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Epigenetics , nutrition and bowel cancer risk

Epigenetics , nutrition and bowel cancer risk. John Mathers Human Nutrition Research Centre UK. Diet and bowel cancer risk .1. WCRF/ AICR Report Comprehensive and systematic assessment of epidemiological evidence 2 nd edition November 2007.

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Epigenetics , nutrition and bowel cancer risk

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  1. Epigenetics, nutrition and bowel cancer risk John Mathers Human Nutrition Research Centre UK

  2. Diet and bowel cancer risk .1 • WCRF/ AICR Report • Comprehensive and systematic assessment of epidemiological evidence • 2nd edition November 2007 http://www.wcrf-uk.org/research_science/expert_report.lasso

  3. Colo-rectal cancer .2

  4. Overview of lecture • Overview of epigenetic mechanisms • Epigenetic events in bowel cancer • Towards novel diet-related DNA methylation biomarkers of bowel cancer risk • MicroRNA, diet and development of bowel cancer

  5. Other genetic and epigenetic events Colon cancer development • ‘Advantageous’ mutations/ epimutations become ‘fixed’ • Development of genomic instability • <10% of adenomas become carcinomas (Darwinian process) Adapted from Rajagopalan et al. (2003) Nat. Rev. Cancer 3, 695-701

  6. Determinants of phenotype Phenotype Epigenome Environment Adapted from Zoghbi HY & Beaudet AL (2007) in “Epigenetics”

  7. Receive and Record Remember Reveal The 4 Rs of (nutritional) epigenomics Environment (diet) Time Mathers JC (2008) Proc. Nutr. Soc. 67, 390-394

  8. Epigenetic Mechanisms DNA methylation Non-coding RNAs Chromatin conformation Histone code Costa FF (2008) Gene410, 9-17

  9. Epigenetic marks DNA methylation Histone “decoration” Qiu J (2006) Nature 441, 143-145

  10. Molecular mechanisms linking diet with bowel cancer risk • All cancers arise from (unrepaired) genomic damage so “protective” dietary factors “must”: • ↓ genomic damage • ↑ genomic repair • ↑ removal of damaged cells by apoptosis

  11. Hypothesis: aberrant methylation of DNA repair genes links diet with cancer Hypothesis: ? Inflammation Tumour

  12. MGMT: role in DNA repair Gerson SL (2004)

  13. Epigenetic events in cancer development – silencing of DNA repair genes Jones PA & Baylin SB (2002)

  14. MGMT methylation correlates with loss of expression Shen L et al. (2005) J. Natl. Cancer Inst. 97, 1330-1338

  15. ↑ MGMT methylation in normal mucosa when adjacent tumour is methylated Causality? Does aberrant methylation cause tumorigenesis? Shen L et al. (2005) J. Natl. Cancer Inst. 97, 1330-1338

  16. 29 genes often methylated in cancer Tumour suppressor genes Ohm JE et al. (2007) Nature Genetics 39, 237-242

  17. Genes frequently hypermethylated in tumours have a stem cell-like chromatin pattern Adult cancers ‘Bivalent’ marks: Active mark – H3K4 Repressive mark – H3K27 Ohm JE et al. (2007) Nature Genetics 39, 237-242

  18. Interpretation of DNA methylation measurements Qiu J (2006) Nature 441, 143-145

  19. “Field effect” v. focal event? • Crypt cells arise from stem cells at base of individual crypts • Colo-rectal tumours derive from a stem cell in a single crypt • Nature of “field effect” in vulnerable colon?

  20. Epigenetic “field effect” • At any CpG, methylation is a binary phenomenon • Percentage methylation = % genomes methylated • Therefore ≈ % stem cells (and crypts) methylated at this locus • Crypts are epigenetically heterogeneous

  21. Epigenetic diversity in colonic mucosa • Colo-rectal mucosal crypts: • Multiple, independent, clonal units • Genetically identical • Epigenetically heterogeneous • Why? • Different local environments? • Stochastic events?

