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

Katarzyna Iżykowska,Cornelis P Tensen,Maarten H Vermeer,Karolina Olek-Hrab,Floriane C Braun,Willem H Zoutman,Christian A Schmidt,Piotr Grabarczyk,Armando N Bastidas Torres,Claudia Gand,Grzegorz K Przybylski,Andreas W Kuss

doi:10.18632/oncotarget.17383

Abstract

Sézary 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 Sézary 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 Sézary 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 Sézary cancer cell genome but also showed an unpreceded large variety of novel gene rearrangements resulting in fusions transcripts and ectopically expressed genes.

Highlights

Sézary syndrome (SS) is an aggressive, leukemic cutaneous T-cell lymphoma variant [1]
Molecular pathogenesis of SS is still unclear despite many studies on genetic alterations, gene expression and epigenetic regulations
Fifteen rearrangements detected in Sézary 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, TFGGPR128, 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)

Summary

Introduction

Sézary syndrome (SS) is an aggressive, leukemic cutaneous T-cell lymphoma variant [1]. Molecular pathogenesis of SS is still unclear despite many studies on genetic alterations, gene expression and epigenetic regulations. Both cytogenetic and molecular studies revealed chromosomal instability with recurrent www.impactjournals.com/oncotarget “hotspots” of chromosomal abnormalities like 17p (loss of TP53) [7], 10q (loss of PTEN and FAS) [8, 9], 8q (gain of MYC) [10, 11], 9p (loss of CDKN2A-CDKN2B) [12], 19p (loss of E2A) [11] and 6q (loss of A20) [13]. Analysis on whole genomes of CTCL patients [18,19,20,21] identified mutations affecting genes involved in important signaling pathways (JAK-STAT, T-cell receptor (TCR) signaling), cell cycle control and epigenetic regulation (chromatin modifying genes, histone and DNA methyltranferases)

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