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  • 1
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    Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-10-09
    Description: Recent advances in next generation sequencing have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (〉43-fold coverage) and transcriptomes of an oestrogen-receptor-alpha-positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1-13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneity can be a property of low or intermediate grade primary breast cancers and that significant evolution can occur with disease progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Sohrab P -- Morin, Ryan D -- Khattra, Jaswinder -- Prentice, Leah -- Pugh, Trevor -- Burleigh, Angela -- Delaney, Allen -- Gelmon, Karen -- Guliany, Ryan -- Senz, Janine -- Steidl, Christian -- Holt, Robert A -- Jones, Steven -- Sun, Mark -- Leung, Gillian -- Moore, Richard -- Severson, Tesa -- Taylor, Greg A -- Teschendorff, Andrew E -- Tse, Kane -- Turashvili, Gulisa -- Varhol, Richard -- Warren, Rene L -- Watson, Peter -- Zhao, Yongjun -- Caldas, Carlos -- Huntsman, David -- Hirst, Martin -- Marra, Marco A -- Aparicio, Samuel -- England -- Nature. 2009 Oct 8;461(7265):809-13. doi: 10.1038/nature08489.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812674" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Vesicular Transport/genetics ; Breast Neoplasms/*genetics/metabolism/*pathology ; DNA Mutational Analysis ; Disease Progression ; Estrogen Receptor alpha/metabolism ; Evolution, Molecular ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Neoplasm/*genetics ; Genome, Human/genetics ; Germ-Line Mutation/genetics ; Humans ; Mutagenesis/*genetics ; Mutation/*genetics ; Neoplasm Metastasis ; Nucleotides/*genetics ; RNA Editing/genetics ; Signal Recognition Particle/genetics ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Differential oestrogen receptor binding is associated with clinical outcome in breast cancer (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-01-06
    Description: Oestrogen receptor-alpha (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272464/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272464/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ross-Innes, Caryn S -- Stark, Rory -- Teschendorff, Andrew E -- Holmes, Kelly A -- Ali, H Raza -- Dunning, Mark J -- Brown, Gordon D -- Gojis, Ondrej -- Ellis, Ian O -- Green, Andrew R -- Ali, Simak -- Chin, Suet-Feung -- Palmieri, Carlo -- Caldas, Carlos -- Carroll, Jason S -- A10178/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Jan 4;481(7381):389-93. doi: 10.1038/nature10730.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22217937" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Breast Neoplasms/*diagnosis/drug therapy/*genetics/pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects/genetics ; Female ; *Gene Expression Regulation, Neoplastic/drug effects ; Hepatocyte Nuclear Factor 3-alpha/metabolism ; Humans ; Neoplasm Metastasis/genetics ; Prognosis ; Protein Binding ; Receptors, Estrogen/*metabolism ; Regulatory Sequences, Nucleic Acid/genetics ; Survival Analysis ; Tamoxifen/pharmacology/therapeutic use ; Treatment Outcome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Distinctive topology of age-associated epigenetic drift in the human interactome (2013)
    National Academy of Sciences
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    Publication Date: 2013-08-12
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data (2013)
    Oxford University Press
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    Publication Date: 2013-01-17
    Description: Motivation: The Illumina Infinium 450 k DNA Methylation Beadchip is a prime candidate technology for Epigenome-Wide Association Studies (EWAS). However, a difficulty associated with these beadarrays is that probes come in two different designs, characterized by widely different DNA methylation distributions and dynamic range, which may bias downstream analyses. A key statistical issue is therefore how best to adjust for the two different probe designs. Results: Here we propose a novel model-based intra-array normalization strategy for 450 k data, called BMIQ (Beta MIxture Quantile dilation), to adjust the beta-values of type2 design probes into a statistical distribution characteristic of type1 probes. The strategy involves application of a three-state beta-mixture model to assign probes to methylation states, subsequent transformation of probabilities into quantiles and finally a methylation-dependent dilation transformation to preserve the monotonicity and continuity of the data. We validate our method on cell-line data, fresh frozen and paraffin-embedded tumour tissue samples and demonstrate that BMIQ compares favourably with two competing methods. Specifically, we show that BMIQ improves the robustness of the normalization procedure, reduces the technical variation and bias of type2 probe values and successfully eliminates the type1 enrichment bias caused by the lower dynamic range of type2 probes. BMIQ will be useful as a preprocessing step for any study using the Illumina Infinium 450 k platform. Availability: BMIQ is freely available from http://code.google.com/p/bmiq/ . Contact: a.teschendorff@ucl.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 5
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    A systems-level integrative framework for genome-wide DNA methylation and gene expression data identifies differential gene expression modules under epigenetic control (2014)
    Oxford University Press
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    Publication Date: 2014-08-06
    Description: Motivation: There is a growing number of studies generating matched Illumina Infinium HumanMethylation450 and gene expression data, yet there is a corresponding shortage of statistical tools aimed at their integrative analysis. Such integrative tools are important for the discovery of epigenetically regulated gene modules or molecular pathways, which play key roles in cellular differentiation and disease. Results: Here, we present a novel functional supervised algorithm, called Functional Epigenetic Modules (FEM), for the integrative analysis of Infinium 450k DNA methylation and matched or unmatched gene expression data. The algorithm identifies gene modules of coordinated differential methylation and differential expression in the context of a human interactome. We validate the FEM algorithm on simulated and real data, demonstrating how it successfully retrieves an epigenetically deregulated gene, previously known to drive endometrial cancer development. Importantly, in the same cancer, FEM identified a novel epigenetically deregulated hotspot, directly upstream of the well-known progesterone receptor tumour suppressor pathway. In the context of cellular differentiation, FEM successfully identifies known endothelial cell subtype-specific gene expression markers, as well as a novel gene module whose overexpression in blood endothelial cells is mediated by DNA hypomethylation. The systems-level integrative framework presented here could be used to identify novel key genes or signalling pathways, which drive cellular differentiation or disease through an underlying epigenetic mechanism. Availability and implementation: FEM is freely available as an R-package from http://sourceforge.net/projects/funepimod . Contact: andrew@picb.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 6
