Elio Riboli MD, MPH, ScM Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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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 Lyon, France

description

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. TROMS Ø. UMEÅ. AARHUS. MALM Ö. COPENHAGEN. UTRECHT. CAMBRIDGE. POTSDAM. BILTHOVEN. OXFORD. HEIDELBERG. PARIS. - PowerPoint PPT Presentation

Transcript of Elio Riboli MD, MPH, ScM Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Page 1: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Elio Riboli MD, MPH, ScM

Head, Nutrition, Hormones and Cancer

Group

I.A.R.C.-W.H.O.

International Agency for

Research on CancerWorld Health Organization

Lyon, France

Page 2: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

LYON

PARIS

FLORENCE

MILAN

RAGUSA

TURIN

NAPLESBARCELONA

OVIEDO

GRANADAMURCIA

PAMPLONA

SAN SEBASTIAN

CAMBRIDGE

OXFORD BILTHOVEN

UTRECHT

ATHENS

HEIDELBERG

POTSDAM

MALMÖ

UMEÅ

AARHUS

COPENHAGEN

TROMSØ

Collaborating centres and cohort subjects

Subjects includedQuestionnaire Q + Blood

France 74 524 21 053Italy 47 749 47 725Spain 41 440 39 579UK 87 942 43 141Netherlands 40 072 36 318Greece 28 555 28 483Germany 53 091 50 678Sweden 53 826 53 781Denmark 57 054 56 131Norway 37 215 11 000All 521 468 387 889

EPIC

LONDON

Page 3: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

BASELINE•Subjects recruitment •Questionnaires data•Anthropometry data•Blood/DNA collection•Data Base & Biorepository

1993…………………………..…….1999………… 2000…….2002……………………2005

EPIC Time Table

SpainNor

way

France

Italy

UKNeth

erlan

d

sGer

man

y

Greec

e

FOLLOW-UP:• Cancer diagnosis• Vital status • Causes of death• Changes in Lifestyle

Development of common/standardized Nutrient and lifestyle Data BasesSetting up of lab facilities for sample handling / DNA extraction etc

ETIOLOGICAL STUDIES

Swed

en

DK

Page 4: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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.

Page 5: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

• Final size of the database : over 100 giga bytes.

• 90 screens have been developed to

facilitate thetransfer, standardization,control andexportof the data

• 521.000 subjects x about 2000 common variables over 1 billions values stored

EPIC Database

Page 6: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Blood Collection and Storage (1993-1998)

• 30 ml venous blood:

– 20 ml citrated +10 ml dry

• 28 aliquots of 500 l :

– plasma 12 (red straws)– serum 8 (yellow straws)(yellow straws)– buffy coat 4 (blue straws)– RBC 4 (green straws)

28 aliquots x 300.000 subjects =

8.4 Million biological aliquots

EPIC

Page 7: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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)

Germany J. Linseisen (DKFZ), H. Boeing (DIFE)

Italy F. Berrino (INT), P.Vineis, D. Palli, S.Panico, R.Tumino,

Netherlands P. Peeters (U. Utrecht), B. Bueno de Mesquita (RIVM)

Norway E. Lund (U. Tromso)

Spain C. Gonzalez (I.C.O.), C. Martinez, C. Navarro, M. Doronsoro

Sweden G. Berglund (U. Lund), G. Hallmans (U.Umea)

UK S. Bingham, K-T Khaw (U.Cambridge), T. Key (CRUK Oxford)

Page 8: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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-DiabetesEPIC-Diabetes Nick Wareham (MRC Cambridge)

Anthropometry Anthropometry Heiner Boeing (DIFE-

Potsdam)

Total MortalityTotal Mortality Kim Overvad (Aaarhus Univ.)

Dietary PatternsDietary Patterns Nadia Slimani

(IARC)

PhytoestrogensPhytoestrogens Petra Peeters (U.

Utrecht)

EPIC Steering Committee

EPIC: Organizational Structure

Page 9: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

IARC Scientific Council, 2005

Follow-up of EPIC subjects, 1994-2003

Breast 220 720 845 797 386 607 2844 557 285 56 7317

Lung 41 224 450 233 154 116 127 92 81 42 1560

Ovary 59 87 94 123 38 59 165 58 47 15 745

Corpus uteri 32 106 129 101 38 65 270 81 58 11 591

Cervix uteri 18 241 29 241 63 32 23 34 40 7 728

Upper GI Tract 2 72 125 99 57 35 . 27 33 2 452

Pancreas 4 101 86 99 54 32 . 26 23 11 406

Kidney 9 73 76 61 78 38 . 49 32 7 423

Colon-rectum 68 342 453 403 197 205 218 168 139 30 2223

Prostate . 650 329 311 235 35 . 66 105 14 1746

Stomach 5 67 54 63 55 37 17 64 38 19 421

Nor Swe Den UK Ger NL Fra Ita Spa Gre EPIC

cancer incidence (28,000 incident cancer cases)

