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Cancer AND epigenom

Tetsushi Sakuma, Takashi Yamamoto
Genome editing includes various edits of the genome, such as short insertions and deletions, substitutions, and chromosomal rearrangements including inversions, duplications, and translocations. These varieties are based on single or multiple DNA double strand break (DSB)-triggered in cellulo repair machineries. In addition to these "conventional" genome editing strategies, tools enabling customized, site-specific recognition of particular nucleic acid sequences have been coming into wider use, e...
October 13, 2018: Cancer Science
Ya Wang, Min Qian, Peifeng Ruan, Andrew E Teschendorff, Shuang Wang
Identifying epigenetic field defects, notably early DNA methylation alterations, is important for early cancer detection. Research has suggested these early methylation alterations are infrequent across samples and identifiable as outlier samples. Here we developed a weighted epigenetic distance-based method characterizing (dis)similarity in methylation measures at multiple CpGs in a gene or a genetic region between pairwise samples, with weights to up-weight signal CpGs and down-weight noise CpGs. Using distance-based approaches, weak signals that might be filtered out in a CpG site-level analysis could be accumulated and therefore boost the overall study power...
October 10, 2018: Nucleic Acids Research
Da Hye Moon, Sung Ok Kwon, Woo Jin Kim, Yoonki Hong
BACKGROUND: The development of lung cancer results from the interaction between genetic mutations and dynamic epigenetic alterations, although the exact mechanisms are not completely understood. Changes in DNA methylation may be a promising biomarker for early detection and prognosis of lung cancer. We evaluated the serial changes in genome-wide DNA methylation patterns in blood samples of lung cancer patients. METHODS: Blood samples were obtained for three consecutive years from three patients (2 years before, 1 year before, and after lung cancer detection) and from three control subjects (without lung cancer)...
September 28, 2018: Tuberculosis and Respiratory Diseases
Natalia Martinez-Soria, Lynsey McKenzie, Julia Draper, Anetta Ptasinska, Hasan Issa, Sandeep Potluri, Helen J Blair, Anna Pickin, Asmida Isa, Paulynn Suyin Chin, Ricky Tirtakusuma, Daniel Coleman, Sirintra Nakjang, Salam Assi, Victoria Forster, Mojgan Reza, Ed Law, Philip Berry, Dorothee Mueller, Alex Elder, Simon N Bomken, Deepali Pal, James M Allan, Gareth J Veal, Peter N Cockerill, Christian Wichmann, Josef Vormoor, Georges Lacaud, Constanze Bonifer, Olaf Heidenreich
Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts...
October 8, 2018: Cancer Cell
Neil Coleman, Subhajyoti De
Mutation signatures - the patterns of acquired genetic changes in somatic genomes - provide critical insights into DNA repair defects and exposure to mutagenic processes during development, aging, and cancer progression. Efforts to decipher the etiology of the emerging computationally predicted mutation signatures in cancer genomes are currently underway. Since chromatin and epigenomic contexts influence DNA damage and repair pathway choices, taking both epigenomic and sequence contexts of the mutations into consideration is likely to benefit interpretation of mutation signatures...
October 2018: Trends in Cancer
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
Md Mohaiminul Islam, Ye Tian, Yan Cheng, Yang Wang, Pingzhao Hu
Background: Epigenetic modification has an effect on gene expression under the environmental alteration, but it does not change corresponding genome sequence. DNA methylation (DNAm) is one of the important epigenetic mechanisms. DNAm variations could be used as epigenetic markers to predict and account for the change of many human phenotypic traits, such as cancer, diabetes, and high blood pressure. In this study, we built deep neural network (DNN) regression models to account for interindividual variation in triglyceride concentrations measured at different visits of peripheral blood samples using epigenome-wide DNAm profiles...
2018: BMC Proceedings
Paramita Basu, Camelia Maier
Breast cancer is one of the leading causes of cancer-related morbidity and mortality among women worldwide. Phytoestrogens, plant-derived polyphenols that structurally and functionally mimic 17β-estradiol, the mammalian estrogen hormone, are known to modulate multiple molecular targets in breast cancer cells. The structural and chemical similarities to estradiol enable phytoestrogens to exert estrogenic or antiestrogenic activities by binding to the estrogen receptors. Although phytoestrogens have low affinity for estrogen receptors, they are able to compete with 17β-estradiol for the ligand-binding domain of the receptors...
November 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Rahul Kumar, Anthony P Y Liu, Brent A Orr, Paul A Northcott, Giles W Robinson
Despite significant improvements in pediatric brain tumor therapy and outcome, too many children still die of disease, and too many survivors experience significant sequelae as a result of conventional therapies. The molecular characterization of pediatric brain tumors has afforded tremendous insight into the basic biology and clinical management of these deadly childhood diseases. Genomic, epigenomic, and transcriptional profiling have facilitated the identification of significant heterogeneity among previously uniform disease entities...
September 26, 2018: Cancer
Runmin Wei, Yanyan Wu
BACKGROUND: Identification of interactions between epigenetic factors and treatments might lead to personalized intervention of diseases. This paper aims to examine the modification effect of fenofibrate therapy on the association of methylation levels and fasting blood triglycerides (TG), and the related biological pathways among methylation sites. RESULTS: Mixed-effects models were employed to assess pre- and posttreatment associations and drug modification effects simultaneously...
