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Classification and Personalized Prognosis in Myeloproliferative Neoplasms.
Grinfeld, Jacob; Nangalia, Jyoti; Baxter, E Joanna; Wedge, David C; Angelopoulos, Nicos; Cantrill, Robert; Godfrey, Anna L; Papaemmanuil, Elli; Gundem, Gunes; MacLean, Cathy; Cook, Julia; O'Neil, Laura; O'Meara, Sarah; Teague, Jon W; Butler, Adam P; Massie, Charlie E; Williams, Nicholas; Nice, Francesca L; Andersen, Christen L; Hasselbalch, Hans C; Guglielmelli, Paola; McMullin, Mary F; Vannucchi, Alessandro M; Harrison, Claire N; Gerstung, Moritz; Green, Anthony R; Campbell, Peter J.
Afiliação
  • Grinfeld J; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Nangalia J; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Baxter EJ; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Wedge DC; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Angelopoulos N; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Cantrill R; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Godfrey AL; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Papaemmanuil E; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Gundem G; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • MacLean C; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Cook J; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • O'Neil L; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • O'Meara S; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Teague JW; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Butler AP; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Massie CE; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Williams N; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Nice FL; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Andersen CL; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Hasselbalch HC; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Guglielmelli P; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • McMullin MF; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Vannucchi AM; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Harrison CN; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Gerstung M; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Green AR; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
  • Campbell PJ; From the Wellcome-MRC Cambridge Stem Cell Institute and Cambridge Institute for Medical Research (J.G., C.E.M., F.L.N., A.R.G., P.J.C.), the Department of Haematology, University of Cambridge (J.G., E.J.B., C.M., J.C., C.E.M., F.L.N., A.R.G.), and the Department of Haematology, Cambridge University
N Engl J Med ; 379(15): 1416-1430, 2018 10 11.
Article em En | MEDLINE | ID: mdl-30304655
ABSTRACT

BACKGROUND:

Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment.

METHODS:

We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort.

RESULTS:

A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy.

CONCLUSIONS:

Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms. Integration of genomic data with clinical variables enabled the personalized predictions of patients' outcomes and may support the treatment of patients with myeloproliferative neoplasms. (Funded by the Wellcome Trust and others.).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Calreticulina / Janus Quinase 2 / Receptores de Trombopoetina / Medicina de Precisão / Mutação / Transtornos Mieloproliferativos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: N Engl J Med Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Calreticulina / Janus Quinase 2 / Receptores de Trombopoetina / Medicina de Precisão / Mutação / Transtornos Mieloproliferativos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: N Engl J Med Ano de publicação: 2018 Tipo de documento: Article