Increased methylation variation in epigenetic domains across cancer types
Kasper D. Hansen,Winston Timp,Winston Timp,Héctor Corrada Bravo,Héctor Corrada Bravo,Sarven Sabunciyan,Benjamin Langmead,Benjamin Langmead,Oliver G. McDonald,Bo Wen,Hao Wu,Yun Liu,Dinh Diep,Eirikur Briem,Kun Zhang,Rafael A. Irizarry,Rafael A. Irizarry,Andrew P. Feinberg +17 more
TLDR
Stochastic methylation variation of the same cDMRs, distinguishing cancer from normal tissue, is shown in colon, lung, breast, thyroid and Wilms' tumors, with intermediate variation in adenomas.Abstract:
Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal tissue, in colon, lung, breast, thyroid and Wilms' tumors, with intermediate variation in adenomas. Whole-genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. We suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer that may contribute to tumor heterogeneity.read more
Citations
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Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
Timothy J. Ley,Christopher A. Miller,Li Ding,Benjamin J. Raphael,Andrew J. Mungall,Gordon Robertson,Katherine A. Hoadley,Timothy J. Triche,Peter W. Laird,Jack Baty,Lucinda Fulton,Robert S. Fulton,Sharon Heath,Joelle Kalicki-Veizer,Cyriac Kandoth,Jeffery M. Klco,Daniel C. Koboldt,Krishna L. Kanchi,Shashikant Kulkarni,Tamara Lamprecht,David E. Larson,G. Lin,Charles Lu,Michael D. McLellan,Joshua F. McMichael,Jacqueline E. Payton,Heather Schmidt,David H. Spencer,Michael H. Tomasson,John W. Wallis,Lukas D. Wartman,Mark A. Watson,John S. Welch,Michael C. Wendl,Adrian Ally,Miruna Balasundaram,Inanc Birol,Yaron S.N. Butterfield,Readman Chiu,Andy Chu,Eric Chuah,Hye Jung E. Chun,Richard Corbett,Noreen Dhalla,Ranabir Guin,An He,Carrie Hirst,Martin Hirst,Robert A. Holt,Steven J.M. Jones,Aly Karsan,Darlene Lee,Haiyan I. Li,Marco A. Marra,Michael Mayo,Richard A. Moore,Karen Mungall,Jeremy Parker,Erin Pleasance,Patrick Plettner,Jacquie Schein,Dominik Stoll,Lucas Swanson,Angela Tam,Nina Thiessen,Richard Varhol,Natasja Wye,Yongjun Zhao,Stacey Gabriel,Gad Getz,Carrie Sougnez,Lihua Zou,Mark D.M. Leiserson,Fabio Vandin,Hsin-Ta Wu,Frederick Applebaum,Stephen B. Baylin,Rehan Akbani,Bradley M. Broom,Ken Chen,Thomas C. Motter,Khanh Thi-Thuy Nguyen,John N. Weinstein,Nianziang Zhang,Martin L. Ferguson,Christopher Adams,Aaron D. Black,Jay Bowen,Julie M. Gastier-Foster,Thomas Grossman,Tara M. Lichtenberg,Lisa Wise,Tanja Davidsen,John A. Demchok,Kenna R. Mills Shaw,Margi Sheth,Heidi J. Sofia,Liming Yang,James R. Downing,Greg Eley,Shelley Alonso,Brenda Ayala,Julien Baboud,Mark Backus,Sean P. Barletta,Dominique L. Berton,Anna L. Chu,Stanley Girshik,Mark A. Jensen,Ari B. Kahn,Prachi Kothiyal,Matthew C. Nicholls,Todd Pihl,David Pot,Rohini Raman,Rashmi N. Sanbhadti,Eric E. Snyder,Deepak Srinivasan,Jessica Walton,Yunhu Wan,Zhining Wang,Jean Pierre J. Issa,Michelle M. Le Beau,Martin Carroll,Hagop M. Kantarjian,Steven M. Kornblau,Moiz S. Bootwalla,Phillip H. Lai,Hui Shen,David Van Den Berg,Daniel J. Weisenberger,Daniel C. Link,Matthew J. Walter,Bradley A. Ozenberger,Elaine R. Mardis,Peter Westervelt,Timothy A. Graubert,John F. DiPersio,Richard K. Wilson +138 more
TL;DR: It is found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients and the databases from this study are widely available to serve as a foundation for further investigations of AMl pathogenesis, classification, and risk stratification.
Journal ArticleDOI
Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA Methylation microarrays
Martin J. Aryee,Andrew E. Jaffe,Hector Corrada-Bravo,Christine Ladd-Acosta,Andrew P. Feinberg,Andrew P. Feinberg,Kasper D. Hansen,Kasper D. Hansen,Rafael A. Irizarry +8 more
TL;DR: A suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data are described that include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale.
Journal ArticleDOI
A decade of exploring the cancer epigenome — biological and translational implications
Stephen B. Baylin,Peter A. Jones +1 more
TL;DR: Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism.
Journal ArticleDOI
methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles
Altuna Akalin,Matthias Kormaksson,Sheng Li,Francine E. Garrett-Bakelman,Maria E. Figueroa,Ari Melnick,Christopher E. Mason +6 more
TL;DR: An R package that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and Hydroxymethylation sequencing experiments is described, which includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNAmethylation.
Journal ArticleDOI
Epigenetic plasticity and the hallmarks of cancer
TL;DR: It is proposed that chromatin and epigenetic aberrations have the potential to confer on cells the full range of oncogenic properties represented in the classic “hallmarks” depiction of cancer, and it is suggested that genetic, environmental, and metabolic factors can make chromatin aberrantly permissive or restrictive.
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TL;DR: This review discusses patterns of DNA methylation and chromatin structure in neoplasia and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.
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