ABSTRACT: To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we performed RNA-sequencing of 15 cases. We describe a recurrent FYN-TRAF3IP2 fusion transcript in PTCL-NOS and PTCL-TFH and a KHDRBS1-LCK fusion transcript in PTCL-NOS.
Project description:DNA extracted from frozen tissue of 47 peripheral T-cell lymphomasânot otherwise specified [PTCL-NOS] was hybridized to 250k StyI SNP arrays 47 PTCL NOS compared to healthy reference DNA. DNA of PTCL NOS was extracted from frozen tissue blocks, DNA of healthy individual was extracted from peripheral blood mononuclear cells. Array hybridization was performed according to manufacturer´s protocol.
Project description:<p>Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non Hodgkin lymphomas. We aim to identify new genetic alterations in PTCL transformation by using a combination of whole exome sequencing of tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing of candidate genes. Our data identified highly recurrent mutations in epigenetic factors such as TET2, DNMT3A and IDH2 as well as a new highly prevalent mutation in RHOA, the G17V allele that is present in almost 70% of angioimmunoblastic T-cell lymphomas (AITL) and almost 20% of not otherwise specified PTCL (PTCL NOS) samples. In addition, we describe new and recurrent genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance processes as key players in the pathogenesis of PTCL.</p>
Project description:Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here we have identified a subgroup of SMARCB1 deficient PTCL-NOS, which is characterized by the lack of the SMARCB1 protein and is more common in young patients. Human and murine Smarcb1-negative PTCL-NOS from a corresponding mouse model show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development.
Project description:Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here we identified a subgroup, PTCL-NOS SMARCB1-, which is characterized by the lack of SMARCB1 protein expression and is more common in young patients under 25 years of age. To investigate the cellular heterogeneity of PTCL-NOS SMARCB1- and the role of its tumor microenvironment, we performed single-nuclei RNA sequencing (snRNA-seq) of five patient samples.
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net) | Affymetrix HG-U133 Plus 2.0 : 7 NKTCL biopsies, 2 NKTCL cell lines (SNK6, SNT8), 16 PTCL NOS biopsies, 2 NK cells samples | Biopsies and cell lines of NK/T-cell lymphoma, nasal-type (NKTCL) were subject to combined gene expression profiling and array-based comparative genomic hybridization analyses. Compared to PTCL, NOS, NKTCL had higher transcript levels for NK-cell markers and cytotoxic molecules, especially granzyme H, a novel sensitive biomarker of NKTCL. Compared to normal NK cells, tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, EBV-induced genes and PDGFRA. Notably, PDGFR? and its phosphorylated form were confirmed at the protein level, and in vitro the MEC04 NKTCL-cell line was sensitive to imatinib. Deregulation of the AKT, JAKSTAT and NF-?B pathways suggested by bioinformatical analysis, was corroborated by nuclear expression of phosphorylated AKT, STAT3 and RelA in NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 (1q44), IL6R (1q21.3), CCL2 (17q12), TNFRSF21 (6p12.3)). Several features of NKTCL uncovered by this analysis (overexpression of VEGFA and its receptor KDR by the tumor cells, overexpression of MET-HGF) suggest deregulation of angiogenic pathways. Integrative analysis also identified a novel putative tumor suppressor HACE1 in the frequently deleted 6q21 region. This study highlights emerging oncogenic pathways in NKTCL and identifies novel diagnostic and therapeutic targets. | Submitter : Aurelien de Reynies <reyniesa@ligue-cancer.fr> | Project leader : Philippe Gaulard <philippe.gaulard@hmn.aphp.fr>
Project description:The molecular biology of the primary nodal EBV-positive variant of PTCL (PTCL-EBV) and its relationship with extranodal NK/T-cell lymphoma (ENKTL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) remains poorly understood. In this study, we assessed the relationship between the three diseases using gene and EBV miRNA expression profiling, and copy number aberration (CNA) analyses and attempted to characterize the degree of genomic instability (GI). This series is the oncoscan CNA data of 77 NKTL samples.
Project description:Genome-wide analysis of nodal peripheral T-cell lymphomas (PTCL/NOS, AITL and ALCL) was used to identify molecular signatures corresponding to different subgroups. We also aimed to define the counterparts of PTCLs/NOS based on their global gene expression profiles. We developed a new molecular classifier able to distinct PTCL/NOS heterogeneity due to the correspondence to different counterparts.
Project description:The molecular biology of the primary nodal EBV-positive variant of PTCL (PTCL-EBV) and its relationship with extranodal NK/T-cell lymphoma (ENKTL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) remains poorly understood. In this study, we assessed the relationship between the three diseases using gene and EBV miRNA expression profiling, and copy number aberration (CNA) analyses and attempted to characterize the degree of genomic instability (GI). This series is the GEP data of 84 cases of FFPE NKTL samples and 4 cases of Lymph node controls.
Project description:Identification of the determinants of PDGFRA activity in PTCL/NOS (Peripheral T-cell lymphoma/not otherwise specified) and to elucidate the biological consequences of its activation. We generated GEP from samples of primary PTCL/NOS cells treated or not with imatinib mesylate (see below) as well as from EOL1 cells (3 samples each)
Project description:Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are aggressive and heterogeneous tumors with poor outcome and scarce genetic characterization. We analyzed by immunohistochemistry tumor tissue of adult and pediatric PTCL-NOS patients and discovered frequent loss of SMARCB1 positivity, mostly associated with pediatric cases (45%). Using a genetically engineered mouse model (PTCL-NOSSmarcb1-) and single-cell RNA sequencing, we investigated the transcriptional landscape of this Smarcb1-negative PTCL-NOS tumor and the functional interactions between tumor and tumor microenvironment (TME). We unrevealed an immunosuppressive, exhausted and proinflammatory TME, characterized by high myeloid cell infiltration (predominantly myeloid derived suppressor cells, MDSC) and reduced lymphoid infiltration. In addition, using a multidrug epigenetic screen in vitro, we identified histone deacetylase inhibitors (HDACi) as promising agents against PTCL-NOSSmarcb1-. Treatment of PTCL-NOSSmarcb1- mice with SAHA, a pan-HDACi, triggered TME remodelling, promoting the replenishment of T- and B-cell compartments and the limitation/reversion of the exhaustion phenotype. In conclusion, we have identified a novel PTCL-NOS subtype characterized by the loss of SMARCB1 at pediatric ages, presenting an exhausted and immunosuppressive TME. Administration of SAHA reshaped the TME increasing lymphoid cells recruitment into the tumor bed, turning the tumor from cold to hot. These results provide the rationale for further investigations based on combination therapies.