Page 10: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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

1999-2000: NCI Bypass programme “Exceptional Opportunities” for research in the Area of Gene-Environment interaction studies

Page 11: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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

Page 12: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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

Page 13: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Estrogens levels and subsequent breast cancer risk; pooled cohort study

Endogenous Hormones and Breast Cancer Collaborative Group, JNCI, 2002; 94: 606

Page 14: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Postmenopausal Serum Sex Steroids and Breast Cancer RiskThe EPIC Study; (677 cases / 1309 controls)

DHEAS

Androstenedione

Testosterone

Estrone

Estradiol

SHBG

Freetestosterone

Freeestradiol

1.001.281.061.681.69

1.001.471.351.701.73

1.001.141.331.561.85

1.001.601.892.051.96

1.001.101.451.542.05

1.000.980.720.870.61

1.001.831.921.862.50

1.001.301.341.712.00

RR

0.5 1 2

P trend

0.0002

0.001

<0.0001

0.0004

<0.0001

0.004

<0.0001

<0.0001

Kaaks et al., Endocr Relat Cancer, in press (2005)

Page 15: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Premenopausal Serum Sex Steroids and Breast Cancer RiskThe EPIC Study; (416 cases, 815 controls)

Testosterone

SHBG

DHEAS

Androstenedione

Estrone

Estradiol

Progesterone

1.00 1.33 1.36 1.58

1.00 1.05 0.97 1.02

1.00 1.34 1.15 1.37

1.00 1.11 1.14 1.64

1.001.13 0.73 1.22

1.00 0.76 0.96 0.99

1.00 1.16 1.07 0.63

OR

0.5 1 2

Ptrend

0.02

0.98

0.17

0.01

0.76

0.75

0.07

Kaaks et al., JNCI (2005)

Page 16: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Total and bioavailable estradiol in relation to BMI:

Post-menopausal women

Key et al., Proc Nutr Soc 2001

Page 17: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Cholesterol

Pregnenolone 17--OH-pregnenolone

DHEA -5-androstenediol

Progesterone 17--OH-progesterone

-4-androstenedione testosterone

Mineralo-corticoids

Gluco-corticoids

estrone estradiol

Pathways of steroid synthesis

Page 18: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Hypothalamus

GNRH

Pituitary

GNRHRCGALHBFSHBPOMC

LH

FSH

ACTH

Blood Ovary / Adrenal gland

receptors: LHCGR, FSHR, ACTHR

cholesterol STAR, CYP11A1, CYP17, HSD3B,

pregnenolone, DHEAprogesterone, 4A

HSD17B

Ovary & Adipose tissue T CYP19

estadiol, estrone

Blood

DHEA(S)4ATE1E2

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,

Page 19: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Regulation of IGF1 and related moleculesRegulation of IGF1 and related molecules

Target tissues: Breast Prostate Colorectum etc.

IGF1RHypothalamus

SST GHRH

Stomach

Ghrelin

-

Pituitary

SSTR GHRHR -

-GH

- +POU1F1

GH

Circulation

Growth

+Ghrelin

Circulation

+

+

GHSR

GHSR

Liver

GHR + IGF1

IGFBP3

IGFALS

IGF1+IGFBP3+IGFALS

Circulation

Page 20: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Study Yearstarted

Subjects withblood samples

Breast cancercases

Prostate cancercases

EPIC 1992 397,256 2,050 900

ACS (CPS-II) 1998 39,000 500 1,450

Harvard

PHS 1982 20,000 - 1,500

NHS 1989 32,826 945 -

HPFS 1993 33,240 - 600

WH 1993 28,263 675 -

Multi Ethnic 100,000 1,990 2,400

PLCO 1993 75,000 - 1,000

Total 797,085 6,160 8,850

ATBC 1991 20,500 - 1,000

Cohort Consortium on Hormone Metabolizing Gene Variants and Breast and Prostate cancer

risk

Page 21: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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 analysismain effects of SNPs and haplotypes,

gene-environment interactionsBreast at IARC

Prostate at Harvard

Selection of candidate genes(53 genes involved in metabolism of IGF-I and steroid hormones)

Page 22: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Whitehead

CEPH

Web ht-SNP Database

Study planning and gene choice

Gene Resequencing

Haplotype determination

Identification of ht-SNPs

Harvard USC & Honolulu

IARC & Cambridge

Un.

