title: Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides.
abstract: The pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin. Targeted ultra-deep sequencing of MF samples and exome sequencing of CTCL cell lines were also performed. Multiple mutations were identified that affected the same pathways, including epigenetic, cell-fate regulation, and cytokine signaling, in MF tumors and CTCL cell lines. Specifically, interleukin-2 signaling pathway mutations, including activating Janus kinase 3 (JAK3) mutations, were detected. Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival. Additionally, the mutation data identified 2 other potential contributing factors to MF, ultraviolet light, and a polymorphism in the tumor suppressor p53 (TP53). Therefore, genetic alterations in specific pathways in MF were identified that may be viable, effective new targets for treatment.
authors.affiliation: Department of Hematology/Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC; and Department of Medicine/Division of Dermatology.
authors.forename: Laura Y
authors.initials: LY
authors.lastname: McGirt
authors.affiliation: Department of Biomedical Informatics, Center for Quantitative Sciences.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Medicine/Division of Dermatology.
authors.forename: Devin A
authors.initials: DA
authors.lastname: Baerenwald
authors.affiliation: Department of Pathology, Microbiology and Immunology.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Duszynski
authors.affiliation: Vanderbilt-Ingram Cancer Center, Department of Cancer Biology.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Dahlman
authors.affiliation: Department of Medicine/Division of Dermatology.
authors.forename: John A
authors.initials: JA
authors.lastname: Zic
authors.affiliation: Department of Medicine/Division of Dermatology.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Zwerner
authors.affiliation: Vanderbilt-Ingram Cancer Center.
authors.forename: Donald
authors.initials: D
authors.lastname: Hucks
authors.affiliation: Department of Medicine/Division of Hematology-Oncology, Tennessee Valley Healthcare System, and.
authors.forename: Utpal
authors.initials: U
authors.lastname: Dave
authors.affiliation: Department of Biomedical Informatics, Center for Quantitative Sciences, Department of Cancer Biology, Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Microbiology and Immunology.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
mesh_terms: D000328:Adult; D000368:Aged; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009182:Mycosis Fungoides / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009857:Oncogenes / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014466:Ultraviolet Rays