Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

• Published in: Nature genetics Vol. 47; no. 12; pp. 1426 - 1434
• Main Authors: Wang, Linghua, Ni, Xiao, Covington, Kyle R, Yang, Betty Y, Shiu, Jessica, Zhang, Xiang, Xi, Liu, Meng, Qingchang, Langridge, Timothy, Drummond, Jennifer, Donehower, Lawrence A, Doddapaneni, Harshavardhan, Muzny, Donna M, Gibbs, Richard A, Wheeler, David A, Duvic, Madeleine
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2015; Nature Publishing Group
• Subjects: 13/31; 38/39; 38/91; 49/22; 49/23; 49/61; 49/90; 631/208/514/1948; 631/208/514/1949; 692/308/2056; 692/699/67; 692/699/67/1857; 82/80; 96/106; 96/21; Agriculture; Animal Genetics and Genomics; Biomedicine; Cancer; Cancer Research; Case-Control Studies; Cell differentiation; Cell Differentiation - genetics; Cellular signal transduction; Charitable foundations; Cytokines; Deoxyribonucleic acid; Development and progression; DNA; Exome - genetics; Fungal infections; Gene expression; Gene Expression Regulation, Neoplastic; Gene Function; Gene mutations; Gene Regulatory Networks; Genetic aspects; Genetic Drift; Genomes; Genomics; Genomics - methods; Health aspects; High-Throughput Nucleotide Sequencing - methods; Human Genetics; Humans; Identification and classification; Innovations; Lymphocyte Activation; Lymphocytes; Lymphoma; Medical research; Molecular targeted therapy; Mutation; Mutation - genetics; Patients; Prognosis; Sezary syndrome; Sezary Syndrome - genetics; Sezary Syndrome - mortality; Sezary Syndrome - pathology; Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Studies; Survival Rate; T-Lymphocytes - cytology; T-Lymphocytes - metabolism
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3444

Madeleine Duvic, David Wheeler and colleagues present an integrated genomic analysis of Sézary syndrome. They identify recurrent alterations in key T cell signaling and differentiation genes and observe overexpression of IL32 and IL2RG in nearly all cases. Sézary syndrome is a rare leukemic form of cutaneous T cell lymphoma characterized by generalized redness, scaling, itching and increased numbers of circulating atypical T lymphocytes. It is rarely curable, with poor prognosis. Here we present a multiplatform genomic analysis of 37 patients with Sézary syndrome that implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent somatic alterations were identified in TP53 , CARD11 , CCR4 , PLCG1 , CDKN2A , ARID1A , RPS6KA1 and ZEB1 . Activating CCR4 and CARD11 mutations were detected in nearly one-third of patients. ZEB1 , encoding a transcription repressor essential for T cell differentiation, was deleted in over one-half of patients. IL32 and IL2RG were overexpressed in nearly all cases. Our results demonstrate profound disruption of key signaling pathways in Sézary syndrome and suggest potential targets for new therapies.