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Cancer epigenomics

Kevin Cheeseman, Gabriela Certad, Jonathan B Weitzman
Over 20 % of cancers have infectious origins, including well-known examples of microbes such as viruses (HPV, EBV) and bacteria (H. pylori). The contribution of intracellular eukaryotic parasites to cancer etiology is largely unexplored. Epidemiological and clinical reports indicate that eukaryotic protozoan, such as intracellular apicomplexan that cause diseases of medical or economic importance, can be linked to various cancers: Theileria and Cryptosporidium induce host cell transformation while Plasmodium was linked epidemiologically to the "African lymphoma belt" over fifty years ago...
October 2016: Médecine Sciences: M/S
Julio Delgado, Neus Villamor, Armando López-Guillermo, Elías Campo
Next-generation sequencing provides a comprehensive understanding of the genomic, epigenomic and transcriptomic underpinnings of chronic lymphocytic leukaemia. Recent studies have uncovered new drivers, including mutations in non-coding regions, and signalling pathways whose role in cancer was previously unknown or poorly understood. Moreover, massive scale epigenomics and transcriptomics have supplied the foundations for the cellular origin of the disease. Some drivers could be targeted pharmacologically, and the ability to detect mutations present in minority subclones might even allow treatment before clonal selection occurs, thus preventing disease refractoriness...
March 2016: Best Practice & Research. Clinical Haematology
Tsuyoshi Hamada, NaNa Keum, Reiko Nishihara, Shuji Ogino
Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality...
October 13, 2016: Journal of Gastroenterology
Stephanie Romanus, Patrick Neven, Adelheid Soubry
The Developmental Origins of Health and Disease (DOHaD) theory focuses on the consequences of periconceptional and in utero exposures. A wide range of environmental conditions during early development are now being investigated as a driving force for epigenetic disruptions that enhance disease risk in later life, including cardiovascular, metabolic, endocrine, and mental disorders and even breast cancer. Most studies involve mother-child dyads, with less focus on environmental influences through the father...
October 12, 2016: Breast Cancer Research: BCR
Meredith Eckstein, Rebekah Eleazer, Matthew Rea, Yvonne Fondufe-Mittendorf
Arsenic is a ubiquitous metalloid that is not mutagenic but is carcinogenic. The mechanism(s) by which arsenic causes cancer remain unknown. To date, several mechanisms have been proposed, including the arsenic-induced generation of reactive oxygen species (ROS). However, it is also becoming evident that inorganic arsenic (iAs) may exert its carcinogenic effects by changing the epigenome, and thereby modifying chromatin structure and dynamics. These epigenetic changes alter the accessibility of gene regulatory factors to DNA, resulting in specific changes in gene expression both at the levels of transcription initiation and gene splicing...
October 4, 2016: Reviews on Environmental Health
Yuki Kuwano, Kensei Nishida, Yoko Akaike, Ken Kurokawa, Tatsuya Nishikawa, Kiyoshi Masuda, Kazuhito Rokutan
Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that phosphorylates and activates the apoptotic program through interaction with diverse downstream targets including tumor suppressor p53. HIPK2 is activated by genotoxic stimuli and modulates cell fate following DNA damage. The DNA damage response (DDR) is triggered by DNA lesions or chromatin alterations. The DDR regulates DNA repair, cell cycle checkpoint activation, and apoptosis to restore genome integrity and cellular homeostasis...
2016: International Journal of Molecular Sciences
Mi Kyeong Lee, Yoonki Hong, Sun-Young Kim, Stephanie J London, Woo Jin Kim
BACKGROUND: Exposure to cigarette smoking can increase the risk of cancers and cardiovascular and pulmonary diseases. However, the underlying mechanisms of how smoking contributes to disease risks are not completely understood. Epigenome-wide association studies (EWASs), mostly in non-Asian populations, have been conducted to identify smoking-associated methylation alterations at individual probes. There are few data on regional methylation changes in relation to smoking. Few data link differential methylation in blood to differential gene expression in lung tissue...
2016: Clinical Epigenetics
Wen Fong Ooi, Manjie Xing, Chang Xu, Xiaosai Yao, Muhammad Khairul Ramlee, Mei Chee Lim, Fan Cao, Kevin Lim, Deepak Babu, Lai-Fong Poon, Joyce Lin Suling, Aditi Qamra, Astrid Irwanto, James Qu Zhengzhong, Tannistha Nandi, Ai Ping Lee-Lim, Yang Sun Chan, Su Ting Tay, Ming Hui Lee, James O J Davies, Wai Keong Wong, Khee Chee Soo, Weng Hoong Chan, Hock Soo Ong, Pierce Chow, Chow Yin Wong, Sun Young Rha, Jianjun Liu, Axel M Hillmer, Jim R Hughes, Steve Rozen, Bin Tean Teh, Melissa Jane Fullwood, Shang Li, Patrick Tan
Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments...
September 28, 2016: Nature Communications
Andrea Mathe, Michelle Wong-Brown, Warwick J Locke, Clare Stirzaker, Stephen G Braye, John F Forbes, Susan J Clark, Kelly A Avery-Kiejda, Rodney J Scott
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Our previous study identified 38 TNBC-specific genes with altered expression comparing tumour to normal samples. This study aimed to establish whether DNA methylation contributed to these expression changes in the same cohort as well as disease progression from primary breast tumour to lymph node metastasis associated with changes in the epigenome. We obtained DNA from 23 primary TNBC samples, 12 matched lymph node metastases, and 11 matched normal adjacent tissues and assayed for differential methylation profiles using Illumina HumanMethylation450 BeadChips...
