Abstract

Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin-homing T lymphocytes. We performed exome and whole-genome DNA sequencing and RNA sequencing on purified CTCL and matched normal cells. The results implicate mutations in 17 genes in CTCL pathogenesis, including genes involved in T cell activation and apoptosis, NF-κB signaling, chromatin remodeling and DNA damage response. CTCL is distinctive in that somatic copy number variants (SCNVs) comprise 92% of all driver mutations (mean of 11.8 pathogenic SCNVs versus 1.0 somatic single-nucleotide variant per CTCL). These findings have implications for new therapeutics.

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Acknowledgements

We gratefully acknowledge the participation of the patients who made this research possible. We are grateful to I. Tikhonova and the staff of the Yale Center for Genome Analysis for their expert production of DNA and RNA sequence. Work was supported by the Dermatology Foundation and the Yale Specialized Program of Research Excellence (SPORE) in Skin Cancer Career Development Award (J.C.);. the Yale SPORE in Skin Cancer, P50 CA121974 (T.J.B.); the Agency for Science, Technology and Research, Singapore (G.G.); and US National Institutes of Health (NIH) grant RO1 CA102703 (M.G.). D.G.S. and R.P.L. are investigators of the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.

    • Jaehyuk Choi
    • , Trent Walradt
    • , Bok S Hong
    • , Christopher G Bunick
    • , Kan Chen
    • , Tiffany Wang
    • , Jesse Tordoff
    • , Kacie Carlson
    • , Kristina J Liu
    • , Julia M Lewis
    • , Francine M Foss
    • , Antonio Subtil
    • , Richard L Edelson
    •  & Michael Girardi
  2. Department of Dermatology, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut, USA.

    • Jaehyuk Choi
  3. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.

    • Gerald Goh
    • , Yaakov Maman
    • , David G Schatz
    •  & Richard P Lifton
  4. Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.

    • Gerald Goh
    •  & Richard P Lifton
  5. Department of Computer Science, Yale University, New Haven, Connecticut, USA.

    • Robert D Bjornson
  6. Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.

    • Yaakov Maman
    •  & David G Schatz
  7. Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA.

    • John D Overton
  8. Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

    • Lesley Devine
  9. Department of Medicine (Hematology), Yale School of Medicine, New Haven, Connecticut, USA.

    • Lisa Barbarotta
    •  & Francine M Foss
  10. Department of Oncology, Sydney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Eric C Vonderheid
  11. Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.

    • Titus J Boggon
  12. Yale Center for Mendelian Genomics, Yale School of Medicine, New Haven, Connecticut, USA.

    • Richard P Lifton

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Contributions

J.C., M.G. and R.P.L. designed the experiments, analyzed data and wrote the manuscript. J.D.O. and R.D.B. directed nucleic acid sequencing and data management. J.C., G.G. and R.P.L. analyzed sequencing results. J.C., T. Walradt, B.S.H., T. Wang, K. Chen, K.J.L., J.M.L., L.B., K. Carlson, F.M.F., A.S., E.C.V., R.L.E. and M.G. collected and annotated clinical samples. C.G.B. and T.J.B. performed structural modeling. J.C., B.S.H., K. Chen and T. Walradt performed functional experiments. J.C., J.T. and T. Walradt assessed TCGA data. J.C. and L.D. performed flow cytometry. J.C., Y.M. and D.G.S. performed analysis of RAG sequences at deletion breakpoints.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Richard P Lifton.

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https://doi.org/10.1038/ng.3356

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