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International Agency for Research on Cancer Lyon, France
The exposome: a new concept to support research on causes and prevention
Dr Christopher P Wild PhD
Director
0 1 2 3 4 5 6 7 8 9 10 11
Low HDI
Medium HDI
High HDI
Very high HDI
2008 2030
Assuming no change in underlying incidence
Global cancer burden - marked increases
million
new cases
% Increase 2008-2030
Bray F et al. Global cancer transitions according to the Human Development
Index (2008-2030): a population based study. Lancet Oncol 2012; 13:790-801
“We cannot treat our way out of the cancer problem”
A balanced and integrated approach to prevention and treatment is required
Franceschi F and Wild CP (2013)
Molec. Oncol. 7: 1-13
Major cancer risk factors
Risk Factor Comments
Tobacco including environmental tobacco smoke
Alcohol
Physical inactivity, overweight and obesity
Unhealthy diet Relatively limited understanding on how specific nutrients or dietary patterns affect cancer risk
Infections
HBV, HPV, H. pylori, HCV; vaccination; avoid contaminated
injections
Radiation UV light; ionising radiation; medical diagnostic, indoor radon
Environmental carcinogens Naturally occurring (arsenic, aflatoxins); air pollution
Occupation Risks of “exporting” at-risk occupational exposures
Reproductive factors and hormones
Allied to earlier age at menarche, later age at first live birth; fewer children; shorter duration of breast feeding
Adapted from Franceschi and Wild, Molec. Oncol., 7: 1-13, 2013
IARC Monographs Volume 100
Primary cancer prevention
• “One third of cancers are preventable – the most cost-effective response” (Action against Cancer: European Partnership)
• Higher estimates from Doll and Peto (1981) for USA; Parkin (2012) for UK
• But the majority (~90%) of cancers have an environmental or lifestyle cause, so the potential for prevention is much higher; “aetiology gap”
Cancers where aetiology is (largely) unknown
Organ sites Estimated annual no. new cases worldwide
Percent global cancer burden
Prostate 1,100,000 7.9
Lymphoma and Leukemia
850,000 6.0
Kidney 340,000 2.4
Pancreas 340,000 2.4
Thyroid 300,000 2.1
Brain 260,000 1.8
Colorectal 1,400,000 9.7
Basic Science
Population Patient Causes and Prevention
Personalized treatment
Two-way Translational Cancer Research
Specific molecular alterations
Risk factors Prognosis
Laboratory Methodologies genomics, transcriptomics, epigenomics, proteomics, metabolomics
Wild CP (2012) Int. J. Epidemiol, 41: 24-32
Wild CP et al., (2013) Env. Molec. Mutagen.54: 480-499
Laboratory science in population studies – five areas of promise
Improved exposure assessment
Contributing to biological plausibility
Stratifying risks by tumour sub-group
Evaluating interventions
Hazard and risk assessment
Importance of environmental exposure assessment
• Most common chronic diseases have an
environmental or lifestyle aetiology
• Currently exposure measurement is problematic
in many areas, leading to misclassification
• Large prospective cohort studies (e.g. UK
Biobank) are predicated on the availability of
accurate exposure assessment
Complementing the genome with an “exposome”
• Wild CP (2005) Cancer Epidemiology,
Biomarkers and Prevention, 14: 1847-1850.
• Wild CP (2009) Mutagenesis 24: 117-125.
• Wild CP (2012) Int. J. Epidemiol, 41: 24-32
Uca Pugnax, the male Fiddler Crab
All exposures throughout the lifetime of an individual from conception to death
Domains of the exposome
metabolism, endogenous
hormones, body
morphology, physical
activity, gut micro flora,
inflammation, aging etc.
Internal radiation, infectious
agents, chemical
contaminants and
pollutants, diet, lifestyle
factors (e.g. tobacco,
alcohol), occupation,
medical interventions,
etc.
