A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms
Outi Kilpivaara,Semanti Mukherjee,Alison M. Schram,Martha Wadleigh,Ann Mullally,Benjamin L. Ebert,Benjamin L. Ebert,Adam J. Bass,Adam J. Bass,Sachie Marubayashi,Adriana Heguy,Guillermo Garcia-Manero,Hagop M. Kantarjian,Kenneth Offit,Richard Stone,D. Gary Gilliland,Robert J. Klein,Ross L. Levine +17 more
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TLDR
Genome-wide analysis identified an allele in the JAK2 locus that predisposes to the development ofJAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci, which suggest that germline variation is an important contributor to MPN phenotype and predisposition.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.read more
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The landscape of somatic copy-number alteration across human cancers
Rameen Beroukhim,Craig H. Mermel,Craig H. Mermel,Dale Porter,Guo Wei,Soumya Raychaudhuri,Soumya Raychaudhuri,Jerry Donovan,Jordi Barretina,Jordi Barretina,Jesse S. Boehm,Jennifer Dobson,Jennifer Dobson,Mitsuyoshi Urashima,Kevin T. Mc Henry,Reid M. Pinchback,Azra H. Ligon,Yoon Jae Cho,Leila Haery,Leila Haery,Heidi Greulich,Michael R. Reich,Wendy Winckler,Michael S. Lawrence,Barbara A. Weir,Barbara A. Weir,Kumiko E. Tanaka,Kumiko E. Tanaka,Derek Y. Chiang,Derek Y. Chiang,Derek Y. Chiang,Adam J. Bass,Adam J. Bass,Adam J. Bass,Alice Loo,Carter Hoffman,Carter Hoffman,John R. Prensner,John R. Prensner,Ted Liefeld,Qing Gao,Derek Yecies,Sabina Signoretti,Sabina Signoretti,Elizabeth A. Maher,Frederic J. Kaye,Hidefumi Sasaki,Joel E. Tepper,Jonathan A. Fletcher,Josep Tabernero,José Baselga,Ming-Sound Tsao,Francesca Demichelis,Mark A. Rubin,Pasi A. Jänne,Pasi A. Jänne,Mark J. Daly,Mark J. Daly,Carmelo Nucera,Ross L. Levine,Benjamin L. Ebert,Benjamin L. Ebert,Benjamin L. Ebert,Stacey Gabriel,Anil K. Rustgi,Cristina R. Antonescu,Marc Ladanyi,Anthony Letai,Levi A. Garraway,Levi A. Garraway,Massimo Loda,Massimo Loda,David G. Beer,Lawrence D. True,Aikou Okamoto,Scott L. Pomeroy,Samuel Singer,Todd R. Golub,Todd R. Golub,Todd R. Golub,Eric S. Lander,Eric S. Lander,Eric S. Lander,Gad Getz,William R. Sellers,Matthew Meyerson,Matthew Meyerson +86 more
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New IBD genetics: common pathways with other diseases
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Journal ArticleDOI
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Robert Kralovics,Francesco Passamonti,Andreas Buser,Soon Siong Teo,Ralph Tiedt,Jakob Passweg,André Tichelli,Mario Cazzola,Radek C. Skoda +8 more
TL;DR: Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
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