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    Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions (2012)
    Oxford University Press
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    Publication Date: 2012-05-22
    Description: Motivation: The standard paradigm in omic disciplines has been to identify biologically relevant biomarkers using statistics that reflect differences in mean levels of a molecular quantity such as mRNA expression or DNA methylation. Recently, however, it has been proposed that differential epigenetic variability may mark genes that contribute to the risk of complex genetic diseases like cancer and that identification of risk and early detection markers may therefore benefit from statistics based on differential variability. Results: Using four genome-wide DNA methylation datasets totalling 311 epithelial samples and encompassing all stages of cervical carcinogenesis, we here formally demonstrate that differential variability, as a criterion for selecting DNA methylation features, can identify cancer risk markers more reliably than statistics based on differences in mean methylation. We show that differential variability selects features with heterogeneous outlier methylation profiles and that these play a key role in the early stages of carcinogenesis. Moreover, differentially variable features identified in precursor non-invasive lesions exhibit significantly increased enrichment for developmental genes compared with differentially methylated sites. Conversely, differential variability does not add predictive value in cancer studies profiling invasive tumours or whole-blood tissue. Finally, we incorporate the differential variability feature selection step into a novel adaptive index prediction algorithm called EVORA (epigenetic variable outliers for risk prediction analysis), and demonstrate that EVORA compares favourably to powerful prediction algorithms based on differential methylation statistics. Conclusions: Statistics based on differential variability improve the detection of cancer risk markers in the context of DNA methylation studies profiling epithelial preinvasive neoplasias. We present a novel algorithm (EVORA) which could be used for prediction and diagnosis of precursor epithelial cancer lesions. Availability: R-scripts implementing EVORA are available from CRAN ( www.r-project.org ). Contact: a.teschendorff@ucl.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 7
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    Menopause accelerates biological aging [Social Sciences] (2016)
    National Academy of Sciences
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    Publication Date: 2016-08-17
    Description: Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 8
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    Network topology of epigenetic drift [Systems Biology] (2013)
    National Academy of Sciences
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    Publication Date: 2013-08-28
    Description: Recently, it has been demonstrated that DNA methylation, a covalent modification of DNA that can regulate gene expression, is modified as a function of age. However, the biological and clinical significance of this age-associated epigenetic drift is unclear. To shed light on the potential biological significance, we here adopt a...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    ChAMP: 450k Chip Analysis Methylation Pipeline (2014)
    Oxford University Press
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    Publication Date: 2014-01-29
    Description: The Illumina Infinium HumanMethylation450 BeadChip is a new platform for high-throughput DNA methylation analysis. Several methods for normalization and processing of these data have been published recently. Here we present an integrated analysis pipeline offering a choice of the most popular normalization methods while also introducing new methods for calling differentially methylated regions and detecting copy number aberrations. Availability and implementation: ChAMP is implemented as a Bioconductor package in R . The package and the vignette can be downloaded at bioconductor.org Contact: tiffany.morris@ucl.ac.uk
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 10
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    The lncRNA HOTAIR impacts on mesenchymal stem cells via triple helix formation (2016)
    Oxford University Press
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    Publication Date: 2016-12-17
    Description: There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage. Overexpression and knockdown of HOTAIR inhibited or stimulated adipogenic differentiation of MSCs, respectively. Modification of HOTAIR expression evoked only very moderate effects on gene expression, particularly of polycomb group target genes. Furthermore, overexpression and knockdown of HOTAIR resulted in DNAm changes at HOTAIR binding sites. Five potential triple helix forming domains were predicted within the HOTAIR sequence based on reverse Hoogsteen hydrogen bonds. Notably, the predicted triple helix target sites for these HOTAIR domains were also enriched in differentially expressed genes and close to DNAm changes upon modulation of HOTAIR . Electrophoretic mobility shift assays provided further evidence that HOTAIR domains form RNA–DNA–DNA triplexes with predicted target sites. Our results demonstrate that HOTAIR impacts on differentiation of MSCs and that it is associated with senescence-associated DNAm. Targeting of epigenetic modifiers to relevant loci in the genome may involve triple helix formation with HOTAIR .
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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