Specific external
social capital, education,
financial status, psychological
stress, urban-rural
environment, climate, etc
General external
Wild CP (2012) Int. J. Epidemiol, 41: 24-32
Mechanism-based exposure biomarkers
• First generation: • a focus on a classical mutagen – carcinogen model
• examples are chemical metabolites, DNA and protein adducts, chromosomal alterations, somatic mutations
• Second generation: • global alterations in mRNA, protein or metabolite
levels using omics technologies
• epigenetic changes (promoter methylation, histone acetylation, microRNA)
• pathway-specific omics approaches e.g. lipidomics
Exposure – clues from transcriptomics
• 127 individuals (47 non-smokers, 58 “healthy” smokers, 22 smokers with COPD)
• Small airway epithelial cells collected by fiberoptic bronchoscopy with subsequent microarray analysis
• Generated a gene expression “index” for each individual using 375 smoking-responsive genes, which distinguished smokers and non-smokers but also “high” and “low” response among smokers
Tilley et al., PLoS ONE 6: July 2011
Gene expression in small airway epithelium of smokers and non-smokers
A
A: Probe sets comparing smokers and nonsmokers:
Top right: higher expression in smokers; Top left:
lower expression in smokers
B: Up-regulated in smokers >1; down-regulated in
smokers <1 compared to nonsmokers
C: Expressed above average in red, below in blue;
each row is one of 375 smoking-responsive genes
Tilley et al., PLoS ONE 6: July 2011
Exposure – clues from transcriptomics
Exposure Tissue References
Acrylamide, dioxin Cord blood Hochstenbach et al., 2012
Arsenic PBL, cord blood Argos et al., 2006; Fry et al., 2007
Benzene PMBC Forrest et al., 2005; McHale et al., 2009; 2011
Dioxin PBMC McHale et al., 2007
Metal fumes Whole blood Wang et al., 2005
Diesel exhaust PBMC Peretz et al., 2007
Tobacco smoke PMBC; airway epithelial cells
Lampe et al., 2004; van Leeuwen et al., 2007; Tilley et al., 2011; Wright et al., 2012; Hackett et al., 2012
Wild CP et al., (2013) Env. Molec. Mutagen.54: 480-499
Exposure – clues from methylomics
Hernandez Vargas et al., PLoS One 2010
Methylation of specific
gene promoter regions by:
Tumour grade
Risk factor
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ny
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87
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3-H
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34
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53
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14
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51
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45
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20
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52
)
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74
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69
1)
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c_
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12
)
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01
2)
L-g
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61
)
Na
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2)/
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62
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77
)
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ac
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14
)
3-H
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zo
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66
5)
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hin
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53
)
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44
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e_
(57
22
)
Hy
dro
xy
pro
lin
e_
(15
7)
ho
mo
va
nil
lic
_a
cid
_s
ulf
ate
_(8
83
)
ge
nti
sic
_a
cid
_s
ulf
ate
_(4
33
5)
(+)-
Ca
tec
hin
_(6
07
2)
Dih
yd
rox
yb
en
zo
ic a
cid
_(7
10
3)
ga
llic
_a
cid
_(8
16
4)
Ph
en
ac
ety
lgly
cin
e_
(51
0)
Va
nil
loy
lgly
cin
e_
(77
95
)
Chocolate..candy.bars..paste..confetti_FFQ
Chocolate..candy.bars..paste..confetti_24DR
Tea_FFQ
Tea_24DR
Apple.and.pear_FFQ
Apple.and.pear_24DR
Citrus.fruits_FFQ
Citrus.fruits_24DR
Red.wine_FFQ
Red.wine_24DR
Coffee_FFQ
Coffee_24DR
Exposure - clues from metabolomics
Urinary polyphenols in
high and low consumers
within the EPIC study
Edmands W, Scalbert A
IARC, unpublished
Exposure – clues from genomics
Stransky et al., Science 333: 1157-1160, 2011
74 matched head and neck tumour and normal tissue; exome seq.
Exposure Disease
Temporal application of exposure biomarkers in cancer epidemiology
Adult cohort Case-control
study
Timing of
exposure
measurement
Carcinogen metabolites
DNA/protein adducts
Cytogenetic alterations
Mutation spectra
Antibodies
Peri-natal
Childhood
Adolescence Adult
Birth cohort
Activation of inflammation/NF-κB signalling in infants born to arsenic-exposed mothers
• 32 pregnant women in Thailand in high and low areas of arsenic exposure
• Toenail analysis of arsenic; cord blood for microarray gene expression
• Expression signatures highly predictive of prenatal arsenic exposure; genes related to stress, inflammation, metal exposure and apoptosis
Fry et al., PLoS Genetics, 3: 2180-2189, 2007
Laboratory science in population studies – what is promised?
