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Epigenetics and Oncogenesis

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Jeffrey Tomaszewski

on 3 September 2013

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Transcript of Epigenetics and Oncogenesis

Regulation of Gene Expression
Objectives
Differentiation is Associated with Global Changes in Chromatin Structure
Jeffrey J. Tomaszewski, M.D.
Central Dogma Of Molecular Biology
Chromatin Structure
Define epigenetics
Epigenetics in development
Demonstrate examples of random variation in cell fate determination
Epigenetics in canalization / fate determination
Epigenetics in oncogenesis
Clinical applications
Histone Modifications are Unique to
Specific Gene Regulatory Elements
Zhou M, et al.; Nat Rev Genet 2011
Zhu J., et al.; Cell 2013
Genome Wide Prevalence of Histone Modifications Varies Among Tissues
Summary: Epigenetics
Chromatin structure and DNA specific modifications (ie methylation) provide a global mechanism of gene regulation
Mellen et al 2012
Phenotypic Variation Among Honeybees
Spannhoff A, et al.; EMBO Rep, 2011
Early Fate Determination in Honeybees is Controlled by Epigenetic Mechansims
Gartnar K, et al.
Int J Epidemiol, 2012
Phenotypic Variability Despite Genetic Similarity in Mice and Cattle
Whitelaw NC, et al.; Genome Biol 2010
Mutations in Dnmt3a Result in Increased Phenotypic Variation in Mice
Developmental Buffering / Canalization
Developmental Buffering / Canalization
Summary: The Role of Epigenetics in Development
Random variability occurs in normal development and differentiation
Epigenetic modifications are one mechanism of containing this innate variability
16,400 sites which were differentially methylated among 5 tissue types
Irizarry RA, et al.;
Nat Genet, 2009
Genome Wide Analysis Reveals Tissue Specific Methylation Patterns
Genome Wide Analysis also Reveals Cancer Specific Methylation Patterns
2700 regions differentially methylated between colon cancer and normal colonic mucosa
Colon Cancer Tissue has Greater Variability in Methylation Patterns
Hansen KD, et al.; Nat Genet 2011
Increased Variability and Heterogeneity in Methylation is Found in Multiple Types of Cancer
Kreso A, et al., Science 2013
Phenotypic Diversity Despite Genetic Similarity in Tumor Cells
Clones Vary in their Response to Treatment with Oxaliplatin
Epigenetic Changes are Associated with Resistance to Chemotherapy
Summary: The Role of Epigenetics in Oncogenesis
Shaikhibrahim Z, et al.; Int J Mol Med 2013
Altered Expression of Epigenetic Factors in Prostate Cancer
Lauss M, et al.; Epigenetics 2012
Epigenetic Subtypes of Urothelial Carcinoma Correlate with Pathologic Stage and Disease Specific Survival
Early Embryo Development
Zhu J., et al.; Cell 2013
Layers of Chromatin Organization in the Mammalian Cell Nucleus
Global chromatin structure and histone modifications vary among differentiated tissues
Gene regulatory elements which interact with tissue specific histone modifications are beginning to be identified
What role does epigenetics play in oncogenesis?
Do epigentic mechanisms also help to contain abnormal phenotypes due to acquired mutations in terminally differentiated tissues?
Spannhoff A, et al.; EMBO Rep, 2011
Wernet MF, et al.; Nature, 2006
Stochastic Gene Expession Controls Cell Fate in the Drosophila Eye
Kreso A, et al., Science 2013
Cells which have undergone oncogenic changes have increased variability in DNA methylation and epigenetic markers
Epigenetic variability is translated into phenotypic variability, leading to variable responses to chemotherapy and growth patterns
Epigenetics: Bridging the Link Between Developmental Plasticity and Oncogenesis
Conclusions
Epigenetic Regulation Can Control miRNA Expression
Clinical Trials of HDACi in Urological Malignancies
Mutant Chromatin-modulating Tumor Suppressors are Associated with Worse Survival in ccRCC
Hakimi A, et al.; Eur Urol May 2013
Current Phase II Trials of Epigenetic Therapy for Urologic Malignancies
Aberrations of the Epigenetic-MicroRNA Network in Urological Tumors
Liep J, et al.; Epigenetics 2012
LOCKS-Large Organized Chromatin Lysine Modifications
Haldrup C, et al.; J Clin Oncol, 2013
DNA Methylation Markers Predict Time to BCR Following Prostatectomy
Sharma SV, et al. Cell 2010.
Mutational Screening in RCC and
Histone Methylation
VHL tumor suppressor gene (Hereditary RCC)
Mutated in most cases of ccRCC
Chromosome 3p
Stabilization of HIF-1/2 alpha
Screen of 3544 protein-coding genes
(101 cases ccRCC)
4 of 5 frequently mutated genes responsible for histone methylation/demethylation
Mutated in > 10% of sporadic ccRCC
PBRM1-chromatin remodeling (~50%)
BAP1-deubiquitination (~15%)
Varela I, et al. Nature, 2012.
Tumors <4cm
10-fold incr upstaging to pT3
Hirata H, et al. PLOS One, 2013
Prostate Cancer Clinical Trials Utilizing Epigenetic Approaches
Inhibition of in vivo Tumor Growth by miR-182-5p Knockdown in PC3 Cells
Coherent variations in the chromatin landscape distinguish cells from different developmental stages, lineages, and growth environments
Full transcript