September 27, 2016: Scientific Reports
Wen-Cai Liu, Yi-Yu Wang, Jun-Hui Liu, Ai-Bing Ke, Zhi-Hui Zheng, Xin-Hua Lu, Yu-Shi Luan, Zhi-Long Xiu, Yue-Sheng Dong
With the aim of finding more potential inhibitors against NADH-fumarate reductase (specific target for treating helminthiasis and cancer) from natural resources, Talaromyces wortmannii was treated with the epigenome regulatory agent suberoylanilide hydroxamic acid, which resulted in the isolation of four new wortmannilactones derivatives (wortmannilactones I-L, 1-4). The structures of these new compounds were elucidated based on IR, HRESIMS and NMR spectroscopic data analyses. These four new compounds showed potent inhibitory activity against NADH-fumarate reductase with the IC50 values ranging from 0...
September 14, 2016: Bioorganic & Medicinal Chemistry Letters
Luke B Hesson, Benedict Ng, Peter Zarzour, Sameer Srivastava, Chau-To Kwok, Deborah Packham, Andrea C Nunez, Dominik Beck, Regina Ryan, Ashraf Dower, Caroline E Ford, John Pimanda, Mathew A Sloane, Nicholas J Hawkins, Michael J Bourke, Jason W H Wong, Robyn L Ward
: Laterally spreading tumors (LSTs) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancer (CRCs) offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large benign colorectal lesions...
September 26, 2016: Molecular Cancer Research: MCR
Yiling Lu, Shiyun Ling, Apurva M Hegde, Lauren A Byers, Kevin Coombes, Gordon B Mills, Rehan Akbani
The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents...
August 2016: Seminars in Oncology
Vibe Nylander, Lars R Ingerslev, Emil Andersen, Odile Fabre, Christian Garde, Morten Rasmussen, Kiymet Citirikkaya, Josephine Bæk, Gitte L Christensen, Marianne Aznar, Lena Specht, David Simar, Romain Barrès
Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes later in life. We hypothesized that irradiation reprograms the epigenome of metabolic progenitor cells, which could account for impaired metabolism after cancer treatment. C57Bl/6 mice were treated with a single dose of irradiation and subjected to high fat diet (HFD). RNA Sequencing and Reduced Representation Bisulfite Sequencing were used to create transcriptomic and epigenomic profiles of preadipocytes and skeletal muscle satellite cells collected from irradiated mice...
September 20, 2016: Diabetes
Avrum Spira, Mary L Disis, John T Schiller, Eduardo Vilar, Timothy R Rebbeck, Rafael Bejar, Trey Ideker, Janine Arts, Matthew B Yurgelun, Jill P Mesirov, Anjana Rao, Judy Garber, Elizabeth M Jaffee, Scott M Lippman
Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Adam Kinnaird, Steven Zhao, Kathryn E Wellen, Evangelos D Michelakis
Alterations in the epigenome and metabolism both affect molecular rewiring in cancer cells and facilitate cancer development and progression. However, recent evidence suggests the existence of important bidirectional regulatory mechanisms between metabolic remodelling and the epigenome (specifically methylation and acetylation of histones) in cancer. Most chromatin-modifying enzymes require substrates or cofactors that are intermediates of cell metabolism. Such metabolites, and often the enzymes that produce them, can transfer into the nucleus, directly linking metabolism to nuclear transcription...
September 16, 2016: Nature Reviews. Cancer
Fade Gong, Li-Ya Chiu, Kyle M Miller
Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD)...
September 2016: PLoS Genetics
Veronika Caplakova, Eva Babusikova, Eva Blahovcova, Tomas Balharek, Maria Zelieskova, Jozef Hatok
During the normal menstrual cycle, endometrial tissue undergoes many biochemical and morphological changes which are under the control of steroid hormone levels. DNA methylation plays a key role in gene expression regulation and influences functional changes in endometrial tissue. Eliminating senescent cells from the functional layer of the endometrium is mediated by apoptotic cell death, which helps maintain cellular homeostasis. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and thus apoptosis resistance development...
September 2016: Anticancer Research
Peter A Jones, Jean-Pierre J Issa, Stephen Baylin
Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA)...
September 15, 2016: Nature Reviews. Genetics
Klev Diamanti, Husen M Umer, Marcin Kruczyk, Michał J Dąbrowski, Marco Cavalli, Claes Wadelius, Jan Komorowski
Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected ∼144k putative regulatory regions among the human cell-lines, with the majority of them being ∼300 bp...
September 12, 2016: Nucleic Acids Research
Aniruddha Chatterjee, Peter A Stockwell, Euan J Rodger, Matthew F Parry, Michael R Eccles
AIM: The Cancer Genome Atlas contains multiple levels of genomic data (mutation, gene expression, DNA methylation, copy number variation) for 33 cancer types for almost 11,000 patients. However, a dearth of appropriate software tools makes it difficult for bench scientists to use these data effectively. MATERIALS & METHODS: Here, we present a suite of flexible, fast and command line-based scripts that will allow retrieval and analysis of DNA methylation (tool: scan_tcga_methylation...
October 2016: Epigenomics
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