A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms Journal Article


Authors: Kilpivaara, O.; Mukherjee, S.; Schram, A. M.; Wadleigh, M.; Mullally, A.; Ebert, B. L.; Bass, A.; Marubayashi, S.; Heguy, A.; Garcia-Manero, G.; Kantarjian, H.; Offit, K.; Stone, R. M.; Gilliland, D. G.; Klein, R. J.; Levine, R. L.
Article Title: A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms
Abstract: Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2(V617F)) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2(V617F)-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2(V617F) is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition. © 2009 Nature America, Inc. All rights reserved.
Keywords: controlled study; major clinical study; myeloproliferative disorder; polymorphism, single nucleotide; sequence deletion; janus kinase 2; disease course; neoplasm; phenotype; allele; cancer susceptibility; genetic predisposition to disease; amino acid substitution; gene locus; genetic variability; genome analysis; hematologic neoplasms; gene identification; homozygote; hematopoiesis; germ-line mutation; myeloproliferative neoplasm; pleiotropy; genome, human; heterozygote detection
Journal Title: Nature Genetics
Volume: 41
Issue: 4
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2009-04-01
Start Page: 455
End Page: 459
Language: English
DOI: 10.1038/ng.342
PUBMED: 19287384
PROVIDER: scopus
PMCID: PMC3676425
DOI/URL:
Notes: --- - "Cited By (since 1996): 55" - "Export Date: 30 November 2010" - "CODEN: NGENE" - "Source: Scopus"
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MSK Authors
  1. Adriana Heguy
    85 Heguy
  2. Kenneth Offit
    527 Offit
  3. Ross Levine
    496 Levine
  4. Robert J. Klein
    60 Klein
  5. Alison Michele Schram
    25 Schram