3735 results for "*oma"

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• Multiomic profiling of early-passage melanoma cell lines.

  This study utilises multiomic profiling of early-passage melanoma cell lines to explore the interactions between distinct modalities of molecular regulation influencing melanoma cellular phenotype.

  Study EGAS00001004536

• Clinical relevance of somatic copy-number alterations in plasma circulating tumor DNA from advanced EGFR-mutated NSCLC patients treated with osimertinib

  Background: Somatic copy-number alterations (SCNAs) are associated with drug resistance in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). The purpose of our study was to assess the clinical relevance and development of genome-wide SCNAs in plasma circulating tumor DNA (ctDNA) under osimertinib therapy.Methods: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR.Results: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 39 (25.6%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 86%, p=0.02) and was an independent predictor for shorter progression-free survival (adjusted HR 3.26, 95% CI 1.37-7.75, p=0.008) and overall survival (adjusted HR 2.41, 95% CI 1.09-5.34, p=0.03).Conclusions: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach allows comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.

  Study EGAS00001004539

• Super enhancers define regulatory subtypes and cell identity in neuroblastoma

  Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.

  Study EGAS00001004551

• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas1. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients2. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

  Study EGAS00001004544

• A Multifactorial Tumor and Immune Cell Profile Determines Response to Immune Checkpoint blockade in Melanoma

  The complex crosstalk between tumor and immune cells during immune checkpoint blockade mandates the development of integrated models that interpret the anti-tumor immune response and predict clinical outcome. We have integrated genome-wide sequence and structural alterations with pre and on-therapy transcriptomic and T cell repertoire features for a cohort of 64 immunotherapy-naïve melanomas treated with anti-PD1 monotherapy or combined anti-PD1 and anti-CTLA4 therapy. While tumor mutation burden (TMB) was associated with improved response to therapy, expressed mutation burden was superior to TMB in predicting outcome. An increased pre-existing T cell density differentiated responding from non-responding tumors independent of therapy. Importantly, T cell repertoire reshaping determined by T cell receptor (TCR) clonotypic regressions and expansions reflected response to therapy such that a more dynamic repertoire predicted improved clinical outcome. Through whole-transcriptome analyses, we discovered differential abundance of B cell subsets in responding tumors, which highlights the importance of the interplay between pre-existing T and B cell immunity in shaping therapeutic response. Tumor temporal trajectories during therapy revealed distinct patterns of molecular response related to expressed mutation elimination or retention that accurately interpreted clinical response. High-dimensional genomic, transcriptomic and immune repertoire data were integrated by both a machine learning and a censored regression approach, resulting in a harmonized multi-modal predictor of response to immune checkpoint blockade. B cell abundance, expressed mutation load and tumor aneuploidy were combined to identify patients at high risk for recurrence, such that high risk patients had a significantly shorter progression-free survival (HR=9.18, 95% CI: 3.14-26.85, p=3.4e-06) especially in the anti-PD1/anti-CTLA4 group (HR=20.34, 95% CI: 4.08-101.32, p=1.68e-06).

  Study EGAS00001004548

• Super enhancers define regulatory subtypes and cell identity in neuroblastoma - RNA-seq

  Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.

  Study EGAS00001004552

• Clinical Outcomes by Tumor Mutational Burden and Inflammatory Gene Expression With Combined Nivolumab and Ipilimumab or Monotherapy in Advanced Melanoma - CM67 WES

  Purpose Exploratory analyses of CheckMate 066 and 067 trials were conducted to investigate associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma. Patients and Methods Patients with known programmed death ligand 1 (PD-L1) expression and BRAF mutation status received nivolumab (NIVO) or dacarbazine in CheckMate 066 and either NIVO, ipilimumab (IPI), or NIVO+IPI in CheckMate 067. Whole exome sequencing and RNA sequencing were used to determine TMB and inflammatory gene expression signature scores, respectively. These biomarkers were evaluated in terms of their association with PFS and OS. Results In the NIVO, NIVO+IPI, and IPI arms of CheckMate 067, longer survival was associated with high (> median) versus low (≤ median) TMB with hazard ratios (HRs) (95% confidence interval [CI]) for PFS of 0.45 (0.30–0.65), 0.55 (0.38–0.81), and 0.60 (0.43–0.82), and for OS of 0.46 (0.30–0.71), 0.53 (0.34–0.82), and 0.52 (0.36–0.74), respectively. For NIVO-treated patients, these results were confirmed in CheckMate 066. A survival benefit was observed with high TMB and absence of BRAF mutation. Survival was associated with high versus low inflammatory signature scores with HRs (95% CI) for PFS of 0.56 (0.34–0.94), 0.40 (0.23–0.72), and 0.43 (0.27–0.70), and for OS of 0.37 (0.20–0.66), 0.38 (0.19–0.74), and 0.46 (0.27–0.79), in the NIVO, NIVO+IPI, and IPI arms, respectively. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Conclusions Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immunotherapy in advanced melanoma.

