV and ET is to prevent thrombotic or hemorrhagic complications and in PMF, to alleviate ane- mia, symptomatic splenomegaly or constitutional S. E. Langabeer (&) Á K. Haslam Cancer Molecular Diagnostics, Central Pathology Laboratory, St. James’s Hospital, Dublin 8, Ireland e-mail: slangabeer@stjames.ie J. Linders Á J. Sargent Department of Haematology, Our Lady of Lourdes Hospital, Drogheda, Ireland M. J. Percy Department of Haematology, Belfast City Hospital, Belfast, UK E. Conneally Department of Haematology, St. James’s Hospital, Dublin, Ireland A. Hayat Á M. Murray Department of Haematology, Galway University Hospital, Galway, Ireland B. Hennessy Department of Haematology, Waterford Regional Hospital, Waterford, Ireland M. Leahy Department of Haematology, University Hospital Limerick, Limerick, Ireland K. Murphy Department of Haematology, St Vincent’s University Hospital, Dublin, Ireland F. Ni Ainle Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland P. Thornton Department of Haematology, Beaumont Hospital, Dublin, Ireland 123 Familial Cancer DOI 10.1007/s10689-014-9743-2