3773 results for "*oma"

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• 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