A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms.
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.
Kilpivaara
Outi
O
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Mukherjee
Semanti
S
Schram
Alison M
AM
Wadleigh
Martha
M
Mullally
Ann
A
Ebert
Benjamin L
BL
Bass
Adam
A
Marubayashi
Sachie
S
Heguy
Adriana
A
Garcia-Manero
Guillermo
G
Kantarjian
Hagop
H
Offit
Kenneth
K
Stone
Richard M
RM
Gilliland
D Gary
DG
Klein
Robert J
RJ
Levine
Ross L
RL
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
C507924:JAK2 protein, human; D053614:Janus Kinase 2