Epigenetic biomarkers for assessing environmental exposures and ...
Transcript of Epigenetic biomarkers for assessing environmental exposures and ...
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COPHES/DEMOCOPHES Workshop, Copenhagen 12 March 2012
Zdenko Herceg,
Head, Section of Mechanisms of Carcinogenesis
International Agency for Research on Cancer (IARC)
Epigenetic biomarkers for assessing environmental exposures and cancer risk
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Genomes
Epigenomes Courtesy of Peter Jones
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Definitions
Epigenetics defines all heritable changes in gene
expression that are not coded in the DNA sequence
itself
Semantic debate…
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Epigenetics, interface between genome and environment
Normal cells Tumour cells
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Fundamental role of genetic and epigenetic events and environment in cancer
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Rearrangement
Epigenetic changes occur more frequently than genetic
changes Deletion
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Duplication
F r e q u e n c y
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Epigenetic carcinogens – “Epimutagens”
1. Environmental agents or toxic drugs:
- tobacco
- cadmium
- arsenic
- ionizing radiation (plutonium)
2. Diet:
- alcohol consumption - colorectal cancer
- diet
3. Infectious agents:
- EB virus in human lymphomas
- HPV genome in cervical cancer
- HBV/HCV in human hepatocellular carcinoma
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Identification of environmental factors associated with
epigenetic changes
Previous studies
• Qualitative assays
• Small sample size
• Lack of statistical power
• Tissues/cells analyzed
• False positives
• Publication bias
Ideal approach
• Quantitative and genome-wide analysis
• Large sample size
• High quality of environmental/lifestyle exposures
• Choice of tissues and cells (cell heterogeneity and averaging?)
• Reliable biomarkers of exposure
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Three types of epigenetic information
Sawan, Vaissiere and Herceg 2008
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Me
Me
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Me
G
C
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Me
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DNMT 3A/B
Maintenance of
methylation
de novo methylation
DNMT 1
Me
G
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DNA replication
DNA methylation is a universal epigenetic modification
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Tissue-specific and tumour-specific epigenetic
signatures
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DNA methylation patterns in normal human tissues
Christensen et al., PLoS Genetics 2009
Placenta Blood other solid tissues
Adult Infant
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Aberrant DNA methylation is a gradual and reversible process
DNMTi HDACi
“Normal”
Pre-neoplastic
Tumour
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CHRNα3 expression can be re-expressed by DNA
demethylating treatment
Paliwal et al. Cancer Research 2010
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Methylation within a gene region is NOT « all or none »
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Introns
Alus
LINEs
Retroelements
miRNAs
(53%)
Coding regions (3%)
Promoter regions (3%)
Chromosomes 20, 21, and 22
(127 MB bp containing 2,122 genes)
Satellites
Alus
LINEs
Retroelements
(41%)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
1 kb 1 kb
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Coding regions (3%)
Promoter regions (3%)
Courtesy of Peter Jones
Methylation of “junk” DNA
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Current developments
• new emerging concepts involving epigenetic mechanisms in
critical cellular processes and disease
• remarkable technological advances in epigenetics and
epigenomics that allow powerful screening of large series of
samples
• the availability of large case-control studies and
population-based cohorts
Recent advances that have resulted in exciting opportunities
for cancer epigenetics in understanding the causes of
cancers:
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Methodologies and approaches to study
epigenetic states in tissues and cells?
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Tumor samples
Analysis of DNA
methylation
Global 5-meC
content
Technologies for epigenetic profiling of cancer
Analysis of histone
modifications
ChIP-
on-
chip
ChIP
candidate
gene IHC
mRNAs
Genome-wide
approaches
RLGS Methyl-DNA
IP with MBDs ChIP-on-chip
DMH with
CpG-island
tiling array
CpG-island
Bead-Array
NGS
MethylC-seq
RRBS
MeDIP-seq
MBD-seq
Mass-spec
LINE-1
LUMA
Gene-specific approaches
MSP Sanger Pyro MALDI-
TOF/Sequ
enom
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Pyrosequencing assays established at IARC
Additional pyrosequencing assays for larger panel of cancer-associated genes
are being established
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DNA methylation changes in liver cancer
Lambert et al., J. Hepatol 2010
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Cell lines HCC samples N BC EC Blood
DNA methylation profiling in HCC (Illumina arrays)
Hernandez-Vargas et al., PLoS One, 2010
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66 genes were found differentially methylated in HCC tumours compared with paired surrounding tissues.
