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Tissue of origin cancer epigenome

Qian Du, Saul A Bert, Nicola J Armstrong, C Elizabeth Caldon, Jenny Z Song, Shalima S Nair, Cathryn M Gould, Phuc-Loi Luu, Timothy Peters, Amanda Khoury, Wenjia Qu, Elena Zotenko, Clare Stirzaker, Susan J Clark
DNA replication timing is known to facilitate the establishment of the epigenome, however, the intimate connection between replication timing and changes to the genome and epigenome in cancer remain largely uncharacterised. Here, we perform Repli-Seq and integrated epigenome analyses and demonstrate that genomic regions that undergo long-range epigenetic deregulation in prostate cancer also show concordant differences in replication timing. A subset of altered replication timing domains are conserved across cancers from different tissue origins...
January 24, 2019: Nature Communications
Stefano Amatori, Giuseppe Persico, Claudio Paolicelli, Roman Hillje, Nora Sahnane, Francesco Corini, Daniela Furlan, Lucilla Luzi, Saverio Minucci, Marco Giorgio, Pier Giuseppe Pelicci, Mirco Fanelli
BACKGROUND: The introduction of pathology tissue-chromatin immunoprecipitation (PAT-ChIP), a technique allowing chromatin immunoprecipitation (ChIP) from formalin-fixed paraffin-embedded (FFPE) tissues, has extended the application of chromatin studies to clinical patient samples. However, extensive crosslinking introduced during routine tissue fixation of clinical specimens may hamper the application of PAT-ChIP to genome-wide studies (PAT-ChIP-Seq) from archived tissue samples. The reduced efficiency in chromatin extraction from over-fixed formalin archival samples is the main hurdle to overcome, especially when low abundant epigenetic marks (e...
November 16, 2018: Clinical Epigenetics
Siddhartha Kumar Miahra, Pir Mohammad Ishfaq, Swati Tripathi, Archana Shukla, Satyaprakash Beraiya
Background - At present, 'pharmaco-epigenomics' constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process and playing a role in malignancy. OBJECTIVE: Chemotherapy has many limitations like host-tissue toxicity, drug resistance. Hence, it is imperative to unearth targets to better treat cancer. Here, we intend to repurpose a set of our previously synthesized difluorinated propanediones (PR) as histone lysine methyltransferase inhibitors (HMTi). METHODS: The cell lines of leukemic origin viz...
October 2, 2018: Anti-cancer Agents in Medicinal Chemistry
Abdulrahman Salhab, Karl Nordström, Gilles Gasparoni, Kathrin Kattler, Peter Ebert, Fidel Ramirez, Laura Arrigoni, Fabian Müller, Julia K Polansky, Cristina Cadenas, Jan G Hengstler, Thomas Lengauer, Thomas Manke, Jörn Walter
BACKGROUND: Partially methylated domains are extended regions in the genome exhibiting a reduced average DNA methylation level. They cover gene-poor and transcriptionally inactive regions and tend to be heterochromatic. We present a comprehensive comparative analysis of partially methylated domains in human and mouse cells, to identify structural and functional features associated with them. RESULTS: Partially methylated domains are present in up to 75% of the genome in human and mouse cells irrespective of their tissue or cell origin...
September 28, 2018: Genome Biology
Graziela de Sá Machado Araújo, Ronaldo da Silva Francisco Junior, Cristina Dos Santos Ferreira, Pedro Thyago Mozer Rodrigues, Douglas Terra Machado, Thais Louvain de Souza, Jozimara Teixeira de Souza, Cleiton Figueiredo Osorio da Silva, Antônio Francisco Alves da Silva, Claudia Caixeta Franco Andrade, Alan Tardin da Silva, Victor Ramos, Ana Beatriz Garcia, Filipe Brum Machado, Enrique Medina-Acosta
A hallmark of imprinted genes in mammals is the occurrence of parent-of-origin-dependent asymmetry of DNA cytosine methylation (5m C) of alleles at CpG islands (CGIs) in their promoter regions. This 5m CpG asymmetry between the parental alleles creates allele-specific imprinted differentially methylated regions (iDMRs). iDMRs are often coupled to the transcriptional repression of the methylated allele and the activation of the unmethylated allele in a tissue-specific, developmental-stage-specific and/or isoform-specific fashion...