Improved exposure assessment
Contributing to biological plausibility
Stratifying risks by tumour sub-group
Evaluating interventions
Hazard and risk assessment
©2012 by American Association for Cancer Research
Kinetics of N2-ethylidene-DNA adducts in the oral cavity after drinking alcohol
• Subjects consumed
approx. 27 (d1), 39
(d2) or 51 (d3) g
ethanol; provided oral
mouthwash for DNA
extraction
• Dose response with
peak adduct after 4
hours; up to 100-fold
above baseline
• Considerable inter-
individual variation
Balbo S et al. Cancer Epidemiol Biomarkers Prev 2012; 21:601-608
Volatile organic carcinogens and home cooking among Chinese women non-smokers
• Lung cancer in non-smoking Chinese women has been associated with Chinese-style wok cooking
• Urinary biomarkers were compared in women who engaged in regular home cooking and those who did not
0
500
1000
1500
2000
Daily cooks Controls
Acrolein Crotonaldehyde
Benzene 1,3-butadiene
Biomarkers of mercapturic acid metabolites
pmol/mg creatinine but x103 for benzene and
x10 for 1,3-butadiene
Hecht et al., CEBP, 19: 1185-1192, 2010
Laboratory science in population studies – what is promised?
Improved exposure assessment
Contributing to biological plausibility
Stratifying risks by tumour sub-group
Evaluating interventions
Hazard and risk assessment
Genomic and transcriptomic architecture of breast tumours
• Analysis of acquired somatic copy number aberrations and gene expression in 2,000 tumours
• Identified novel molecular sub-groups of breast cancers with distinct clinical outcomes
• Subgroup-specific gene networks associated with aberration hotspots
• A basis for stratified medicine (beyond Herceptin)
• But any implications for breast cancer aetiology?
Curtis et al., Nature 2012
• Standardized protocol for clinical, pathological information and biological specimens
• Identification of specific endogenous (genetics and genomics) and exogenous factors (biological modifications, behavioral, dietary and cultural factors) with specific subtypes of premenopausal BC, identified based on molecular and pathological phenotypes
• Provide advanced training, development of the BC research community in Latin America, and influence the public health agenda regarding the management of BC
IARC PI: Dr Isabelle Romieu, Section of
Nutrition and Metabolism, IARC
Molecular subtypes of premenopausal breast cancer in Latin American Women
Laboratory science in population studies – what is promised?
Improved exposure assessment
Contributing to biological plausibility
Stratifying risks by tumour sub-group
Evaluating interventions
Hazard and risk assessment
Sept/Oct Dec/Jan Feb/Mar
Survey 1 Survey 2 Survey 3
20 Villages (10 intervention, 10 control), 30 subjects per village
Blood sample collection Groundnut sample collection
Intermediate Survey 1
Intermediate Survey 2
Biomarkers and intervention studies – aflatoxin in subsistence farms in Guinea
Laboratory science in population studies – what is promised?
Improved exposure assessment
Contributing to biological plausibility
Stratifying risks by tumour sub-group
Evaluating interventions
Hazard and risk assessment
IARC Monographs: mechanistic upgrade New research continues to find additional human carcinogens &
Use of mechanistic data to identify carcinogens is accelerating
Types of mechanistic upgrades
Ethylene oxide: Dose-related increase in the frequency of SCE, CA, and
MN in lymphocytes of exposed workers.
DNA adducts and A:T→T:A transversions in TP53 identified aristolochic acid as the carcinogen in herbal remedies -> environmental exposures: cereal fields in the Balkans where Aristolochia plants grow as weeds
Benzidine-based dyes: Metabolism results in the release of free
benzidine in humans and in all experimental
animal species studied.
Conclusions
• The challenge of a rising cancer burden must be met by an integrated approach of prevention (including early detection) and treatment
• Recent advances in the molecular (epi)genetics of cancer and related tools offer exciting inter-disciplinary approaches to cancer prevention
• There are barriers to be overcome in relation to vision, inter-disciplinary working and resources to benefit from these opportunities
