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

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.

An Update on Molecular Biology of Cutaneous T Cell Lymphoma

“…All these studies confer that there is a wide variety of genomic alterations in MF/SS and the genetic signature of tumors can differ between patients. Hence, choosing personalized therapy for each patient is worthwhile according to the individual tumor's molecular pattern (70).…”

Cutaneous T-cell Lymphoma

“…Patients are typically 55–60 years old and present with erythroderma (>80% BSA), itching, and lymph node enlargement. Median overall survival is 63 months, and 5 year survival may be as low as 28%[22]. …”

“…Copy number variations are typically numerous, and may be recurrent. [22] Microsatellite instability has been reported to be increased in stage IIB MF and in large cell transformation, and has been reported in 24% of CTCL overall. Mutational data continues to be gathered and analyzed on this diverse group of disease showing alterations in multiple pathways including TCR signaling and chromatin modification (e.g.…”

Genome-Wide Analysis of Interchromosomal Interaction Probabilities Reveals Chained Translocations and Overrepresentation of Translocation Breakpoints in Genes in a Cutaneous T-Cell Lymphoma Cell Line

“…Data on DNA copy number alterations in Se-Ax that have been generated by means of arrayCGH in a previous study ( 30 ) were visualized for each translocation within a 2 Mb interval surrounding the breakpoint by means of R and the R packages reshape2 ( 31 ) and ggplot2 ( 32 ). The expression of fusion genes was tested using previously published RNA-Seq data ( 33 , 34 ). Translocation breakpoints were verified by screening paired-end sequencing data for Se-Ax ( 33 , 34 ) and the analysis of these data by Breakdancer ( 35 ).…”