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Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes

Leukemia volume 28, pages 935–938 (2014)Cite this article

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Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by an elevated red cell mass caused by excessive myelopoiesis with propensity to transformation to myelofibrosis and acute leukemia.1 JAK2V617F mutation2 and acquired uniparental disomy on chromosome 9p (9p UPD)3, 4 are the most frequent somatic alterations. JAK2 is mutated in over 90% of PV patients;2 however, in spite of its prevalence it is regarded as necessary but not sufficient to cause the disease.5 Yet, systematic mutation analysis of exome coding sequence has to be described. We here analyzed 31 JAK2V617F-positive patients by whole-exome sequencing and single nucleotide polymorphism array and further investigated the mutational evolution using longitudinal samples collected from seven patients (Supplementary Methods).

Whole-exome sequencing targeting ∼43 Mb of coding sequence yielded an average of 125-fold coverage (Supplementary Figure 1), with 95% of targeted bases covered to a depth of × 20 (Supplementary Figure 2). In this study, we use the exomes of T cells as a reference genome and we defined sequence variants present in granulocytes but not in the T cells from the same patient as somatic mutations. DNA copy-number analysis revealed multiple recurrent chromosomal arm-length changes including 9p UPD, trisomy of 9p and 1q, LOH at 18p and single patients with 2p and 9q LOH, trisomy 2q and UPD at 22q. Through serial sampling, we observed a focal hemizygous deletion in PV28 (Supplementary Figure 3) at 9q22.31-32. No known tumor suppressors or oncogenes were found in this region and its functional importance is unclear at this time.

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Acknowledgements

This study was supported by research funding from the National Human Genome Research Institute (NHGRI, grant number: 5U54HG003273) to DW and from the National Institutes of Health (NIH, grant number: NIH-P01CA108671) to JP. We thank Christian Buhay, Donna Morton, Huyen Dinh, Ritika Raj, Lora Lewis, Christie Kovar, Sandra Lee, Michelle Bellair and Zhu Yiming for their excellent technical support.

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  1. J T Prchal: Josef Prchal also represents investigators of MPD-RC (Myeloproliferative Disorders Research Consortium).

Authors and Affiliations

  1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, TX, USA

    L Wang, J Drummond, K Walker, H Doddapaneni, D M Muzny, R A Gibbs & D A Wheeler

  2. Division of Hematology, The University of Utah School of Medicine and VAH, Salt Lake City, 84132, UT, USA

    S I Swierczek, K Hickman, SJ Kim & J T Prchal

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  1. L Wang
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Correspondence to D A Wheeler or J T Prchal.

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Wang, L., Swierczek, S., Drummond, J. et al. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. Leukemia 28, 935–938 (2014). https://doi.org/10.1038/leu.2014.7

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