title: Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome.
abstract: Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome. Some of the genes that are affected by somatic point mutations include ITPR1, ITPR2, DSC1, RIPK2, IL6, and RAG2, with some of them mutated in more than one patient. We observed several somatic copy number variations shared between patients, including deletions and duplications of large segments of chromosome 17. Genes with potential function in the T-cell receptor signaling pathway and tumorigenesis were disrupted in Sézary syndrome patients, for example, CBLB, RASA2, BCL7C, RAMP3, TBRG4, and DAD1. Furthermore, we discovered several fusion events of interest involving RASA2, NFKB2, BCR, FASN, ZEB1, TYK2, and SGMS1. Our work has implications for the development of potential therapeutic approaches for this aggressive disease.
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Aparna
authors.initials: A
authors.lastname: Prasad
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rabionet
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Laboratory of Molecular Cytogenetics, Pathology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Espinet
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Zapata
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Laboratory of Molecular Cytogenetics, Pathology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Puiggros
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Laboratory of Molecular Cytogenetics, Pathology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Melero
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Puig
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Yaris
authors.initials: Y
authors.lastname: Sarria-Trujillo
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ossowski
authors.affiliation: Dermatology Service, Hospital del Sant Pau, Barcelona, Spain.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Garcia-Muret
authors.affiliation: Department of Dermatology, Hospital Clinic, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Estrach
authors.affiliation: Dermatology Service, Hospital de Bellvitge, Barcelona, Spain.
authors.forename: Octavio
authors.initials: O
authors.lastname: Servitje
authors.affiliation: Department of Dermatology, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lopez-Lerma
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Dermatology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gallardo
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Dermatology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Pujol
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Experimental Genetics, Sidra Medical and Research Centre, Doha, Qatar. Electronic address: xavier.estivill@crg.eu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017423:Sequence Analysis, RNA; D012751:Sezary Syndrome / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion