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A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms

Nature Genetics volume 41, pages 455–459 (2009)Cite this article

Abstract

Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis1,2,3,4,5. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2V617F) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis6,7,8,9,10, 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 loci11. 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 JAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2V617F is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.

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Figure 1: Principal component analysis of MPN cases and WTCCC controls.
Figure 2: JAK2V617F is acquired in cis with JAK2 SNP rs10974944.
Figure 3: Genome-wide SNP analysis of MPN cases and WTCCC controls.

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Acknowledgements

We would like to acknowledge the subjects who have contributed to our understanding of these disorders. We thank S. Thomas, I. Dolgalev and T. Landers for assistance with high-throughput resequencing, A. Viale for assistance with JAK2 expression analysis, and T. Kirchhoff for advice and suggestions. This study makes use of data generated by the Wellcome Trust Case-Control Consortium; a full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk and funding was provided by the Wellcome Trust under award 076113. This work was supported by grants from the National Institutes of Health, the Starr Cancer Consortium, the Myeloproliferative Disorders Foundation, the Howard Hughes Medical Institute, the Doris Duke Charitable Foundation and the Kristen Amico Sesselman Leukemia Research Fund. O.K. is supported by a grant from the Academy of Finland. D.G.G. is an Investigator of the Howard Hughes Medical Institute and is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. Work in the laboratory of R.J.K. is supported by Memorial Sloan Kettering Cancer Center through US National Institutes of Health grant P30 CA008748. R.L.L. is an Early Career Award recipient of the Howard Hughes Medical Institute and a Clinical Scientist Development Award recipient of the Doris Duke Charitable Foundation and is the Geoffrey Beene Junior Chair at Memorial Sloan Kettering Cancer Center.

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Author notes

  1. Outi Kilpivaara and Semanti Mukherjee: These authors contributed equally to this work.

Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Outi Kilpivaara, Alison M Schram, Sachie Marubayashi, Adriana Heguy & Ross L Levine

  2. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Semanti Mukherjee & Robert J Klein

  3. Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, New York, New York, USA

    Semanti Mukherjee

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Martha Wadleigh, Ann Mullally, Adam Bass, Richard M Stone & D Gary Gilliland

  5. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Ann Mullally, Benjamin L Ebert & D Gary Gilliland

  6. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

    Benjamin L Ebert, Adam Bass & D Gary Gilliland

  7. Department of Leukemia, M.D. Anderson Cancer Center, Houston, Texas, USA

    Guillermo Garcia-Manero & Hagop Kantarjian

  8. Department of Medicine, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Kenneth Offit

  9. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

    D Gary Gilliland

  10. Harvard Stem Cell Institute, Boston, Massachusetts, USA

    D Gary Gilliland

  11. Department of Medicine, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Ross L Levine

Authors
  1. Outi Kilpivaara
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Contributions

The study was designed by O.K., S. Mukherjee, R.J.K. and R.L.L. with advice from K.O. SNP arrays were performed and analyzed by A.B., B.L.E. and R.L.L, and analysis of SNP array data for modifier and predisposition loci was performed by S. Mukherjee and R.J.K. Genotyping, sequence analysis and real-time PCR assays were performed by O.K., A.M.S., S. Marubayashi, A.H. and R.L.L. Principal component analysis was done by S. Mukherjee and R.J.K. Identification of subjects, sample collection and phenotypic assessment were done by M.W., A.M., G.G.-M., H.K., R.M.S, D.G.G. and R.L.L. The paper was written by O.K., S. Mukherjee, K.O., D.G.G., R.J.K. and R.L.L. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Robert J Klein or Ross L Levine.

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Kilpivaara, O., Mukherjee, S., Schram, A. et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms. Nat Genet 41, 455–459 (2009). https://doi.org/10.1038/ng.342

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