P< 0.001 FDR 0.15
Specific DNA methylation signature in liver cancer
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Parametricp-value FDR UniqueID Name Location Status Expressed Allele
0.0044384 0.0274 GFI1_P208_ 4071 1:92702908- Predicted paternal
0.0003924 0.00591 GFI1_E136_ 607 1:92702908- Predicted paternal
0.0019333 0.0157 HOXA5_E18 3470 7:27137520- Predicted maternal
0.0011385 0.0111 HOXA11_P6 1066 7:27177300- Predicted maternal
0.0002617 0.00433 GLI3_E148_ 630 7:41957071- Predicted maternal
0.002281 0.017 ASB4_P52_R 87 7:94943219- Unknown Unknown
0.0047648 0.029 ASB4_E89_F 3011 7:94943219- Unknown Unknown
0.0002987 0.00478 CPA4_P1265 377 7:129710229- Imprinted maternal
0.001986 0.016 MEST_P4_F 1390 7:129903281- Imprinted paternal
2.02E-05 0.000859 MEST_P62_ 1392 7:129903281- Imprinted paternal
0.0014373 0.0127 FASTK_P598 4874 7:150394640- Predicted maternal
0.0047203 0.0289 H19_P541_F 949 11:1962981-1985640 Imprinted maternal
0.0001402 0.00274 INS_P804_R 1203 11:2127584-2148999 Imprinted paternal
0.0011466 0.0111 ASCL2_P360 103 11:2236303-2258757 Conflicting maternal
6.60E-06 0.000394 TRPM5_P97 2155 11:2372335-2410850 Provisional paternal
0.0001076 0.00225 TRPM5_P72 2153 11:2372335-2410850 Provisional paternal
4.50E-06 0.000294 TRPM5_E87 3986 11:2372335-2410850 Provisional paternal
0.0029305 0.0198 KCNQ1_P54 1267 11:2412796-2836915 Imprinted maternal
0.0011178 0.0109 CDKN1C_P6 240 11:2851440-2873550 Imprinted maternal
0.001211 0.0115 DCN_P1320 3592 12:90053165- Unknown Unknown
0.0021316 0.0167 DIO3_P674_ 636 14:101087440- Unknown Unknown
0.0006213 0.00795 PWCR1_P81 1790 15:260567-280661 Imprinted paternal
1.00E-06 0.000107 PWCR1_E81 3846 15:260567-280661 Imprinted paternal
0.0041615 0.0261 SNRPN_seq 6124 15:1443610-1616684 Imprinted paternal
0.0027452 0.0188 SNRPN_E14 3936 15:1443610-1616684 Imprinted paternal
0.0001198 0.00244 SNRPN_P23 2029 15:1443610-1616684 Imprinted paternal
8.00E-07 1.00E-04 MKRN3_E14 3676 15:21351546- Imprinted paternal
2.00E-07 5.02E-05 MKRN3_P10 1439 15:21351546- Imprinted paternal
0.0026996 0.0187 MAGEL2_E1 3624 15:21429787- Imprinted paternal
0.0016337 0.0141 MAGEL2_P1 1339 15:21429787- Imprinted paternal
0.0013901 0.0126 NDN_P1110 1595 15:21471646- Imprinted paternal
1.00E-06 0.000107 GABRA5_P8 840 15:24732695- Conflicting paternal
1.14E-05 0.000618 GABRA5_P1 844 15:24732695- Conflicting paternal
4.00E-07 6.69E-05 GABRA5_E4 3295 15:24732695- Conflicting paternal
2.10E-06 0.000158 GABRG3_E1 3303 15:24787860- Conflicting paternal
0.0039607 0.0252 USP29_P205 2184 19:62313320- Unknown Unknown
< 1e-07 < 1e-07 USP29_E274 4004 19:62313320- Unknown Unknown
4.42E-05 0.00136 ZIM3_P451_ 2204 19:62327275- Unknown Unknown
4.00E-07 6.69E-05 ZIM3_P718_ 2205 19:62327275- Unknown Unknown
2.00E-07 5.02E-05 ZIM3_E203_ 4010 19:62327275- Unknown Unknown
0.0023747 0.0175 NNAT_P544 1634 20:35573020- Imprinted paternal
0.0021678 0.0167 GNAS_E58_ 3330 20:56838189- Imprinted maternal
0.0017671 0.0148 GNAS_P86_ 915 20:56838189- Imprinted maternal15 11 7
chr7
chr11
chr15
Identification of genes and pathways that are differentially methylated in HCC
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DNA methylation and tumor stage
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Predictive value of DNA methylation signature
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Epigenetic changes as signatures of environmental
exposures to risk factors
- In tumour cells
- In non-tumour (target or surrogate) tissues
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Distinct DNA Methylation Profiles In HCC Of Different Etiologies
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Epigenetic signatures in peripheral blood predicts ovarian cancer
Teschendorff et al., 2009 PLoS One
Cancer and age appear to elicit a common methylation changes in
blood cells that may reflect changes in the cellular composition
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Schembri et al. 2009 PNAS
Smoking-dependent changes in microRNA expression profiles in normal lung epithelium
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All three diet groups pooled together (at T0 and T4)
Randomized trial with flavonoid rich diet
Scoccianti et al., 2011in press
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Alterations in DNA methylation status during development
Skinner & Jirtle Nature Rev/Genet. 2007
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Birth Gametes Childhood Adulthood
Epigenome reprogramming Cancer Leukemia
Parental exposures Maternal diet/lifestyle C
on
cep
tio
n
In utero life
Epigenetic profiling Cancer risk Exposure markers
Impact of early life exposure on epigenome and cancer risk in childhood and adulthood
Windows of susceptibility
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Pregnant women Pregnant women
Dry season (high aflatoxin)
Wet season (low aflatoxin)