  22. Maintenance of DNA methylation patterns through mitosis Shibata D (2009) J. Pathol. 217, 199-205

  23. Stochastic development of divergent methylation patterns ↑ epigenetic diversity with age (and dietary exposure?) Shibata D (2009) J. Pathol. 217, 199-205

  24. Hypothesis: “Field effects” occur in the “normal” colo-rectal epithelium Similar epigenetic patterns, similar gene expression Young, healthy “High risk” stem cells in individual crypts Older, ↑ CRC risk

  25. Stool as a surrogate “tissue” for DNA methylation measurements

  26. Methylation at specific CpGs (%) Quantification of gene methylation using stool samples Healthy volunteers Belshaw NJ et al. (2004) Cancer Epid. Biomark. Prev. 13, 1495-1501

  27. ESR1 methylation (%) Age (years) Methylation of promoter region of oestrogen receptor gene  with age in the colon 200 healthy people in NE England Garg D et al. unpublished

  28. ↑ promoter methylation in DNA from stools compared with mucosa Elliott GO et al. (2010) unpublished

  29. A ↑ Methylation in stool from adenoma patients v. healthy volunteers ** *** *** *** B *** ** * Healthy volunteer Adenoma patient *** Elliott GO et al. (2010) unpublished C *** *** *** **

  30. Stool-based DNA methylation measurements • Human DNA can be harvested from stool • Quality of DNA is adequate for quantification of promoter methylation • Some results as anticipated e.g. age-dependent ↑ in ESR1 methylation • Levels of methylation are consistently higher than those seen in corresponding mucosal biopsies • ? Differential survival of methylated sequences? • Potential use in developing biomarkers of CRC risk

  31. “All seeing, all controlling” Claudia Bentley (2006)

  32. MicroRNA (miRNA) • Large family of small (≈ 22 nucleotides long) non-coding RNAs; • At least 721 miRNA in human genome; • Regulate transcription of ≈30% of all protein-encoding genes through sequence-specific binding to RNA; • Inhibit translation and/or signal degradation of target mRNA; • Regulate almost all cellular processes investigated.

  33. Gene regulation by miRNA Ryan BM et al. (2010) Nature Rev. Cancer 10, 389-402

  34. miRNA and cancer • Some miRNA which are normally “silent” in adult tissues become re-expressed • Persistent stem cell-like de-differentiated state • miRNA over-expressed in tumours may act like oncogenes • ↑ proliferation, ↓ apoptosis • miRNA with tumour suppressor (TS) regulatory activity may beome down regulated • loss of TS activity Oncomirs = miRNA with a role in cancer Jeffrey SS (2008) Nature Biotech. 26, 400-401

  35. Esquela-Kerscher A & Slack FJ (2006) Nature Rev. Cancer 6, 259-269

  36. Anti-cancer effect of P53 via miRNA Toledo F & Bardot B (2009) Nature 460, 466-467

  37. Methylation of miR-34a in tumours Methylation of promoter of miRNA-34a gene detected in tumours including bowel cancer Lodygin D et al. (2008) Cell Cycle 7, 2591-2600

  38. Diet, miRNA and bowel cancer risk ? • Understanding aetiological mechanisms • Development of novel diet-responsive biomarkers of bowel cancer risk

  39. Effect of dietary factors on miRNA signatures in rat colon • 2*2*2 factorial designed study in Sprague-Dawley rats • 2 types of dietary fibre • 2 types of fat • + and – AOM treatment • Assayed 368 mature miRNAs in colonic mucosa Cellulose Pectin Corn oil Fish oil Davidson LA et al. (2009) Carcinogenesis 30, 2077-2084

  40. Diet alters miRNA in rat colon Cellulose Pectin Corn oil Fish oil Davidson LA et al. (2009) Carcinogenesis 30, 2077-2084

  41. miRNA patterns linked with adenocarcinoma risk Davidson LA et al. (2009) Carcinogenesis 30, 2077-2084

  42. Fish oil “prevented” down regulation of 5 specific miRNA (oncomirs) Davidson LA et al. (2009) Carcinogenesis 30, 2077-2084

  43. Summary • Diet is a major modulator of bowel cancer risk • Epigenetics mechanisms link dietary exposure with development of bowel cancer • DNA methylation shows promise as route to novel (diet-related) biomarkers of bowel cancer risk • DNA methylation measurements can be made in stool • Altered miRNA patterns occur in cancer and may be diet responsive

  44. Research priorities • Which epigenetic changes in macroscopically normal mucosa are causal for ↑ bowel cancer risk? • What are major exposures causing ↑ epigenetic heterogeneity with age? • What dietary (and other lifestyle) factors prevent, or reverse, these early epigenetic changes?

  45. Acknowledgements Ian Johnson Nigel Belshaw Giles Elliott Mike Bradburn DharmendraGarg Wendy Bal Liz Williams

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