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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Semanti
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Alison M
authors.initials: AM
authors.lastname: Schram
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: Adam
authors.initials: A
authors.lastname: Bass
authors.forename: Sachie
authors.initials: S
authors.lastname: Marubayashi
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D019943:Amino Acid Substitution; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D018095:Germ-Line Mutation; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2