Aflatoxin-albumin biomarker analysis in maternal plasma
Newborn babies Newborn babies
Infant blood samples taken at birth
DNA methylation profiling (Illumina 450K Arrays)
Bioinformatics analysis
Technical validation
Identification of epigenetic biomarkers of aflatoxin exposures
and dietary deprivation
Identification of epigenetic biomarkers of growth impairment
and dietary interventions
Validation of top hits in an independent cohort
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HumanMethylation450K arrays provide coverage throughout gene regions
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Every requested content category is included on the array
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Comprehensive gene coverage
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450K arrays (Illumina)
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Bioinformatic analysis
Normalization
Probes filtering
Unsupervised clustering
Clustering Class comparison Class prediction
Survival prediction Gene ontology
HCC T vs S tumor stages risk factors
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High aflatoxin
Differentially methylated CpG sites between high vs low aflatoxin
Low aflatoxin
low
me
thyla
tio
n h
igh
me
thyla
tio
n
Distribution of all CpG sites
Distribution of differentially
methylated CpG sites
Hernandez-Vargas and Herceg, unpublished results
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116
20
15
31
Absolute number of differentially methylated CpG sites in CpG
islands, shores, shelves and open sea between high vs low
aflatoxin
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Differentially methylated genes between aflatoxin exposure
groups
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Toward DNA Methylomes at single base
resolution
Quantitative and genome-wide analysis of DNA methylation
1) MethC-seq - Arabidopsis DNA methylome at base resolution - Genomic
DNA is treated with sodium bisulphite subjected to Illumina Genetic
Analyser (GA) - (Lister et al., Cell 2008)
2) BS-seq - Arabidopsis DNA methylome at base resolution - Genomic DNA
is treated with sodium bisulphite subjected to Illumina Genetic Analyser
and Solexa technology for Shotgun sequencing (Cokus et al., Cell 2008)
3) MethC-seq - Human DNA methylome at base resolution - Genomic DNA
from human ES and fibroblasts is treated with sodium bisulphite subjected
to Illumina GA - 94% of all cytosines covered (Lister et al., Nature 2009)
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Lister et al. Nature 2009
Human DNA methylome at base resolution show
widespread epigenomic differences
Embryo Fibroblasts
ES cells
One-quarter of cytosine methylation in ES cells occurs in non-CG context and non-CG methylation is restored in iPS cells
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ChIP-seq of Trrap and Oct4 binding in ES cells and MEFs
Sawan and Herceg, 2012, manuscript in revision
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Genome-wide redistribution of Trrap and Oct4 following cell
differentiation
Sawan and Herceg, 2012, manuscript in revision
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Summary and perspectives
- The fields of epigenetics has become “mainstream” and a
new branch (Environmental Epigenetics) is now emerging
- Epigenome is profoundly altered in cancer cells (driver vs
functionally inert « passenger » changes)
- Epigenetic changes in tumours and surrogate tissues as
biomarkers of environmental exposures and cancer risk
- Mechanisms by which environmental factors influence the
epigenome
- Effects of in utero and early life conditions on epigenetic
states and disease risk in childhood and adulthood
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Epigenetics Group (IARC)
Cyrille Cuenin
Hector Hernandez
Marie-Pierre Lambert
Rabih Murr (now at FMI, Basel)
Maria Ouzounova
Anupam Paliwal
Carla Sawan
Thomas Vaissière (now at Scripps)
Sheila Lima
Joanna Loizou (now at CR UK)
Vivek Shukla (now at MD Anderson)
Pushpinder Kaur
Karen Balassiano
Anastas Gospodinov
Marion Martin
Gabriel Ichim
Ho-Sun Lee
Pierre-Benoit Ancey
Acknowledgments
Joanna Rabih Vivek
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Epigenetics Group
Karen Balassiano
Marie-Pierre Cros
Cyrille Cuenin
Marion Essig
Hector Hernandez
Anastas Gospodinov
Gabriel Ichim
Marie-Pierre Lambert
Pushpinder Kaur
Vladimir Krutovskikh
Maria Ouzounova
Anupam Paliwal
Carla Sawan
Thomas Vaissière
Cat Int Oncol Barcelona
Carlos González
FLI-Jena, Germany
Zhao-Qi Wang
CRC Cambridge, UK
Steve Jackson
INSERM, Lyon
Jean-Yves Scoazec
Isabelle Chemin
Christian Trepo
Fabien Zoulim
LIGHT, Leeds
Yun Yun Gong
INCA, Rio de Janeiro
Luis Felipe Ribeiro Pinto
External Collaborators
Acknowledgments IARC
IGBMC, Strasbourg
Laszlo Tora
IEO, Milan
Bruno Amati
CNG, Paris
Jorg Tost
Univ. Ottawa
Chantal Matar
ICL London
Paolo Vineis
ISREC, Lausanne
Andreas Trumpp
Ohio State Univ.
