Epigenetics – Cancer Epidemiology University of Exeter Medical School Nick Osborne
On going controversy- The American Cancer Soc estimates that about 6% of cancer deaths — nearly 34,000 a year — are caused by environmental pollutants Higher/lower? President's Cancer Panel ‘10 = higher Depends of definition of environment Children (weight+development) Aged (time and accumulation) Tobacco (168,000pa), obesity, alcohol, infections, hormones, sunlight
Complex disease Genetic Environmental Gene-environment Gene-gene No silver bullet Epigenetics? Hypo- and hyper-methylation Epidemiologists view ???
Epigenetics ‘how genotypes give rise to phenotypes during development’ ‘the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence’ • Nature 447, 2007
Cornwall Mining Industry Kick started the Bronze age with the supply of Sn before 2000 BC –As, Cu, Zn, Ag, plus Rn Deposits of W near Plymouth Sample prior to opening again
Other clues Added to list of chemicals of interest at US EPA Industrial uses – it is increasing • Tungsten carbide • Green ammunition • Cooling blocks in PCs – 72,000 tons in 2011 Don’t know how much is in drinking water & soil How bioavailable? application of sewage sludge, fertilizers, municipal solid waste ash, and industrial wastes that contain tungsten, or deposition of atmospheric aerosols
NHANES – US Study Cross-sectional Cancer outcomes tricky in this popn. sample 6 Waves W < 0.24 to 1.1 ng/ml in urine (creatinine adjusted) Cancer in those 18-50 years Adjust for a range of risk factors – measured concurrently Look in prospective cohort next
NHANES - ?? Presents a certain level of evidence Cross-sectional Cancer cases – participant bias Accessible Modifiable risk factors Don’t target chemicals already banned or regulated
Low level chronic exposure to environmental chemicals Technology to measure = ppb Large cohorts with biosamples Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D. JAMA. 2008 Sep 17;300(11):1303-10. Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Melzer D, Osborne NJ, Henley WE, Cipelli R, Young A, Money C, McCormack P, Luben R, Khaw KT, Wareham NJ, Galloway TS. Circulation. 2012 Mar 27;125(12):1482-90.
Potential biological mechanisms Epigenetics • heavy metals, pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria, and basic nutrients W toxicology poorly understood Others? – almost certainly Can we glean information from epidemiological studies to inform potential pathological routes Spectrum of aetiologies
W harmless? I thought so Inactive? No/little data? WO4 Bioavailability?
Cancer “Causing” metals Arsenite Nickel Chromium Cadmium Molecular mechanism largely unknown Not mutagenesis Initiator/promotor??
Hill’s Criteria - Plausibility Disturb a vast array of cellular processes Silencing of DNA repair Tumour repressor genes directly by binding various metal response elements in the target gene promoters ChengJournal of Applied Toxicology 2012 Complexity on complexity? Excuse to dodge the complexity What appears random at individual level is often predictable at population level
Complexity on Complexity GD Smith, 2011
We cannot imagine these diseases, they are called idiopathic, spontaneous in origin, but we know instinctively there must be something more, some invisible weakness they are exploiting. It is impossible to think they fall at random, it is unbearable to think it. • James Salter, Light Years, 1975
Tissue specificity Epidemiology – non-invasive bio-sampling Blood/urine/saliva/hair/toenail/buccal swab Organ specific • Lung • Gut • Pancreas What can be studied?
Genes and environment in social animals In families • Genes are the same/similar • Exposures are the same/similar • Then why are siblings so different? • Are you the same as your sister/brother • The black sheep (brebis galeuse??)? • Twin differences (young and old)
Twin Studies 79 studies on pubmed
Dutch Famine 1944-45 Those in utero less methylation of the IGF2 gene 60 years later compared with their same sexed siblings Offspring of non-famine siblings higher rates of schizophrenia and cardiac problems
Many may be linked Inflammation: rheumatoid arthritis, MS, cancers, obesity, and atopic disorders Backdahl 2009 Int J Biochem Cell Biol 41:176 causal in disease pathogenesis epigenetic mechanisms contribute to the transcriptional regulation of inflammatory responses Medzhitov 2009 Nature Rev Immunol 9: 692
UK Biobank 500,000 40-69 year olds Access to baseline data http://www.ukbiobank.ac.uk/ Funded by MRC and Wellcome Trust, DH, Scottish & Welsh gov.,British Heart Found. Open to all – apply Sub sample will be reapproached Potential access to tissue-med records-biosamp UK Biobank: Cancer outcomes working group
UK-wide audit of environmental metals Heavy metal audit DEFRA and BGS Account for differences in conc. Centre for Ecology & Hydrology - NERC
Conclusions - Great opportunities Applying skills learnt in environmental and genetic epidemiology Basic science of effect of metals on epigenetic markers – lab based Use of these in epidemiological cohorts heritability of these epigenetic marks correlate them to heritable gene expression patterns
firstname.lastname@example.org Collaborators: Jessica Tyrrell, Tamara S Galloway, David Melzer, Michael Depledge and Lora Fleming