2018: Frontiers in Genetics
Lee Ad Cooper, Elizabeth G Demicco, Joel H Saltz, Reid T Powell, Arvind Rao, Alexander J Lazar
The Cancer Genome Atlas (TCGA) represents one of several international consortia dedicated to performing comprehensive genomic and epigenomic analyses of selected tumour types to advance our understanding of disease and provide an open-access resource for worldwide cancer research. Thirty-three tumour types (selected by histology or tissue of origin, to include both common and rare diseases), comprising >11 000 specimens, were subjected to DNA sequencing, copy number and methylation analysis, and transcriptomic, proteomic and histological evaluation...
April 2018: Journal of Pathology
Ayako Suzuki, Shin Kawano, Toutai Mitsuyama, Mikita Suyama, Yae Kanai, Katsuhiko Shirahige, Hiroyuki Sasaki, Katsushi Tokunaga, Katsuya Tsuchihara, Sumio Sugano, Kenta Nakai, Yutaka Suzuki
DBTSS (Database of Transcriptional Start Sites)/DBKERO (Database of Kashiwa Encyclopedia for human genome mutations in Regulatory regions and their Omics contexts) is the database originally initiated with the information of transcriptional start sites and their upstream transcriptional regulatory regions. In recent years, we updated the database to assist users to elucidate biological relevance of the human genome variations or somatic mutations in cancers which may affect the transcriptional regulation. In this update, we facilitate interpretations of disease associated genomic variation, using the Japanese population as a model case...
January 4, 2018: Nucleic Acids Research
Eric W Lin, Tatiana A Karakasheva, Dong-Jin Lee, Ju-Seog Lee, Qi Long, Adam J Bass, Kwok K Wong, Anil K Rustgi
Advances in genomics in recent years have provided key insights into defining cancer subtypes "within-a-tissue"-that is, respecting traditional anatomically driven divisions of medicine. However, there remains a dearth of data regarding molecular profiles that are shared across tissues, an understanding of which could lead to the development of highly versatile, broadly applicable therapies. Using data acquired from The Cancer Genome Atlas (TCGA), we performed a transcriptomics-centered analysis on 1494 patient samples, comparing the two major histological subtypes of solid tumors (adenocarcinomas and squamous cell carcinomas) across organs, with a focus on tissues in which both subtypes arise: esophagus, lung, and uterine cervix...
August 2017: PLoS Genetics
Sebastián Moran, Anna Martinez-Cardús, Stergios Boussios, Manel Esteller
Epigenetic alterations are a common hallmark of human cancer. Single epigenetic markers are starting to be incorporated into clinical practice; however, the translational use of these biomarkers has not been validated at the 'omics' level. The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings, addressing an unmet need in the diagnostic and clinical management of these patients. Despite the great diagnostic advances made in the past decade, the use of traditional diagnostic procedures only enables the tissue of origin to be determined in ∼30% of patients with CUP...
November 2017: Nature Reviews. Clinical Oncology
Shuli Kang, Qingjiao Li, Quan Chen, Yonggang Zhou, Stacy Park, Gina Lee, Brandon Grimes, Kostyantyn Krysan, Min Yu, Wei Wang, Frank Alber, Fengzhu Sun, Steven M Dubinett, Wenyuan Li, Xianghong Jasmine Zhou
We propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome-wide DNA methylation data. CancerLocator outperforms two established multi-class classification methods on simulations and real data, even with the low proportion of tumor-derived DNA in the cell-free DNA scenarios...
March 24, 2017: Genome Biology
Tanya Guha, David Malkin
Li-Fraumeni syndrome (LFS) is a complex hereditary cancer predisposition disorder associated with early-onset cancers in diverse tissues of origin. Germline TP53 mutations are identified in 75% of patients with classic LFS. The lifetime likelihood of a TP53 mutation carrier developing cancer approaches 75% in males and almost 100% in females. Several genetic modifiers have been implicated to account for the phenotypic variability within and across LFS families; however, efforts to develop predictive algorithms of age of onset and type of cancers in individual patients have not yet found clinical use...
April 3, 2017: Cold Spring Harbor Perspectives in Medicine
T A L Brevini, G Pennarossa, E F M Manzoni, C E Gandolfi, A Zenobi, F Gandolfi
In the presence of different environmental cues that are able to trigger specific responses, a given genotype has the ability to originate a variety of different phenotypes. This property is defined as plasticity and allows cell fate definition and tissue specialization. Fundamental epigenetic mechanisms drive these modifications in gene expression and include DNA methylation, histone modifications, chromatin remodeling, and microRNAs. Understanding these mechanisms can provide powerful tools to switch cell phenotype and implement cell therapy...
