title: Molecular heterogeneity of familial myeloproliferative neoplasms revealed by analysis of the commonly acquired JAK2, CALR and MPL mutations.
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.
authors.affiliation: Cancer Molecular Diagnostics, Central Pathology Laboratory, St. James's Hospital, Dublin 8, Ireland, slangabeer@stjames.ie.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Langabeer
authors.forename: Karl
authors.initials: K
authors.lastname: Haslam
authors.forename: Jennifer
authors.initials: J
authors.lastname: Linders
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: Eibhlin
authors.initials: E
authors.lastname: Conneally
authors.forename: Amjad
authors.initials: A
authors.lastname: Hayat
authors.forename: Brian
authors.initials: B
authors.lastname: Hennessy
authors.forename: Maeve
authors.initials: M
authors.lastname: Leahy
authors.forename: Karen
authors.initials: K
authors.lastname: Murphy
authors.forename: Margaret
authors.initials: M
authors.lastname: Murray
authors.forename: Fionnuala
authors.initials: F
authors.lastname: Ni Ainle
authors.forename: Patrick
authors.initials: P
authors.lastname: Thornton
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sargent
mesh_terms: D037282:Calreticulin / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D053628:Receptors, Thrombopoietin / Q000235:genetics*
chemical_list: C576483:CALR protein, human; D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2
references.citation: Lancet. 2005 Mar 19-25;365(9464):1054-61
references.pmid: 15781101
references.citation: J Mol Diagn. 2013 Nov;15(6):733-44
references.pmid: 23978506
references.citation: Acta Haematol. 2009;121(4):221-2
references.pmid: 19521067
references.citation: Nat Rev Cancer. 2007 Sep;7(9):673-83
references.pmid: 17721432
references.citation: Ther Adv Hematol. 2013 Aug;4(4):237-53
references.pmid: 23926457
references.citation: N Engl J Med. 2007 Feb 1;356(5):459-68
references.pmid: 17267906
references.citation: Nat Genet. 2009 Apr;41(4):455-9
references.pmid: 19287384
references.citation: Semin Thromb Hemost. 2013 Feb;39(1):101-11
references.pmid: 23264112
references.citation: Leukemia. 2010 Jun;24(6):1128-38
references.pmid: 20428194
references.citation: Blood. 2014 Apr 10;123(15):2416-9
references.pmid: 24553179
references.citation: Eur J Hum Genet. 2014 Feb;22(2):
references.pmid: 23736217
references.citation: N Engl J Med. 2012 Mar 8;366(10):967-9
references.pmid: 22397670
references.citation: Nat Genet. 2009 Apr;41(4):450-4
references.pmid: 19287385
references.citation: Haematologica. 2011 Mar;96(3):367-74
references.pmid: 21173100
references.citation: Leukemia. 2014 Jun;28(6):1357-60
references.pmid: 24441291
references.citation: Haematologica. 2010 Jan;95(1):6-8
references.pmid: 20065077
references.citation: Clin Genet. 2013 Feb;83(2):99-107
references.pmid: 23094849
references.citation: Leukemia. 2009 Oct;23(10):1924-6
references.pmid: 19440215
references.citation: Hematol Oncol. 2008 Sep;26(3):131-8
references.pmid: 18484677
references.citation: N Engl J Med. 2013 Dec 19;369(25):2391-2405
references.pmid: 24325359
references.citation: Am J Hematol. 2014 Jan;89(1):117-8
references.pmid: 24142793
references.citation: Ann Hematol. 2012 Oct;91(10):1555-62
references.pmid: 22706669
references.citation: Haematologica. 2007 Dec;92(12):1607-14
references.pmid: 18055983
references.citation: Hematol Oncol Clin North Am. 2012 Oct;26(5):1083-99
references.pmid: 23009939
references.citation: Am J Hematol. 2012 Nov;87(11):1028-36
references.pmid: 22641564
references.citation: Blood Cells Mol Dis. 2012 Oct 15-Dec 15;49(3-4):170-6
references.pmid: 22818858
references.citation: Blood. 2010 Jun 3;115(22):4517-23
references.pmid: 20304805
references.citation: N Engl J Med. 2013 Dec 19;369(25):2379-90
references.pmid: 24325356
references.citation: Nat Genet. 2009 Apr;41(4):446-9
references.pmid: 19287382
references.citation: Hum Mutat. 2014 Jan;35(1):15-26
references.pmid: 24115288
references.citation: Blood. 2014 Feb 13;123(7):1059-68
references.pmid: 24381227
references.citation: J Clin Oncol. 2007 Dec 10;25(35):5630-5
references.pmid: 17998545
references.citation: Am J Hematol. 2012 Feb;87(2):175-82
references.pmid: 22076943
references.citation: J Clin Oncol. 2011 Feb 10;29(5):573-82
references.pmid: 21220604