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Identification of gene mutations and fusion genes in patients with SÃ©zary Syndrome

ABSTRACT: Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course. The goal of our study is to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sezary cels, fourteen of them fulfilling the diagnostic criteria of SS. Peripheral blood samples were collected for each patient and CD4+ T-lymphocytes and Granulocytes were isolated. DNA and RNA was extracted for matched normal and tumor materials. Whole exome sequencing was performed on matched normal and tumor tissues of 12 patients and RNA sequencing was performed on 10 patients. For 7 of these patients, we have both exome as well as RNA sequencing data. In this study, we present a complex genomic landscape of Sezary syndrome with several point mutations, copy number variations and fusion events which could contribute to the pathogenesis of SS.

PROVIDER: EGAS00001001706 | EGA |

REPOSITORIES: EGA

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Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome.

Prasad Aparna A Rabionet Raquel R Espinet Blanca B Zapata Luis L Puiggros Anna A Melero Carme C Puig Anna A Sarria-Trujillo Yaris Y Ossowski Stephan S Garcia-Muret Maria P MP Estrach Teresa T Servitje Octavio O Lopez-Lerma Ingrid I Gallardo Fernando F Pujol Ramon M RM Estivill Xavier X

The Journal of investigative dermatology 20160330 7

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. ...[more]

PMID: 27039262

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Project description:This study used tumour and paired normal samples from 28 Sézary Syndrome (SS) patients to define recurrent regions of chromosomal aberrations. Our data identified recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71 and 68% of cases respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in more than 30% of tumours: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. In the Sézary Syndrome cases analysed, we could find several small and few large Uniparental Disomies involving interstitial or telomeric regions of LOH occurring mainly for chromosome 10 and to a lesser extent for chromosome 9 and 17. In the attempt to correlate Copy Number data and clinical parameters we find a relationship between complex pattern of chromosomal aberrations, involving at least three recurrent Copy Number alterations, and shorter survival. Integrating mapping and transcriptional data we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer related genes such as members of the NF-kB pathway (BAG4, BTRC, NKIRAS2, PSMD3, TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times we identify several common candidates that might exert critical roles in Sézary Syndrome, like BUB3 and PIP5K1B. Experiment Overall Design: Affymetrix SNP arrays were performed, according to the manufacturer's directions, on DNA extracted from cryopreserved lymphomonocytes purified by Ficoll density gradient centrifugation and positive selection using anti-human CD3-conjugated dynabeads (tumour samples) and from granulocytes (normal matched cells) obtained by collecting the upper phase overlying the Ficoll density gradient sediment. Copy number and LOH analyses of Affymetrix 10K SNP arrays were performed for 28 tumour samples and 28 matched normal samples used as references.

Project description:Primary Sjögren’s syndrome (SS or autoimmune epithelitis) is a relatively common autoimmune disorder that is primarily characterized by chronic lymphoepithelial inflammatory reactions in the exocrine glands, mainly the salivary and lachrymal glands. It may extend from disease confined to the exocrine glands (organ-specific exocrinopathy) to various extraglandular manifestations (systemic disease) and the development of B-cell lymphoma. Several studies from our laboratory had provided evidence for the strong implication of ductal salivary gland epithelial cells (SGEC) in the pathogenesis of Sjögren’s syndrome (SS), including the development of salivary gland infiltrating lesions and of adverse systemic clinical complications, such as the development of B-cell lymphoma. In fact, the comparative assessment of non-neoplastic SGEC lines derived from SS patients and disease controls had indicated that the ductal epithelia of SS patients manifest an “intrinsically activated” status that is associated with distinct aberrant phenotypic and functional features encountered in “inflamed” cells. Herein, using microarray analysis, we sought to comparatively analyze the constitutive gene expression in long-term cultured non-neoplastic SGEC lines derived from non-SS sicca control individuals and from SS patients. The study aimed to reveal the genes that are differentially expressed between SGEC lines derived from SS patients and controls, as well as between SGEC lines derived from SS patients with moderate lymphocytic infiltrations (focus score<2; SS-Group-1) and SS patients with severe lymphocytic infiltrations (focus score ≥2; SS-Group-2). The transcriptome profiling analysis presented herein lends further support to the intrinsic activation status of patients’ ductal epithelia and its association with distinct proinflammatory and metabolism-related gene signatures, which occur primarily among patients with heavy tissue infiltrates and high risk for lymphoma development.

Dataset Information

Identification of gene mutations and fusion genes in patients with SÃ©zary Syndrome

Publications

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome.

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