2016: Clinical Epigenetics
Dina Cramer, Luis Serrano, Martin H Schaefer
Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position, but the sources of this variability are not known. CNA number and length are linked to patient survival, suggesting clinical relevance. We have identified genes that tend to be mutated in samples that have few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers...
November 10, 2016: ELife
Paloma Cejas, Lewyn Li, Nicholas K O'Neill, Melissa Duarte, Prakash Rao, Michaela Bowden, Chensheng W Zhou, Marta Mendiola, Emilio Burgos, Jaime Feliu, Juan Moreno-Rubio, Héctor Guadalajara, Víctor Moreno, Damián García-Olmo, Joaquim Bellmunt, Stephanie Mullane, Michelle Hirsch, Christopher J Sweeney, Andrea Richardson, X Shirley Liu, Myles Brown, Ramesh A Shivdasani, Henry W Long
Extensive cross-linking introduced during routine tissue fixation of clinical pathology specimens severely hampers chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) analysis from archived tissue samples. This limits the ability to study the epigenomes of valuable, clinically annotated tissue resources. Here we describe fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq), a method that enables reliable extraction of soluble chromatin from formalin-fixed paraffin-embedded (FFPE) tissue samples for accurate detection of histone marks...
June 2016: Nature Medicine
Esterina D'Asti, Shilpa Chennakrishnaiah, Tae Hoon Lee, Janusz Rak
Brain tumors can be viewed as multicellular 'ecosystems' with increasingly recognized cellular complexity and systemic impact. While the emerging diversity of malignant disease entities affecting brain tissues is often described in reference to their signature alterations within the cellular genome and epigenome, arguably these cell-intrinsic changes can be regarded as hardwired adaptations to a variety of cell-extrinsic microenvironmental circumstances. Conversely, oncogenic events influence the microenvironment through their impact on the cellular secretome, including emission of membranous structures known as extracellular vesicles (EVs)...
April 2016: Cellular and Molecular Neurobiology
Shivani N Kamdar, Linh T Ho, Ken J Kron, Ruth Isserlin, Theodorus van der Kwast, Alexandre R Zlotta, Neil E Fleshner, Gary Bader, Bharati Bapat
BACKGROUND: Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer. RESULTS: Our cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions...
2016: Clinical Epigenetics
Silvia M Sirchia, Alice Faversani, Davide Rovina, Maria V Russo, Leda Paganini, Federica Savi, Claudia Augello, Lorenzo Rosso, Alessandro Del Gobbo, Silvia Tabano, Silvano Bosari, Monica Miozzo
BACKGROUND: Tumor epigenetic defects are of increasing relevance to clinical practice, because they are 'druggable' targets for cancer therapy using chromatin-remodeling agents (CRAs). New evidences highlight the importance of the microenvironment on the epigenome regulation and the need to use culture models able to preserve tissue morphology, to better understand the action of CRAs. Methods & methods: We studied the epigenetic response induced by culturing and CRAs in a preclinical model, preserving ex vivo the original tissue microenvironment and morphology, assessing different epigenetic signatures...
March 2016: Epigenomics
Shaun Tulley, Qiang Zhao, Huan Dong, Michael L Pearl, Wen-Tien Chen
The ability to capture, enrich, and propagate circulating cancer cells/circulating tumor cells (CTCs) for downstream analyses such as ex vivo drug-sensitivity testing of short-term cultures of CTCs, single cell sorting of CTCs by fluorescence activated cell sorting (FACS), animal injection tumor and/or metastasis formation studies, next generation sequencing (NGS), gene expression profiling, gene copy number determination, and epigenomic analyses is of high priority and of immense importance to both the basic research and translational/clinical research communities...
2016: Methods in Molecular Biology
Leonie Roos, Jenny van Dongen, Christopher G Bell, Andrea Burri, Panos Deloukas, Dorret I Boomsma, Tim D Spector, Jordana T Bell
BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip...
2016: Clinical Epigenetics
Dingming Wu, Dongfang Wang, Michael Q Zhang, Jin Gu
BACKGROUND: One major goal of large-scale cancer omics study is to identify molecular subtypes for more accurate cancer diagnoses and treatments. To deal with high-dimensional cancer multi-omics data, a promising strategy is to find an effective low-dimensional subspace of the original data and then cluster cancer samples in the reduced subspace. However, due to data-type diversity and big data volume, few methods can integrative and efficiently find the principal low-dimensional manifold of the high-dimensional cancer multi-omics data...
2015: BMC Genomics
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