9,853 research outputs found

    A cancer cell-line titration series for evaluating somatic classification.

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    BackgroundAccurate detection of somatic single nucleotide variants and small insertions and deletions from DNA sequencing experiments of tumour-normal pairs is a challenging task. Tumour samples are often contaminated with normal cells confounding the available evidence for the somatic variants. Furthermore, tumours are heterogeneous so sub-clonal variants are observed at reduced allele frequencies. We present here a cell-line titration series dataset that can be used to evaluate somatic variant calling pipelines with the goal of reliably calling true somatic mutations at low allele frequencies.ResultsCell-line DNA was mixed with matched normal DNA at 8 different ratios to generate samples with known tumour cellularities, and exome sequenced on Illumina HiSeq to depths of >300Ă—. The data was processed with several different variant calling pipelines and verification experiments were performed to assay >1500 somatic variant candidates using Ion Torrent PGM as an orthogonal technology. By examining the variants called at varying cellularities and depths of coverage, we show that the best performing pipelines are able to maintain a high level of precision at any cellularity. In addition, we estimate the number of true somatic variants undetected as cellularity and coverage decrease.ConclusionsOur cell-line titration series dataset, along with the associated verification results, was effective for this evaluation and will serve as a valuable dataset for future somatic calling algorithm development. The data is available for further analysis at the European Genome-phenome Archive under accession number EGAS00001001016. Data access requires registration through the International Cancer Genome Consortium's Data Access Compliance Office (ICGC DACO)

    Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

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    © 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

    Clinical value of bioelectrical properties of cancerous tissue in advanced epithelial ovarian cancer patients

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    Currently, there are no valid pre-operatively established biomarkers or algorithms that can accurately predict surgical and clinical outcome for patients with advanced epithelial ovarian cancer (EOC). In this study, we suggest that profiling of tumour parameters such as bioelectrical-potential and metabolites, detectable by electronic sensors, could facilitate the future development of devices to better monitor disease and predict surgical and treatment outcomes. Biopotential was recorded, using a potentiometric measurement system, in ex vivo paired non-cancerous and cancerous omental tissues from advanced stage EOC (n = 36), and lysates collected for metabolite measurement by microdialysis. Consistently different biopotential values were detected in cancerous tissue versus non-cancerous tissue across all cases (p < 0.001). High tumour biopotential levels correlated with advanced tumour stage (p = 0.048) and tumour load, and negatively correlated with stroma. Within our EOC cohort and specifically the high-grade serous subtype, low biopotential levels associated with poorer progression-free survival (p = 0.0179, p = 0.0143 respectively). Changes in biopotential levels significantly correlated with common apoptosis related pathways. Lactate and glucose levels measured in paired tissues showed significantly higher lactate/glucose ratio in tissues with low biopotential (p < 0.01, n = 12). Our study proposes the feasibility of biopotential and metabolite monitoring as a biomarker modality profiling EOC to predict surgical and clinical outcomes

    A Bayesian spatial random effects model characterisation of tumour heterogeneity implemented using Markov chain Monte Carlo (MCMC) simulation

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    The focus of this study is the development of a statistical modelling procedure for characterising intra-tumour heterogeneity, motivated by recent clinical literature indicating that a variety of tumours exhibit a considerable degree of genetic spatial variability. A formal spatial statistical model has been developed and used to characterise the structural heterogeneity of a number of supratentorial primitive neuroecto-dermal tumours (PNETs), based on diffusionweighted magnetic resonance imaging. Particular attention is paid to the spatial dependence of diffusion close to the tumour boundary, in order to determine whether the data provide statistical evidence to support the proposition that water diffusivity in the boundary region of some tumours exhibits a deterministic dependence on distance from the boundary, in excess of an underlying random 2D spatial heterogeneity in diffusion. Tumour spatial heterogeneity measures were derived from the diffusion parameter estimates obtained using a Bayesian spatial random effects model. The analyses were implemented using Markov chain Monte Carlo (MCMC) simulation. Posterior predictive simulation was used to assess the adequacy of the statistical model. The main observations are that the previously reported relationship between diffusion and boundary proximity remains observable and achieves statistical significance after adjusting for an underlying random 2D spatial heterogeneity in the diffusion model parameters. A comparison of the magnitude of the boundary-distance effect with the underlying random 2D boundary heterogeneity suggests that both are important sources of variation in the vicinity of the boundary. No consistent pattern emerges from a comparison of the boundary and core spatial heterogeneity, with no indication of a consistently greater level of heterogeneity in one region compared with the other. The results raise the possibility that DWI might provide a surrogate marker of intra-tumour genetic regional heterogeneity, which would provide a powerful tool with applications in both patient management and in cancer research

    MRI in multiple myeloma : a pictorial review of diagnostic and post-treatment findings

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    Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity. This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message aEuro cent Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. aEuro cent Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. aEuro cent Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. aEuro cent Combined morphological and functional MRI provides optimal bone marrow assessment for staging. aEuro cent Combined morphological and functional MRI is of considerable value in treatment follow-up

    Intracranial solitary fibrous tumor

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    Solitary fibrous tumours are rare mesenchymal spindle-cell tumours that occur most often in the visceral pleura or liver. If they occur intracranially, they are extra-axially located and develop from the meninges. In those cases, the differential diagnosis has to be made with other intracranial extra-axial-located tumours, such as meningeoma and hemangiopericytoma. We report a 32-year-old woman with an intracranial solitary fibrous tumour and review the latest literature regarding the imaging characteristics of this tumour

    The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1

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    The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5 + malignant melanoma-initiating cells (ABCB5 + MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro

    Nodular Fasciitis of Neck in Childhood.

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    Nodular fasciitis, is a benign, pseudo sarcomatous proliferative lesion of the soft tissue, which is frequently misinterpreted as sarcoma, both clinically and microscopically. It is a reactive lesion composed of fibroblasts/myofibroblasts and most commonly found in extremities and trunk. NF has been described in the head and neck region in 10-20% of cases. Many pathologists do not consider NF in the differential diagnosis of soft tissue masses arising in the Head neck region. NF that occurs in otherwise healthy individuals usually presents with a history of rapid growth, and is commonly found in the upper extremities and on the chest and trunk. The importance of otolaryngologists being aware of the existence of this entity in this area of the body is stressed. It has a confirmed perfectly benign clinical course, and simple excision, as tissue-sparing as possible, is the treatment of choice. A case of NF over the neck in a 05-year-old female not associated with trauma who presented with a localized mass over her left neck is presented

    Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

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    Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-offunction mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, nÂĽ40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC
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