Genetic rearrangements result in altered gene expression and novel fusion transcripts in Sézary syndrome

// Katarzyna Izykowska 1 , Grzegorz K. Przybylski 1 , Claudia Gand 2 , Floriane C. Braun 2 , Piotr Grabarczyk 2 , Andreas W. Kuss 3 , Karolina Olek-Hrab 4 , Armando N. Bastidas Torres 5 , Maarten H. Vermeer 5 , Willem H. Zoutman 5 , Cornelis P. Tensen 5 , Christian A. Schmidt 2 1 Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland 2 Clinic for Internal Medicine C, University Medicine Greifswald, Greifswald, Germany 3 Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany 4 Department of Dermatology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland 5 Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands Correspondence to: Grzegorz K. Przybylski, email: grzegorz.przybylski@igcz.poznan.pl Keywords: Sezary syndrome, NGS, whole genome, RNASeq, rearrangement Received: July 26, 2016      Accepted: March 27, 2017      Published: April 24, 2017 ABSTRACT Sezary syndrome (SS) is an aggressive, leukemic cutaneous T-cell lymphoma variant. Molecular pathogenesis of SS is still unclear despite many studies on genetic alterations, gene expression and epigenetic regulations. Through whole genome and transcriptome next generation sequencing nine Sezary syndrome patients were analyzed in terms of copy number variations and rearrangements affecting gene expression. Recurrent copy number variations were detected within 8q ( MYC, TOX ), 17p ( TP53, NCOR1 ), 10q ( PTEN, FAS ), 2p ( DNMT3A ), 11q ( USP28 ), 9p ( CAAP1 ), but no recurrent rearrangements were identified. However, expression of five genes involved in rearrangements ( TMEM244, EHD1, MTMR2, RNF123 and TOX) was altered in all patients. Fifteen rearrangements detected in Sezary syndrome patients and SeAx resulted in an expression of new fusion transcripts, nine of them were in frame ( EHD1-CAPN12, TMEM66-BAIAP2, MBD4-PTPRC, PTPRC-CPN2, MYB-MBNL1, TFG-GPR128, MAP4K3-FIGLA, DCP1A-CCL27, MBNL1-KIAA2018 ) and five resulted in ectopic expression of fragments of genes not expressed in normal T-cells ( BAIAP2, CPN2, GPR128, CAPN12, FIGLA). Our results not only underscored the genomic complexity of the Sezary cancer cell genome but also showed an unpreceded large variety of novel gene rearrangements resulting in fusions transcripts and ectopically expressed genes.