title: The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.
abstract: Sézary syndrome is a leukemic and aggressive form of cutaneous T cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4(+) T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 patients with Sézary syndrome and 17 patients with other CTCLs. These analyses identified a distinctive pattern of somatic copy number alterations in Sézary syndrome, including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors. Mutation analysis identified a broad spectrum of somatic mutations in key genes involved in epigenetic regulation (TET2, CREBBP, KMT2D (MLL2), KMT2C (MLL3), BRD9, SMARCA4 and CHD3) and signaling, including MAPK1, BRAF, CARD11 and PRKG1 mutations driving increased MAPK, NF-κB and NFAT activity upon T cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sézary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: da Silva Almeida
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, New York, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, New York, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Department of Dermatopathology, Northwestern Medical Faculty Foundation, Chicago, Illinois, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Martinez-Escala
authors.affiliation: Department of Dermatopathology, Northwestern Medical Faculty Foundation, Chicago, Illinois, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Guitart
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Tensen
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Vermeer
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, New York, USA.|Department of Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.|Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
mesh_terms: D016022:Case-Control Studies; D002872:Chromosome Deletion; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D059472:Exome / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D012307:Risk Factors; D012751:Sezary Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D005819:Genetic Markers