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Elio Riboli MD, MPH, ScM Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O. International Agency for Research on Cancer World Health Organization.

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Presentation on theme: "Elio Riboli MD, MPH, ScM Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O. International Agency for Research on Cancer World Health Organization."— Presentation transcript:

1 Elio Riboli MD, MPH, ScM Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O. International Agency for Research on Cancer World Health Organization Lyon, France

2 LYON PARIS FLORENCE MILAN RAGUSA TURIN NAPLES BARCELONA OVIEDO GRANADA MURCIA PAMPLONA SAN SEBASTIAN CAMBRIDGE OXFORD BILTHOVEN UTRECHT ATHEN S HEIDELBERG POTSDA M MALMÖ UMEÅ AARHUS COPENHAGEN TROMSØ Collaborating centres and cohort subjects EPIC LONDON

3 BASELINE Subjects recruitment Questionnaires data Anthropometry data Blood/DNA collection Data Base & Biorepository 1993…………………………..…….1999………… 2000…….2002……………………2005 EPIC Time Table Spain Norway France Italy UK Netherlands Germany Greece FOLLOW-UP: Cancer diagnosis Vital status Causes of death Changes in Lifestyle Development of common/standardized Nutrient and lifestyle Data Bases Setting up of lab facilities for sample handling / DNA extraction etc ETIOLOGICAL STUDIES Sweden DK

4 Western Lifestyle: - Energy dense diet, rich in - fat, - refined carbohydrates - animal protein - Low physical activity - Smoking and drinking Consequences: - Greater adult body height - Early menarche - Obesity - Diabetes - Cardiovascular disease - Hypertension …and cancer ! “Westernization” of lifestyle and cancer.

5 Final size of the database : over 100 giga bytes. 90 screens have been developed to facilitate the transfer, standardization, control and export of the data subjects x about 2000 common variables  over 1 billions values stored EPIC Database

6 Blood Collection and Storage ( ) 30 ml venous blood: –20 ml citrated +10 ml dry 28 aliquots of 500  l : –plasma 12 (red straws) (yellow straws) –serum 8 (yellow straws) –buffy coat 4 (blue straws) –RBC 4 (green straws) 28 aliquots x subjects = 8.4 Million biological aliquots EPIC

7 IARC Scientific Council, 2005 EPIC: Organizational Structure EPIC Steering Committee IARC E. Riboli, N. Slimani, R. Kaaks, R.Saracci Danemark A.Tjonneland (DK Cancer Soc.), K. Overvad (U. Aarhus) France F. Clavel, MC Boutron (I.G.R-INSERM, Paris) Greece A. Trichopoulou, D. Trochopoulos (U. Athens/Harvard) GermanyJ. Linseisen (DKFZ), H. Boeing (DIFE) ItalyF. Berrino (INT), P.Vineis, D. Palli, S.Panico, R.Tumino, NetherlandsP. Peeters (U. Utrecht), B. Bueno de Mesquita (RIVM) NorwayE. Lund (U. Tromso) SpainC. Gonzalez (I.C.O.), C. Martinez, C. Navarro, M. Doronsoro Sweden G. Berglund (U. Lund), G. Hallmans (U.Umea) UKS. Bingham, K-T Khaw (U.Cambridge), T. Key (CRUK Oxford)

8 Working groups on risk factors, end-points other than cancer, methodological issues: Coordinators: EPIC-Elderly-EC (Aging) EPIC-Elderly-EC (Aging) Antonia Trichopoulou (Athens Univ.) EPIC-Heart-EC (M.I.) EPIC-Heart-EC (M.I.) John Danesh (Cambridge Univ.) EPIC-Diabetes EPIC-Diabetes Nick Wareham (MRC Cambridge) Anthropometry Anthropometry Heiner Boeing (DIFE-Potsdam) Total Mortality Total Mortality Kim Overvad (Aaarhus Univ.) Dietary Patterns Dietary Patterns Nadia Slimani (IARC) Phytoestrogens Phytoestrogens Petra Peeters (U. Utrecht) EPIC Steering Committee EPIC: Organizational Structure

9 IARC Scientific Council, 2005 Follow-up of EPIC subjects, Breast Lung Ovary Corpus uteri Cervix uteri Upper GI Tract Pancreas Kidney Colon-rectum Prostate Stomach NorSweDenUKGerNLFraItaSpaGreEPIC cancer incidence (28,000 incident cancer cases)

10 2003: 1st Funded Project : Cohort Consortium on Hormone Metabolizing Gene Variants and Breast and Prostate cancer risk 2000: NCI Cohort Studies Consortium on gene environment interaction : NCI Bypass programme “Exceptional Opportunities” for research in the Area of Gene-Environment interaction studies