  Study EGAS00001004555

• Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

  Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAEs) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the break-down of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Tregs) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127– Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings propose an inflammatory Treg reprogramming as a feature of immunotherapy-induced irAEs, that may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

  Study EGAS00001004694

• Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma

  Study EGAS00001004558

• RNASeq of PDX and CDX tumours treated with ADC

  Enapotamab vedotin (EnaV), an antibody-drug conjugate (ADC) targeting AXL, effectively targets tumors that display insensitivity to immunotherapy and/or tumor-specific T cells in several melanoma and lung cancer models. Mechanistically, EnaV treatment induced an inflammatory response and immunogenic cell death in tumor cells, and promoted induction of a memory-like phenotype in cytotoxic T cells. Combining EnaV with tumor-specific T cells proved superior to any treatment alone in models of melanoma and lung cancer, and increased ICB benefit in models otherwise insensitive to anti-PD-1 treatment.

  Study EGAS00001004562

• Clinical Outcomes by Tumor Mutational Burden and Inflammatory Gene Expression With Combined Nivolumab and Ipilimumab or Monotherapy in Advanced Melanoma

  Purpose Exploratory analyses of CheckMate 066 and 067 trials were conducted to investigate associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma. Patients and Methods Patients with known programmed death ligand 1 (PD-L1) expression and BRAF mutation status received nivolumab (NIVO) or dacarbazine in CheckMate 066 and either NIVO, ipilimumab (IPI), or NIVO+IPI in CheckMate 067. Whole exome sequencing and RNA sequencing were used to determine TMB and inflammatory gene expression signature scores, respectively. These biomarkers were evaluated in terms of their association with PFS and OS. Results In the NIVO, NIVO+IPI, and IPI arms of CheckMate 067, longer survival was associated with high (> median) versus low (≤ median) TMB with hazard ratios (HRs) (95% confidence interval [CI]) for PFS of 0.45 (0.30–0.65), 0.55 (0.38–0.81), and 0.60 (0.43–0.82), and for OS of 0.46 (0.30–0.71), 0.53 (0.34–0.82), and 0.52 (0.36–0.74), respectively. For NIVO-treated patients, these results were confirmed in CheckMate 066. A survival benefit was observed with high TMB and absence of BRAF mutation. Survival was associated with high versus low inflammatory signature scores with HRs (95% CI) for PFS of 0.56 (0.34–0.94), 0.40 (0.23–0.72), and 0.43 (0.27–0.70), and for OS of 0.37 (0.20–0.66), 0.38 (0.19–0.74), and 0.46 (0.27–0.79), in the NIVO, NIVO+IPI, and IPI arms, respectively. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Conclusions Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immunotherapy in advanced melanoma.

  Study EGAS00001004564

• Clinical Outcomes by Tumor Mutational Burden and Inflammatory Gene Expression With Combined Nivolumab and Ipilimumab or Monotherapy in Advanced Melanoma - CM066-WES

  Purpose Exploratory analyses of CheckMate 066 and 067 trials were conducted to investigate associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma. Patients and Methods Patients with known programmed death ligand 1 (PD-L1) expression and BRAF mutation status received nivolumab (NIVO) or dacarbazine in CheckMate 066 and either NIVO, ipilimumab (IPI), or NIVO+IPI in CheckMate 067. Whole exome sequencing and RNA sequencing were used to determine TMB and inflammatory gene expression signature scores, respectively. These biomarkers were evaluated in terms of their association with PFS and OS. Results In the NIVO, NIVO+IPI, and IPI arms of CheckMate 067, longer survival was associated with high (> median) versus low (≤ median) TMB with hazard ratios (HRs) (95% confidence interval [CI]) for PFS of 0.45 (0.30–0.65), 0.55 (0.38–0.81), and 0.60 (0.43–0.82), and for OS of 0.46 (0.30–0.71), 0.53 (0.34–0.82), and 0.52 (0.36–0.74), respectively. For NIVO-treated patients, these results were confirmed in CheckMate 066. A survival benefit was observed with high TMB and absence of BRAF mutation. Survival was associated with high versus low inflammatory signature scores with HRs (95% CI) for PFS of 0.56 (0.34–0.94), 0.40 (0.23–0.72), and 0.43 (0.27–0.70), and for OS of 0.37 (0.20–0.66), 0.38 (0.19–0.74), and 0.46 (0.27–0.79), in the NIVO, NIVO+IPI, and IPI arms, respectively. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Conclusions Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immunotherapy in advanced melanoma.

  Study EGAS00001004567

• Single cell RNA sequencing of CD19 CAR T-cell infusion products

  We performed single cell RNA sequencing of remnants from CD19 CAR T-cell infusion products used for standard of care treatment for relapsed/refractory large B-cell lymphoma. Libraries were prepared using 10X 5’ GEX chemistry and sequenced on an Illumina HiSeq 4000 to obtain >50,000 reads per cell.