September 17, 2018: BMC Genetics
Kimberly C Olney, David B Nyer, Daniel A Vargas, Melissa A Wilson Sayres, Karmella A Haynes
BACKGROUND: Mounting evidence from genome-wide studies of cancer shows that chromatin-mediated epigenetic silencing at large cohorts of genes is strongly linked to a poor prognosis. This mechanism is thought to prevent cell differentiation and enable evasion of the immune system. Drugging the cancer epigenome with small molecule inhibitors to release silenced genes from the repressed state has emerged as a powerful approach for cancer research and drug development. Targets of these inhibitors include chromatin-modifying enzymes that can acquire drug-resistant mutations...
September 25, 2018: BMC Systems Biology
Masato Nakamura, Tetsuhiro Chiba, Kengo Kanayama, Hiroaki Kanzaki, Tomoko Saito, Yuko Kusakabe, Naoya Kato
Due to the advances made in research based on next generation sequencers, it is now possible to detect and analyze epigenetic abnormalities associated with cancer. DNA methylation, various histone modifications, chromatin remodeling, and non-coding RNA associated gene silencing are considered to be transcriptional regulatory mechanisms associated with gene expression changes. The breakdown of this precise regulatory system is involved in the transition to cancer. The important role of epigenetic regulation can be observed from the high rate of genetic mutations and abnormal gene expression leading to a breakdown in epigenetic gene expression regulation seen in hepatocellular carcinoma (HCC)...
September 20, 2018: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Tyler Risom, Ellen M Langer, Margaret P Chapman, Juha Rantala, Andrew J Fields, Christopher Boniface, Mariano J Alvarez, Nicholas D Kendsersky, Carl R Pelz, Katherine Johnson-Camacho, Lacey E Dobrolecki, Koei Chin, Anil J Aswani, Nicholas J Wang, Andrea Califano, Michael T Lewis, Claire J Tomlin, Paul T Spellman, Andrew Adey, Joe W Gray, Rosalie C Sears
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture...
September 19, 2018: Nature Communications
Bryan A Smith, Nikolas G Balanis, Avinash Nanjundiah, Katherine M Sheu, Brandon L Tsai, Qingfu Zhang, Jung Wook Park, Michael Thompson, Jiaoti Huang, Owen N Witte, Thomas G Graeber
Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers...
September 18, 2018: Cell Reports
Rodrigo Dienstmann, Ramon Salazar, Josep Tabernero
Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade...
May 23, 2018: American Society of Clinical Oncology Educational Book
Qing Zhou, Shuhua Xi
Long-term exposure to arsenic (inorganic arsenic) is a world-wide environmental health concern. Arsenic is classified as the Group 1 human carcinogen by the International Agency for Research on Cancer (IARC). Epidemiological studies have established a strong association between inorganic arsenic (iAs) exposure in drinking water and an increased incidence of cancer including bladder, liver, lung, prostate, and skin cancer. iAs also increases the risk of other diseases such as cardiovascular disease, hypertension and diabetes...
September 15, 2018: Regulatory Toxicology and Pharmacology: RTP
Bhavna Hurgobin, Emma de Jong, Anthony Bosco
Respiratory diseases such as asthma, chronic obstructive pulmonary disease and lung cancer represent a critical area for medical research as millions of people are affected globally. The development of new strategies for treatment and/or prevention, and the identification of biomarkers for patient stratification and early detection of disease inception are essential to reducing the impact of lung diseases. The successful translation of research into clinical practice requires a detailed understanding of the underlying biology...
September 14, 2018: Respirology: Official Journal of the Asian Pacific Society of Respirology
Austin Yeon, Sungyong You, Minhyung Kim, Amit Gupta, Myung Hee Park, Daniel J Weisenberger, Gangning Liang, Jayoung Kim
Alterations in DNA methylation are important epigenetic markers in bladder cancer (BC). These epigenome modifications may drive the mechanisms of aggressive chemo-resistant BC. Clinicopathological biomarkers that indicate chemotherapeutic resistance are critical for better assessing treatment strategies for individual patients. Thus, in this study, we aimed to determine whether DNA methylation of certain metabolic enzymes is significantly altered in cisplatin-resistant BC cells. Methods: To characterize CpG methylation and nucleosome accessibility in cisplatin-resistant BC cells, the Illumina Infinium HM450 DNA methylation assay was performed...
2018: Theranostics
Chenchen Yang, Theresa Ryan Stueve, Chunli Yan, Suhn K Rhie, Daniel J Mullen, Jiao Luo, Beiyun Zhou, Zea Borok, Crystal N Marconett, Ite A Offringa
AIM: To identify functional lung adenocarcinoma (LUAD) risk SNPs. MATERIALS & METHODS: Eighteen validated LUAD risk SNPs (p ≤ 5 × 10-8 ) and 930 SNPs in high linkage disequilibrium (r2  > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression...
September 2018: Epigenomics
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