title: Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.
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.
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.|Division of Hematology, Stanford University, Stanford, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ungewickell
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Bhaduri
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.
authors.forename: Eon
authors.initials: E
authors.lastname: Rios
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Reuter
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Mah
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Zehnder
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ohgami
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Shashikant
authors.identifier: http://orcid.org/0000-0002-9349-0787
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Armstrong
authors.affiliation: Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA.
authors.forename: Wen-Kai
authors.initials: WK
authors.lastname: Weng
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Dita
authors.initials: D
authors.lastname: Gratzinger
authors.affiliation: Multidisciplinary Cutaneous Lymphoma Program, Stanford University, Stanford, California, USA.
authors.forename: Mahkam
authors.identifier: http://orcid.org/0000-0002-3543-7259
authors.initials: M
authors.lastname: Tavallaee
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Rook
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Multidisciplinary Cutaneous Lymphoma Program, Stanford University, Stanford, California, USA.
authors.forename: Youn
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Program in Epithelial Biology, Stanford University, Stanford, California, USA.|Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D000069286:Bortezomib / Q000494:pharmacology; D018106:CD28 Antigens / Q000235:genetics; D060908:CTLA-4 Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D009182:Mycosis Fungoides / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017354:Point Mutation; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000378:metabolism; D012751:Sezary Syndrome / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015514:Oncogene Proteins, Fusion; D047889:Receptors, Tumor Necrosis Factor, Type II; D000069286:Bortezomib