  Study EGAS00001004576

• Whole Exome Sequences from Iberian Roma samples

  Study of high-depth Roma whole exomes to analyse the impact of complex demography on the functional genomic variation. This study also includes genome-wide array data of Iberian Roma individuals

  Study EGAS00001004599

• Queensland Melanoma Genomic Biomarker Study

  There is a clinical need to identify melanoma patients not likely to benefit from current targeted and immuno-therapy and identify biomarkers that can predict patient outcome. Genomic biomarkers are not yet part of staging but show promising results. The aim of this study was to determine genomic and image-based biomarkers as adverse prognostic factors in stage III/IV melanoma patients with resected disease. We found combining genomic and PET/CT derived biomarkers with current clinical assessment may offer additional prognostic tools to stratify patients in the clinic.

  Study EGAS00001004619

• Mutational landscape of eccrine porocarcinoma (sweat gland tumour)

  Eccrine porocarcinoma (EP) is the most common form of sweat gland malignancy. The aetiology of EP is largely unknown. The current lack of data on somatic mutation patterns in EP hampers the development of effective therapies. We performed whole-exome sequencing in a well-characterized sample of 14 matched EP tumour/healthy surrounding tissue samples. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. The analyses revealed alterations in the cancer driver genes and in crucial oncogenic pathways.

  Study EGAS00001004632

• RNA sequencing of follicular T cell lymphoma

  Study EGAS00001004646

• Targeted sequencing of Burkitt lymphoma tumour samples from the UK's Haematological Malignancy Research Network

  The UK’s Haematological Malignancy Research Network (www.HMRN.org) was established in 2004 to provide robust generalizable data to inform clinical practice and research. HMRN is a collaboration between researchers in the Epidemiology & Statistics Group (ECSG) at the University of York, a unified Clinical Network operating across 14 hospitals, and an integrated Haematological Malignancy Diagnostic Service (HMDS) in Leeds. Covering a population of around 4 million, HMRN collects detailed information about all patients diagnosed with a haematological malignancy within the HMRN region, accruing around 2,400 new diagnoses each year. The population has a similar socio-demographic profile to the country as a whole, and HMRN’s maturing data present an increasingly valuable resource to address real questions of concern to haematologists, commissioners and health service researchers – locally, nationally and internationally. This study forms part of a larger project employing targeted exome sequencing on tumour samples from patients diagnosed with a variety of both lymphoid and myeloid malignancies. The results for samples collected from 39 Burkitt lymphoma patients, diagnosed within HMRN from 2005 to 2012, are provided.

  Study EGAS00001004649

• Cerebrospinal fluid circulating tumour DNA allows the characterisation and monitoring of medulloblastoma

  The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. In this study we show that CSF ctDNA allows the molecular characterisation and monitoring of medulloblastoma. This can ultimately facilitate the clinical management of medulloblastoma patients.

  Study EGAS00001004651

• Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

  Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We used differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR=1.63, p=5.24x10-5) and overall survival (HR=1.61, p=1.67x10-4), and validated in 177 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC=0.02), or published prognostic signatures. The signature score negatively correlated with measures of immune cell infiltration (ρ=-0.75, p<2.2x10-16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

  Study EGAS00001004664

• Lymphoma Group

  Dac EGAC00001001243

• Ultraviolet radiation drives mutations in a subset of mucosal melanomas

  Although identified as the key environmental driver of common cutaneous melanoma, the role of ultraviolet radiation (UVR)-induced DNA damage in mucosal melanoma is poorly defined. We present the largest cohort of mucosal melanomas of conjunctival origin to be analyzed by whole genome sequencing and show a predominance of UVR-associated single base substitution signature 7 (SBS7) in the majority of the samples. Our data shows mucosal melanomas with SBS7 dominance have similar genomic patterns to cutaneous melanomas and therefore this subset could benefit from treatments currently used for common cutaneous melanoma.

  Study EGAS00001004697

• A novel orthotopic patient-derived xenograft model of radiation-induced glioma following medulloblastoma

  Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phospho-S6, -4EBP1 and -ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.

  Study EGAS00001004709

• STAT5 is a therapeutically targetable vulnerability in cutaneous T-cell lymphoma

  Cutaneous T-cell lymphomas represent a heterogeneous group of lymphoproliferative disorders characterized by the infiltration and expansion of mature malignant T-cells into the skin. The disease encompasses distinct variants such as mycosis fungoides a skin resident variant, in which the malignant cells are restricted to skin lesions, and leukemic variant sézary syndrome characterized by circulating malignant T-cells. Here we integrated shallow whole genome sequencing and whole exome sequencing, on samples from four sézary syndrome patients and two advanced mycosis fungoides patients with blood involvement, to characterize genetic alterations and assess their therapeutic actionability. We identified an elevated copy number of 17q, resulting in increased STAT5 expression and activation, as a key factor in the pathophysiology of the disease.

  Study EGAS00001004719

• Multi Omics of glioma in the the Chinese Glioma Genome Atlas (CGGA) project

  Study EGAS00001004729