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.

This project was funded by “Retos de la Sociedad 2013: Europa Redes y Gestores” Programme from the Spanish Ministry of Economy and Competitiveness no. SAF2013-49108-R (to XE) and RD12/0036/0044 Red Temática de Investigación Cooperativa en Cancer, Fondo Europeo de Desarrollo Regional (to BE, FG, and RP), the Generalitat de Catalunya AGAUR 2014 SGR-1138 (to XE) and 2014 SGR-585 (to BE, A Puiggros, and FG), the European Commission 7th Framework Program (FP7/2007-2013) under grant agreement 282510 (A BLUEPRINT of haematopoietic Epigenomes to XE) and 262055 (European Sequencing and Genotyping Infrastructure to XE), Instituto de Salud Carlos III FEDER (PT13/0010/0005), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya.” We would also like to thank “Xarxa de Limfomes Cutanis de Catalunaya.” A Prasad is a Marie Curie Postdoctoral fellow supported by the European Commission 7th framework program (FP7/2007-2013) under grant agreement no. 625356. We acknowledge the support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017, SEV-2012-0208.