4774 results for "*oma"

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• 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

• whole genome sequence data of multifocal hepatocellular carcinoma

  Background & Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics pro?ling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual speci?city protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identi?cation of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002338

• 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

• Genomic analysis of patient-derived xenograft models reveals intratumor-heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib

  Background: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods: Here, we report whole exome or whole genome sequencing of 11 PDX models and the matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. Results: PDX models were successfully generated with similar histomorphology from all four molecular subtypes of EC and uterine carcinosarcomas. We also observed a wide range of inter-tumor and intra-tumor heterogeneity across different PDX lineages, however one arm of most PDX models recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease, however all lacked the HR deficiency genomic signature. Conclusions: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.

  Study EGAS00001004666

• Mutational Landscape and Tumor Burden Assessed by Cell-Free DNA in Diffuse Large B-Cell Lymphoma: a Population-based Study

  Purpose: We analyzed the utility of cfDNA in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with DLBCL. Experimental Design: One-hundred patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed paraffin-embedded samples and volumetric PET/CT were assessed when available. Results: Appropriate cfDNA to perform the analyses was obtained in 79/100 cases. At least one mutation could be detected in 69/79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% CI: 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of ctDNA significantly correlated with clinical parameters related to tumor burden (elevated LDH and β2-microglobulin serum levels, advanced stage, and high-risk IPI) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%, P<0.004), shorter progression-free survival (65% vs. 85%, P=0.038) and overall survival (73% vs. 100%, P=0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses. Conclusions: In a population-based prospective DLBCL series, cfDNA resulted an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored

  Study EGAS00001004733

• Identification of rare germline variants in familial multiple myeloma

  The risk of developing multiple myeloma (MM) in first-degree relatives of affected individuals is 2 to 4 fold higher than in the general population, implying the existence of inherited susceptibility. While over 20 common, low-penetrance variants have been associated with MM risk, less is known about rare, high-penetrance germline predisposition. We aimed to identify and characterize high/moderated penetrance germline variants in MM families using whole genome sequencing. For that purpose we identified families with at least two individuals diagnosed with MM or its precursors MGUS and smoldering MM. Also, patients with solitary plasmacytoma and AL amyloidosis were enrolled. We also recruited unaffected family members, and they were screened to exclude undetected MM or its precursor stages. After whole genome sequencing of blood DNA and filtering for rare variants (minor allele frequency <0.1%) and family segregation, variants are prioritized by a range of published in silico tools and literature search. The most promising variants are subjected to experimental validation to evaluate their functional relevance. Our data will provide guidance to worldwide efforts to unravel germline predisposition in MM and validation of the proposed variants and genes.

  Study EGAS00001004734

• DIPG RNA and exome sequencing

  DIPG is a paediatric high-grade glioma that diffusely infiltrates the brainstem and is the leading cause of paediatric brain tumour death. Here we performed RNA and whole exome sequencing on DIPG and control samples to analyse transcriptomic and genetic alterations associated with this devastating disease, and to understand the relationship between them.

  Study EGAS00001004749

• Integrated genomic, transcriptional and epigenomic analyses in germinal center-cell lymphomas link the mutation landscape with differential DNA methylation in Burkitt lymphoma

  Biologically and clinically diverse B-cell neoplasms, including Burkitt, follicular and diffuse large B-cell lymphoma, show features of germinal center (GC) B-cells. Here we present a comprehensive analysis of the epigenetic landscape of GC-B-cell lymphomas using whole genome bisulfite sequencing paired with genome and transcriptome sequencing from 29 primary tumor samples and four normal GC-B-cell samples. All lymphomas studied showed extensive genome-wide methylation losses as well as intragenic regions where DNA methylation levels were strongly correlated with expression of associated genes. Pathway analysis revealed that these intragenic regions were enriched in signaling networks differentially activated in Burkitt and follicular lymphomas and affected regulatory mechanisms deregulated by recurrent mutations in a large fraction of Burkitt lymphomas (including the ID3/TCF3 complex, the SWI/SNF remodeling complex and the inhibitory GI signaling pathway). Taken together, these results provide a global picture of Burkitt lymphoma pathomechanism and demonstrate a tight connection between epigenetic regulation and other levels of regulatory control in these tumors.

  Study EGAS00001001067

• Investigate the evolutionary trajectories during invasiveness acquisition in early lung adenocarcinoma

  The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.

  Study EGAS00001004754

• Targeted resequencing of ribosomal proteins in multiple myeloma patient samples.

  We studied 38 multiple myeloma samples to discover mutations in ribosomal proteins. To this end, we ran a specifically designed targeted resequencing study to resequence the coding regions of all ribosomal proteins.

  Study EGAS00001002405