2,095 research outputs found

    Increased entropy of signal transduction in the cancer metastasis phenotype

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    Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis. Further exploration of such integrated cancer expression and protein interaction networks will therefore be a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table

    Functional and Topological Properties in Hepatocellular Carcinoma Transcriptome

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    Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non-random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well-connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems-wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease

    Network-based approaches to explore complex biological systems towards network medicine

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    Network medicine relies on different types of networks: from the molecular level of protein–protein interactions to gene regulatory network and correlation studies of gene expression. Among network approaches based on the analysis of the topological properties of protein–protein interaction (PPI) networks, we discuss the widespread DIAMOnD (disease module detection) algorithm. Starting from the assumption that PPI networks can be viewed as maps where diseases can be identified with localized perturbation within a specific neighborhood (i.e., disease modules), DIAMOnD performs a systematic analysis of the human PPI network to uncover new disease-associated genes by exploiting the connectivity significance instead of connection density. The past few years have witnessed the increasing interest in understanding the molecular mechanism of post-transcriptional regulation with a special emphasis on non-coding RNAs since they are emerging as key regulators of many cellular processes in both physiological and pathological states. Recent findings show that coding genes are not the only targets that microRNAs interact with. In fact, there is a pool of different RNAs—including long non-coding RNAs (lncRNAs) —competing with each other to attract microRNAs for interactions, thus acting as competing endogenous RNAs (ceRNAs). The framework of regulatory networks provides a powerful tool to gather new insights into ceRNA regulatory mechanisms. Here, we describe a data-driven model recently developed to explore the lncRNA-associated ceRNA activity in breast invasive carcinoma. On the other hand, a very promising example of the co-expression network is the one implemented by the software SWIM (switch miner), which combines topological properties of correlation networks with gene expression data in order to identify a small pool of genes—called switch genes—critically associated with drastic changes in cell phenotype. Here, we describe SWIM tool along with its applications to cancer research and compare its predictions with DIAMOnD disease genes

    Chromatin network markers of leukemia

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    Motivation The structure of chromatin impacts gene expression. Its alteration has been shown to coincide with the occurrence of cancer. A key challenge is in understanding the role of chromatin structure (CS) in cellular processes and its implications in diseases. Results We propose a comparative pipeline to analyze CSs and apply it to study chronic lymphocytic leukemia (CLL). We model the chromatin of the affected and control cells as networks and analyze the network topology by state-of-the-art methods. Our results show that CSs are a rich source of new biological and functional information about DNA elements and cells that can complement protein–protein and co-expression data. Importantly, we show the existence of structural markers of cancer-related DNA elements in the chromatin. Surprisingly, CLL driver genes are characterized by specific local wiring patterns not only in the CS network of CLL cells, but also of healthy cells. This allows us to successfully predict new CLL-related DNA elements. Importantly, this shows that we can identify cancer-related DNA elements in other cancer types by investigating the CS network of the healthy cell of origin, a key new insight paving the road to new therapeutic strategies. This gives us an opportunity to exploit chromosome conformation data in healthy cells to predict new drivers. Availability and implementation Our predicted CLL genes and RNAs are provided as a free resource to the community at https://life.bsc.es/iconbi/chromatin/index.html. Supplementary information Supplementary data are available at Bioinformatics online.This work was supported by the European Research Council (ERC) Consolidator Grant 770827, the Serbian Ministry of Education and Science Project III44006, the Slovenian Research Agency project J1-8155, The Prostate Project, and the Foundation Toulouse Cancer Santé and Pierre Fabre Research Institute as part of the Chair of Bio-Informatics in Oncology of the CRCT.Peer ReviewedPostprint (published version

    Chromatin network markers of leukemia

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    MOTIVATION: The structure of chromatin impacts gene expression. Its alteration has been shown to coincide with the occurrence of cancer. A key challenge is in understanding the role of chromatin structure (CS) in cellular processes and its implications in diseases. RESULTS: We propose a comparative pipeline to analyze CSs and apply it to study chronic lymphocytic leukemia (CLL). We model the chromatin of the affected and control cells as networks and analyze the network topology by state-of-the-art methods. Our results show that CSs are a rich source of new biological and functional information about DNA elements and cells that can complement protein–protein and co-expression data. Importantly, we show the existence of structural markers of cancer-related DNA elements in the chromatin. Surprisingly, CLL driver genes are characterized by specific local wiring patterns not only in the CS network of CLL cells, but also of healthy cells. This allows us to successfully predict new CLL-related DNA elements. Importantly, this shows that we can identify cancer-related DNA elements in other cancer types by investigating the CS network of the healthy cell of origin, a key new insight paving the road to new therapeutic strategies. This gives us an opportunity to exploit chromosome conformation data in healthy cells to predict new drivers. AVAILABILITY AND IMPLEMENTATION: Our predicted CLL genes and RNAs are provided as a free resource to the community at https://life.bsc.es/iconbi/chromatin/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

    Role of network topology based methods in discovering novel gene-phenotype associations

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    The cell is governed by the complex interactions among various types of biomolecules. Coupled with environmental factors, variations in DNA can cause alterations in normal gene function and lead to a disease condition. Often, such disease phenotypes involve coordinated dysregulation of multiple genes that implicate inter-connected pathways. Towards a better understanding and characterization of mechanisms underlying human diseases, here, I present GUILD, a network-based disease-gene prioritization framework. GUILD associates genes with diseases using the global topology of the protein-protein interaction network and an initial set of genes known to be implicated in the disease. Furthermore, I investigate the mechanistic relationships between disease-genes and explain the robustness emerging from these relationships. I also introduce GUILDify, an online and user-friendly tool which prioritizes genes for their association to any user-provided phenotype. Finally, I describe current state-of-the-art systems-biology approaches where network modeling has helped extending our view on diseases such as cancer.La cèl•lula es regeix per interaccions complexes entre diferents tipus de biomolècules. Juntament amb factors ambientals, variacions en el DNA poden causar alteracions en la funció normal dels gens i provocar malalties. Sovint, aquests fenotips de malaltia involucren una desregulació coordinada de múltiples gens implicats en vies interconnectades. Per tal de comprendre i caracteritzar millor els mecanismes subjacents en malalties humanes, en aquesta tesis presento el programa GUILD, una plataforma que prioritza gens relacionats amb una malaltia en concret fent us de la topologia de xarxe. A partir d’un conjunt conegut de gens implicats en una malaltia, GUILD associa altres gens amb la malaltia mitjancant la topologia global de la xarxa d’interaccions de proteïnes. A més a més, analitzo les relacions mecanístiques entre gens associats a malalties i explico la robustesa es desprèn d’aquesta anàlisi. També presento GUILDify, un servidor web de fácil ús per la priorització de gens i la seva associació a un determinat fenotip. Finalment, descric els mètodes més recents en què el model•latge de xarxes ha ajudat extendre el coneixement sobre malalties complexes, com per exemple a càncer
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