119 research outputs found

    Jetset: selecting the optimal microarray probe set to represent a gene

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    <p>Abstract</p> <p>Background</p> <p>Interpretation of gene expression microarrays requires a mapping from probe set to gene. On many Affymetrix gene expression microarrays, a given gene may be detected by multiple probe sets, which may deliver inconsistent or even contradictory measurements. Therefore, obtaining an unambiguous expression estimate of a pre-specified gene can be a nontrivial but essential task.</p> <p>Results</p> <p>We developed scoring methods to assess each probe set for specificity, splice isoform coverage, and robustness against transcript degradation. We used these scores to select a single representative probe set for each gene, thus creating a simple one-to-one mapping between gene and probe set. To test this method, we evaluated concordance between protein measurements and gene expression values, and between sets of genes whose expression is known to be correlated. For both test cases, we identified genes that were nominally detected by multiple probe sets, and we found that the probe set chosen by our method showed stronger concordance.</p> <p>Conclusions</p> <p>This method provides a simple, unambiguous mapping to allow assessment of the expression levels of specific genes of interest.</p

    Computational Analysis Reveals the Temporal Acquisition of Pathway Alterations during the Evolution of Cancer

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    Cancer metastasis is the lethal developmental step in cancer, responsible for the majority of cancer deaths. To metastasise, cancer cells must acquire the ability to disseminate systemically and to escape an activated immune response. Here, we endeavoured to investigate if metastatic dissemination reflects acquisition of genomic traits that are selected for. We acquired mutation and copy number data from 8332 tumours representing 19 cancer types acquired from The Cancer Genome Atlas and the Hartwig Medical Foundation. A total of 827,344 non-synonymous mutations across 8332 tumour samples representing 19 cancer types were timed as early or late relative to copy number alterations, and potential driver events were annotated. We found that metastatic cancers had a significantly higher proportion of clonal mutations and a general enrichment of early mutations in p53 and RTK/KRAS pathways. However, while individual pathways demonstrated a clear time-separated preference for specific events, the relative timing did not vary between primary and metastatic cancers. These results indicate that the selective pressure that drives cancer development does not change dramatically between primary and metastatic cancer on a genomic level, and is mainly focused on alterations that increase proliferation

    A breast cancer meta-analysis of two expression measures of chromosomal instability reveals a relationship with younger age at diagnosis and high risk histopathological variables

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    Breast cancer in younger patients often presents with adverse histopathological features, including increased frequency of estrogen receptor negative and lymph node positive disease status. Chromosomal instability (CIN) is increasingly recognised as an important prognostic variable in solid tumours. In a breast cancer meta-analysis of 2423 patients we examine the relationship between clinicopathological parameters and two distinct chromosomal instability gene expression signatures in order to address whether younger age at diagnosis is associated with increased tumour genome instability. We find that CIN, assessed by the two independently derived CIN expression signatures, is significantly associated with increased tumour size, ER negative or HER2 positive disease, higher tumour grade and younger age at diagnosis in ER negative breast cancer. These data support the hypothesis that chromosomal instability may be a defining feature of breast cancer biology and clinical outcome

    Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer

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    UNLABELLED: The cGAS-STING pathway serves a critical role in anticancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance. Here, we used combined expression data from 2,307 tumors from five cancer types from The Cancer Genome Atlas to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy-treated cohort, patients with low cGAS-STING expression showed limited response to treatment, while patients with high expression showed improved response and prognosis, particularly among patients with high CIN and more neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this suggests a potential role of cGAS-STING activity as a predictive biomarker for the application of immunotherapy. SIGNIFICANCE: The cGAS-STING pathway is induced by CIN, triggers inflammation and is often deficient in cancer. We provide a tool to evaluate cGAS-STING activity and demonstrate clinical significance in immunotherapy response

    Method for identification of tissue or organ localization of a tumour

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    The invention relates to a method for predicting the localization of a primary tumour, wherein said method comprises the use of genomic profile data, and wherein the method is capable of predicting the type of cancer by a classification score ranking among a variety of the possible tumour types.</p

    Quantification of within-sample genetic heterogeneity from SNP-array data

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    Intra-tumour genetic heterogeneity (ITH) fosters drug resistance and is a critical hurdle to clinical treatment. ITH can be well-measured using multi-region sampling but this is costly and challenging to implement. There is therefore a need for tools to estimate ITH in individual samples, using standard genomic data such as SNP-arrays, that could be implemented routinely. We designed two novel scores S and R, respectively based on the Shannon diversity index and Ripley’s L statistic of spatial homogeneity, to quantify ITH in single SNP-array samples. We created in-silico and in-vitro mixtures of tumour clones, in which diversity was known for benchmarking purposes. We found significant but highly-variable associations of our scores with diversity in-silico (p < 0.001) and moderate associations in–vitro (p = 0.015 and p = 0.085). Our scores were also correlated to previous ITH estimates from sequencing data but heterogeneity in the fraction of tumour cells present across samples hampered accurate quantification. The prognostic potential of both scores was moderate but significantly predictive of survival in several tumour types (corrected p = 0.03). Our work thus shows how individual SNP-arrays reveal intra-sample clonal diversity with moderate accuracy

    Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma

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    SIMPLE SUMMARY: Checkpoint inhibitors have emerged as an effective therapy for patients with metastatic melanoma significantly improving survival for these patients. Despite this, many patients do not respond to the therapy and no current biomarkers can identify responders from non-responders. Using machine learning, we analysed cytokine levels in serially collected liquid biopsy to identify cytokine changes associated with response to checkpoint inhibitors in advanced-stage melanoma patients. The results presented here highlight that serial measurements of cytokine levels are a strong predictor of treatment response. Particularly, we demonstrate that high increases of soluble PD-1 measured from baseline to on-treatment is significantly associated with superior PFS in patients treated with nivolumab plus ipililumab. These results suggest that monitoring cytokine levels using serial samples is informative of treatment response and can improve guidance of treatment modality and the outcome of cancer patients. ABSTRACT: Background: Checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, yielding long-term survival in a considerable proportion of the patients. Yet, 40–60% of patients do not achieve a long-term benefit from such therapy, emphasizing the urgent need to identify biomarkers that can predict response to immunotherapy and guide patients for the best possible treatment. Here, we exploited an unsupervised machine learning approach to identify potential inflammatory cytokine signatures from liquid biopsies, which could predict response to immunotherapy in melanoma. Methods: We studied a cohort of 77 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab plus ipilimumab or pembrolizumab. Baseline and on-treatment plasma samples were tested for levels of PD-1, PD-L1, IFNγ, IFNβ, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNFα and analyzed by Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis. Results: Interestingly, using UMAP analysis, we found that treatment-induced cytokine changes measured as a ratio between baseline and on-treatment samples correlated significantly to progression-free survival (PFS). For patients treated with nivolumab plus ipilimumab we identified a group of patients with superior PFS that were characterized by significantly higher baseline-to-on-treatment increments of PD-1, PD-L1, IFNγ, IL10, CXCL10, and TNFα compared to patients with worse PFS. Particularly, a high PD-1 increment was a strong individual predictor for superior PFS (HR = 0.13; 95% CI 0.034–0.49; p = 0.0026). In contrast, decreasing levels of IFNγ and IL6 and increasing levels of CXCL5 were associated with superior PFS in the pembrolizumab group, although none of the cytokines were individually predictors for PFS. Conclusions: In short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response

    Parallel evolution of tumor subclones mimics diversity between tumors

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    Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
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