11 OBJECTIVES: to study the role in the etiology of breast and prostate cancer of genetic variations in the: steroid hormone pathway, insulin-like growth factor (IGF) pathway, associated receptor and transport proteins HORMONE METABOLIZING GENE VARIANTS AND BREAST AND PROSTATE CANCER RISK

12 UNDERLYING HYPOTHESIS: 1- Hormones can modulate cancer risk by: 1.1 increasing the rate of cell division and/or 1.2 suppressing apoptosis in the target tissues; 2- Relatively common genetic polymorphisms could affect cancer risk by determining: 2.1 the rate of hormone synthesis or breakdown, 2.2 the activity of hormones secreted by the hypotalamus- pituitary axis that regulate steroidogenesis 2.3 the amount or effectiveness of binding proteins that regulate bioavailability 2.4 the magnitude of the cellular response to hormonal stimulation via membrane and intracellular receptors. HORMONE METABOLIZING GENE VARIANTS AND BREAST AND PROSTATE CANCER RISK

13 Estrogens levels and subsequent breast cancer risk; pooled cohort study Endogenous Hormones and Breast Cancer Collaborative Group, JNCI, 2002; 94: 606

14 Postmenopausal Serum Sex Steroids and Breast Cancer Risk The EPIC Study; (677 cases / 1309 controls) Kaaks et al., Endocr Relat Cancer, in press (2005)

15 Premenopausal Serum Sex Steroids and Breast Cancer Risk The EPIC Study; (416 cases, 815 controls) Testosterone SHBG DHEAS Androstenedione Estrone Estradiol Progesterone OR Ptrend Kaaks et al., JNCI (2005)

16 Total and bioavailable estradiol in relation to BMI: Post-menopausal women Key et al., Proc Nutr Soc 2001

17 Cholesterol Pregnenolone 17-  -OH- pregnenolone DHEA  -5-androstenediol Progesterone 17-  -OH- progesterone  -4-androstenedione testosterone Mineralo- corticoids Gluco- corticoids estroneestradiol Pathways of steroid synthesis

18 Hypotha lamus GNRH Pituitary GNRHR CGA LHB FSHB POMC LH FSH ACTH BloodOvary / Adrenal gland receptors: LHCGR, FSHR, ACTHR cholesterol STAR, CYP11A1, CYP17, HSD3B, pregnenolone, DHEA progesterone,  4A HSD17B Ovary & Adipose tissue T CYP19 estadiol, estrone Blood DHEA(S)  4A T E1 E2 SHBG Liver SHBG Breast tissue steroid receptors: ESR1, ESR2, PGR, AR  4A, T CYP19 E1 E2 HSD17B1, HSD17B2 CYP1A1, CYP1B1, CYP3A4, COMT hydroxy / methoxy estrogens Genes encoding enzymes that are central to the synthesis, conversions and hydroxylation/methoxylation of sex steroids, or encoding steroid-binding proteins and receptors,

19 Regulation of IGF1 and related molecules Target tissues: Breast Prostate Colorectum etc. IGF1R Hypothalamus SSTGHRH Stomach Ghrelin - Pituitary SSTRGHRHR - - GH -+ POU1F1 GH Circulation Growth + Ghrelin Circulation + + GHSR Liver GHR + IGF1 IGFBP3 IGFALS IGF1+ IGFBP3+ IGFALS Circulation

20 StudyYear started Subjects with blood samples Breast cancer cases Prostate cancer cases EPIC ,256 2, ACS (CPS-II) , ,450 Harvard PHS ,000-1,500 NHS , HPFS199333, WH , Multi Ethnic100,000 1,990 2,400 PLCO , ,000 Total797,0856,1608,850 ATBC , ,000 Cohort Consortium on Hormone Metabolizing Gene Variants and Breast and Prostate cancer risk

21 Project flowchart SNP discovery by gene resequencing (CEPH, WI-MIT) Haplotype tagging (CEPH, WI-MIT) Genotyping (IARC, Cambridge, Harvard, USC, Hawaii, NCI) Hormone measurement (IARC, Harvard) Statistical analysis main effects of SNPs and haplotypes, gene-environment interactions Breast at IARC Prostate at Harvard Selection of candidate genes (53 genes involved in metabolism of IGF-I and steroid hormones) 

22 WhiteheadCEPH Web ht-SNP Database Study planning and gene choice Gene Resequencing Haplotype determination Identification of ht-SNPs Harvard USC & Honolulu IARC & Cambridge Un. NCI Harvard Cohorts Multiethnic Cohort ACS EPIC PLCOATBC Breast Cancer Database IARC Collaborative Statistical Analysis Web and Journal Publications Exposure Data Cohort Consortium Work Flow Chart Prostate Cancer Database Harvard Genotyping Centres Database consolidation Steering Group and Secretariat PUBLIC ACCESS PUBLIC ACCESS NCI

