Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Nat Genet. 2015 Sep;47(9):1056-60. doi: 10.1038/ng.3370. Epub 2015 Aug 10.


Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Bortezomib / pharmacology
  • CD28 Antigens / genetics
  • CTLA-4 Antigen / genetics
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genomics
  • Humans
  • Mycosis Fungoides / genetics*
  • Oncogene Proteins, Fusion / genetics
  • Point Mutation
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Sezary Syndrome / genetics*
  • Signal Transduction
  • Skin Neoplasms / genetics*


  • Antineoplastic Agents
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Oncogene Proteins, Fusion
  • Receptors, Tumor Necrosis Factor, Type II
  • Bortezomib