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

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

Author information

1
Program in Epithelial Biology, Stanford University, Stanford, California, USA.
2
Division of Hematology, Stanford University, Stanford, California, USA.
3
Department of Genetics, Stanford University, Stanford, California, USA.
4
Department of Pathology, Stanford University, Stanford, California, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
6
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
7
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
8
Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA.
9
Multidisciplinary Cutaneous Lymphoma Program, Stanford University, Stanford, California, USA.
10
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
11
Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.

Abstract

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.

PMID:
26258847
PMCID:
PMC6091217
DOI:
10.1038/ng.3370
[Indexed for MEDLINE]
Free PMC Article

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