Carlo Croce
IARC collaborators
Pierre Hainaut
Paul Brennan
Florence Le Calvez
James McKay
Bakary Sylla
Massimo Tommasino
Mazda Janeb
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Research supported by:
European Network of Excellence
(ECNIS)
La Ligue National Contre le Cancer,
France
Institut National du Cancer
(Cancéropôle “EpiPro - Epigenetic
Network”)
European Molecular Biology
Organisation (EMBO)
Association for International Cancer
Research (AICR), UK
NIH - National Cancer Institute, USA
Swiss Bridge Award 2006
Association pou la Recheche sur le
Cancer (ARC)
International Agency for Research on Cancer (IARC)
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Education and Training at IARC
Postdoctoral fellowships to junior scientists from …
Visiting Scientist Award is also offered for a qualified and experienced investigator …
Expertise Transfer Fellowship to enable an established investigator to spend from six…
http://www.iarc.fr/en/education-training/index.php
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La passerelle Saint-Vincent, Lyon
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Cell fate switching in epigenetic landscape
Waddington, 1956
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Epigenetic gene regulation during mammalian development
Reik, Nature 2007
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Aberrant DNA methylation and cancer
Promoter-specific hypermethylation
- inactivation of tumour suppressors and other
cancer associated genes
Global hypomethylation
- activation of cellular proto-oncogenes
- genomic instability
Loss of imprinting (LOI)
- abnormal biallelic expression of critical cellular
and developmental regulators
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DNA methylation profiles in ESCCs
Lima et al., 2011
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“Healthy” smokers were recruited and randomly assigned to
3 groups:
1.normal isocaloric diet (adequate administration of fruit and
vegetables)
2. flavonoid rich diet (cruciferous vegetables: cauliflower,
cabbage, broccoli…)
3. flavonoid supplementation diet (green tea and soy
products)
Randomized trial with flavonoid rich diet
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Experimental strategy for identification of
molecular changes associated with HCC
RNA signatures
DNA methylation
profiling (Illumina
arrays and NGS)
microRNA, lncRNA, RNA expression
analysis
Identification of
candidate genes
Mechanistic
studies
Human liver
samples
Validation of
biomarkers
Isolation of DNA Isolation of non-coding RNAs
DNA sequencing
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DNA methylation states in tumour vs surrounding tissues (liver cancer)
1257 genes were found significantly differentially expressed between Tumour and Surrounding tissues from HBV positive patients with HCC.
Tumour Surrounding
Hernandez and Herceg, in preparation Illumina arrays
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DNA methylation changes in HCC (Illumina arrays)
Hernandez-Vargas et al. 2010 PLoS ONE
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DNA methylation profiles in HCCs vs ESCCs
Liver cancer (HCC) Oesophageal squamous cell carcinoma
Hernandez Vargas et al., PLoS One 2010 Lima et al., 2011 submitted
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Correlation analysis
Specific DNA methylation signature in HCC
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INSERT OUR JIA’s Study (Faseb J) Epigenetic signatures in
peripheral blood predicts ovarian cancer
Teschendorff et al., 2009 PLoS One
Cancer and age appear to elicit a common methylation changes in
blood cells that may reflect changes in the cellular composition
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Birth Childhood Adulthood
Epigenetic reprogramming Disease Impaired growth
In utero life Windows of susceptibility
Altered epigenetic states at birth
Biomarkers for disease risk
and dietary interventions
Epigenetic biomarkers of exposure
Environmental factors Aflatoxin exposure Dietary deprivation
Frequent infections Impaired mental development
Higher mortality rate