Abstract

Sézary syndrome is a rare leukemic form of cutaneous T cell lymphoma characterized by generalized redness, scaling, itching and increased numbers of circulating atypical T lymphocytes. It is rarely curable, with poor prognosis. Here we present a multiplatform genomic analysis of 37 patients with Sézary syndrome that implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1 and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly one-third of patients. ZEB1, encoding a transcription repressor essential for T cell differentiation, was deleted in over one-half of patients. IL32 and IL2RG were overexpressed in nearly all cases. Our results demonstrate profound disruption of key signaling pathways in Sézary syndrome and suggest potential targets for new therapies.

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Acknowledgements

We thank J. Hu, M. Wang, Y. Han, H. Chao and M.G. Evans for their excellent technical support. We thank L. Sandra for help with sample intake and J. Jayaseelan for project management. We thank W. Hale, D. Kalra, S. Dugan-Perez and J. Watt for their kind help with data submission. Special thanks is given to D. Burgess and M. Chase from Roche NimbleGen for their great help with the design and fast delivery of the custom capture array. This work was supported by research funding from the National Human Genome Research Institute (NHGRI; grant 5U54HG003273) and the Cancer Prevention Research Institute of Texas (CPRIT; grant RP121018) to D.A.W., the Drs. Martin and Dorothy Spatz Charitable Foundation (grant 00005840), the Blanche Bender Professorship in Cancer Research and the MD Anderson Cancer Center Core Grant (grant CA16672) to M.D.

Author information

Affiliations

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

    • Linghua Wang
    • , Kyle R Covington
    • , Liu Xi
    • , Qingchang Meng
    • , Jennifer Drummond
    • , Harshavardhan Doddapaneni
    • , Donna M Muzny
    • , Richard A Gibbs
    •  & David A Wheeler
  2. Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Xiao Ni
    • , Betty Y Yang
    • , Jessica Shiu
    • , Xiang Zhang
    • , Timothy Langridge
    •  & Madeleine Duvic
  3. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.

    • Lawrence A Donehower

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Contributions

L.W. conducted the major bioinformatics analyses of the multiplatform data, and wrote and revised the manuscript. X.N. contributed to performing the research, data interpretation and manuscript preparation. K.R.C. contributed to mutation signature analysis. B.Y.Y. and J.S. contributed to performing the research. X.Z. collected tumor specimens and performed DNA and RNA extraction, and immunoblot assays. L.X. and J.D. contributed to the RNA-seq and whole-exome sequencing pipeline. Q.M. contributed to the fusion gene validation experiments. T.L. helped with the serum and ELISA assays. D.M.M. and H.D. managed the production pipeline of exome, RNA-seq and SNP array analysis. L.A.D. contributed the somatic mutation significance analysis. R.A.G. contributed to revision of the manuscript. D.A.W., M.D. and L.W. conceived the study and supervised the research. D.A.W. and M.D. also contributed to the writing and revision of the manuscript. M.D. recruited, consented, staged, characterized and cared for the patients and supervised the skin biopsies.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David A Wheeler or Madeleine Duvic.

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https://doi.org/10.1038/ng.3444

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