23 STEERING COMMITTEE: Harvard David Hunter, Michael Gaziano, Julie Buring, Graham Colditz, Walter Willett EPIC,CEPH & Cambridge Elio Riboli, Rudolf Kaaks, Bruce Ponder, Gilles Thomas, ACS Michael Thun, Heather Feigelson, NCI Richard Hayes, Demetrius Albanes, Louise Brinton, Sandra Melnick MEC & Whitehead Brian Henderson, Laurence Kolonel, David Altshuler SECRETARIAT: David Hunter Elio Riboli GENOMICS & GENOTYPING subgroup: David Altshuler Federico Canzian Steve Channock Alison Dunning Raju Kucherlapati David Kwiatkowski Gilles Thomas Chris Haiman STATISTICS subgroup: Doug Easton Jun Liu Dan Stram Duncan Thomas, Shalom Wacholder Harvard cohorts ACS cohort EPIC cohorts Multiethnic Cohort PLCO cohort ATBC cohort Whitehead Genome Center NCI Core Genotyping Facility

24 CEPH: Gilles Thomas Helene Blanche Gene Resequencing Haplotype determination Identification of ht-SNPs Cambridge Univ Alison Dunning Paul Pharoah Genotyping Prostate Cancer Cases/Controls Oxford CRUK Tim Key Ruth Travis Naomi Allen Stat. analyses prostate data IARC Federico Canzian Genotyping Breast Cancer Cases/Controls Genotyping QC IARC Elio Riboli Rudolf Kaaks Coordination Pooled Bata Base for Breast Cancer Pooled statistical analyses Lab analyses of Endogenous Hormones EPIC components of BPC3,

25 Imperial College London Elio Riboli Scientific Coordination Statistical Methods and Analyses Cambridge U. Alison Dunning Paul Pharoah Genotyping Prostate Cancer Cases/Controls Oxford CRUK Tim Key Stat. analyses prostate data DKFZ, Heidelberg Federico Canzian Genotyping Breast Cancer Cases/Controls Genotyping QC IARC Rudolf Kaaks Pooled Data Base for Breast Cancer Pooled statistical analyses EPIC components of BPC3,

26 Elio Riboli MD, MPH, ScM Chair, Cancer Epidemiology and Prevention, Department of Epidemiology Faculty of Medicine Imperial College London

27 WhiteheadCEPH Web ht-SNP Database Study planning and gene choice Gene Resequencing Haplotype determination Identification of ht-SNPs Harvard USC & Honolulu DKFZ & Cambridge NCI Harvard Cohorts Multiethnic Cohort ACS EPIC PLCOATBC Breast Cancer IARC-ICL Collaborative Statistical Analysis Web and Journal Publications Exposure Data Cohort Consortium Work Flow Chart Prostate Cancer Harvard Genotyping Centres Database consolidation and Statistical Analyses Steering Group and Secretariat PUBLIC ACCESS PUBLIC ACCESS NCI

28 THE END

29 Regulation of IGF1 and related molecules Target tissues: Breast Prostate Colorectum etc. IGF1R Hypothalamus SSTGHRH Stomach Ghrelin - Pituitary SSTRGHRHR - - GH -+ POU1F1 GH Circulation Growth + Ghrelin Circulation + + GHSR Liver GHR + IGF1 IGFBP3 IGFALS IGF1+ IGFBP3+ IGFALS Circulation 

30 Project flowchart SNP discovery by gene resequencing (CEPH, WI-MIT) Haplotype tagging (CEPH, WI-MIT) Genotyping (IARC, Cambridge, Harvard, USC, Hawaii, NCI) Hormone measurement (IARC, Harvard) Statistical analysis main effects of SNPs and haplotypes, gene-environment interactions Breast at IARC Prostate at Harvard Selection of candidate genes (53 genes involved in metabolism of IGF-I and steroid hormones) 

31

32 Relation between Western Lifestyle, hormone metabolism, and cancer Western Lifestyle; Overnutrition Increased IGF-I bio- activity Alterations in steroid hormone metabolism Cancer of breast endometrium, ovary, or prostate Kaaks, IARC Other cancers: colon/rectum, lung pancreas,

33 Total Plasma IGF-I  IGF-I bio-activity  IGFBP-1  IGFBP-2  Diet / Low Physical activity Obesity, hyper- insulinemia (Unknown mechanisms) Cancer  Insulin, IGF-I and cancer development Kaaks, IARC

34 RR trend-p < Testosterone Androstenedione Estrone <0.001 Estradiolo Androgens levels and subsequent breast cancer relative risk: Pooled cohort study Endogenous Hormones and Breast Cancer Collaborative Group, JNCI, 2002; 94: 606

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