5032 results for "*oma"

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• The_Transcriptome_of_PLX4032_resistance

  We have collected material from a patient who had BrafV600E mutant melanoma that wastreated with PLX4032. We have germline DNA from the patient and DNA and RNA fromdistinct lesions before and after treatment with PLX4032. We have transcriptome sequenced these samples to obtain a snap shot of the mechanisms of resistance that are operative.

  Study EGAS00001000413

• The exomic landscape of t(14,18) negative diffuse follicular lymphoma with 1p36 deletion

  t(14,18) negative diffuse follicular lymphoma with 1p36 deletion is a well characterized variant of follicular lymphoma with typical clinical, morphological, immunophenotypical and genetic features. The genetic landscape of this variant is however largely unknown. We performed exome sequencing of six well characterised cases and detected 1642 single nucleotide variations and 641 insertions-deletions not reported in common databases (dbSNP and 1000G). We report several recurrent mutations, among which CREBBP, STAT6, KMT2D, HEATR6, LAMA5 and VPS13B are the most prevalent. Pathway annotation using GSEA showed an enrichment in mutated genes belonging to the MAPK pathway.

  Study EGAS00001002594

• Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

  Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

  Study EGAS00001002606

• The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma

  Patients with metastatic uveal melanoma (UM) have an abysmal prognosis. Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. Here we test if epigenetic therapy would enhance PD-1 immunotherapy in patients with metastatic UM. We report the results of the PEMDAC phase 2 clinical trial (n=29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic UM. The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Extensive genomics studies were performed using DNA/RNA and single cell sequencing and flow cytometry. Objective responses and prolonged survival were seen in three patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM. Further exploration of combined immunotherapy and epigenetic therapy in metastatic UM is warranted.

  Study EGAS00001005478

• RNA-sequencing of six Pilocytic astrocytoma tumors

  Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aim of this study was to characterize the genetic alterations underlying the development of PA tumor in six cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5’ gene fusion partner GTF2I (7q11.23), not previously described in PA. The novel GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene. Comparing fusion detection methods, Fluorescence in situ hybridization with BRAF break apart probe was the most sensitive method for detection of the two different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a novel BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Also, the growing list of BRAF/RAF gene fusions suggests these to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.

  Study EGAS00001002149

• Detection of clinically relevant genetic and transcriptomic landscape in DLBCL uniformly treated by R-CHOP

  Recent studies using next-generation sequencing strategies have described the landscape of genetic alterations in diffuse large B-cell lymphoma (DLBCL). However, little is known about the clinical relevance of recurrent mutations and copy number alterations and their transcriptional footprints. This study examines the frequency, interaction and clinical impact of recurrent genetic aberrations in DLBCL using high-resolution technologies in a large population-based cohort.

  Study EGAS00001002657

• Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000812

• Sex-biased patterns shaped the genetic history of Roma

  Whole mtDNA sequences and Y chromosomes from Roma and Non-Roma European samples.

  Study EGAS00001004207

• WGS of 32 paired SRCC samples

  Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however with no systematical investigation for prognostic genomic features. We systematically investigated the clinical characteristics of 1,868 Chinese gastric cancer patients, and found that signet-ring cell content was significantly related to multiple clinical characteristics and treatment outcomes. Next, we performed whole genome sequencing for 32 SRCC patients with > 80% signet-ring cells in tumor, and identified frequent5 CLDN18-ARHGAP26/6 fusion (25%). With additional 797 patients for validation, we notice that prevalence of CLDN18-ARHGAP26/6 fusion is positively associated with signet-ring cell content (P = 4.1 x 10 -9 ), younger age at diagnosis (P = 4.2 x 10 -10 ), female/male ratio (P = 1.7 x 10 -9 ), and advanced TNM stage (P = 1.7 x 10 -5 ). Importantly, patients with CLDN18-ARHGAP26/6 fusion had a worse survival outcomes (P = 0.03), and got no benefit0 from platinum/fluoropyrimidines based chemotherapy (P = 0.92) compared to fusion-free patients (P = 0.001), which is consistent with the fact of oxaliplatin/fluoropyrimidine resistance acquired in CLDN18-ARHGAP26 introduced gastric cancer cell lines. Overall, this study provides new insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

  Study EGAS00001002668

• Gene fusion and transcriptomic landscapes of sarcomas

  Sarcoma represents a highly heterogeneous group of tumors. We report here the first unbiased and systematic search for gene fusions and analysis of transcriptomic profiles in 100 monomorphic sarcomas cases using RNA-sequencing profiling. Fusion genes were detected in two thirds of samples. Similarly to fusion genes such as PAX3/7-FOXO1, EWSR1/FUS-ETS, SS18-SSX, BRD3/4-NUTM1 or EWSR1/FUS/TAF15-NR4A3 characterizing well-defined entities, we show that all sarcomas displaying CIC fusions- whatever their fusion partner (being DUX4, NUTM1 or FOXO4) - form a transcriptionally homogeneous group of tumors. Likewise, tumors with either a BCOR fusion (with CCNB3, MAML3 or ZC3H7B partners) or with a BCOR internal duplication form a single biological entity. We also found that EML4-ALK fusions also characterize a homogeneous infantile fibrosarcoma subgroup. In contrast, fusions like VGLL2-NCOA2/CITED2, TMP3/TRP-NTRK1 or ETV6-NTRK3 are observed in more heterogeneous tumors. Finally, we also describe a new group of bone sarcomas characterized by EWSR1- or FUS-TFCP2 fusions.

  Study EGAS00001002189