NCI

HarvardCohorts

Multiethnic

Cohort

ACS

EPIC PLCO

ATBC

Breast Cancer

Database IARC

Collaborative Statistical Analysis

Web and Journal Publications

Exposure Data

Cohort Consortium Work Flow Chart

Prostate Cancer

DatabaseHarvard

Genotyping

Centres

Database consolidation

Steering Group and

Secretariat

PUBLIC ACCESS

PUBLIC ACCESS

NCI

Page 23: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

STEERING COMMITTEE:Harvard David Hunter, Michael Gaziano, Julie Buring, Graham Colditz, Walter WillettEPIC,CEPH & Cambridge Elio Riboli, Rudolf Kaaks, Bruce Ponder, Gilles Thomas,ACS Michael Thun, Heather Feigelson, NCI Richard Hayes, Demetrius Albanes, Louise Brinton, Sandra MelnickMEC & Whitehead Brian Henderson, Laurence Kolonel, David Altshuler

SECRETARIAT:

David HunterElio Riboli

GENOMICS & GENOTYPING

subgroup:

David Altshuler Federico CanzianSteve ChannockAlison DunningRaju KucherlapatiDavid KwiatkowskiGilles ThomasChris Haiman

STATISTICS subgroup:

Doug EastonJun LiuDan StramDuncan Thomas, Shalom Wacholder

Harvard cohorts

ACS cohort

EPIC cohorts

Multiethnic Cohort

PLCO cohort

ATBC cohort

WhiteheadGenome Center

NCI Core Genotyping

Facility

Page 24: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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 CRUKTim Key

Ruth TravisNaomi Allen

Stat. analyses prostate data

IARC

Federico Canzian

Genotyping Breast Cancer Cases/Controls

Genotyping QC

IARC

Elio RiboliRudolf Kaaks

Coordination

Pooled Bata Base for Breast Cancer

Pooled statistical analyses

Lab analyses of EndogenousHormones

EPIC components of BPC3 , 2003-2005

Page 25: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Imperial College London

Elio Riboli

Scientific Coordination

StatisticalMethods and Analyses

Cambridge U.

Alison Dunning Paul Pharoah

Genotyping Prostate Cancer Cases/Controls

Oxford CRUKTim 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 , 2005-2007

Page 26: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Elio Riboli MD, MPH, ScM

Chair, Cancer Epidemiology and

Prevention,

Department of Epidemiology

Faculty of Medicine

Imperial College London

e.riboli@[email protected]

Page 27: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Whitehead

CEPH

Web ht-SNP Database

Study planning and gene choice

Gene Resequencing

Haplotype determination

Identification of ht-SNPs

Harvard USC & Honolulu

DKFZ & Cambridge

NCI

HarvardCohorts

Multiethnic

Cohort

ACS

EPIC PLCO

ATBC

Breast Cancer IARC-ICL

Collaborative Statistical Analysis

Web and Journal Publications

Exposure Data

Cohort Consortium Work Flow Chart

Prostate Cancer Harvard

Genotyping

Centres

Database consolidationand Statistical Analyses

Steering Group and

Secretariat

PUBLIC ACCESS

PUBLIC ACCESS

NCI

Page 28: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

THE END

Page 29: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Regulation of IGF1 and related moleculesRegulation of IGF1 and related molecules

Target tissues: Breast Prostate Colorectum etc.

IGF1RHypothalamus

SST GHRH

Stomach

Ghrelin

-

Pituitary

SSTR GHRHR -

-GH

- +POU1F1

GH

Circulation

Growth

+Ghrelin

Circulation

+

+

GHSR

GHSR

Liver

GHR + IGF1

IGFBP3

IGFALS

IGF1+IGFBP3+IGFALS

Circulation

Page 30: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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 analysismain effects of SNPs and haplotypes,

gene-environment interactionsBreast at IARC

Prostate at Harvard

Selection of candidate genes(53 genes involved in metabolism of IGF-I and steroid hormones)

Page 31: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Kaaks / IARC / 98

Available IGF-I

IGFBP1 in plasma, target-tissues

Plasma insulin

Insulin resistance

Plasma SHBG

Ovarian androgen production

Plasma testosterone

Estrogen binding to SHBG

Free estrogen

Regulation of plasma steroid hormones by insulin / IGF-I in women

Page 32: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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,

Page 33: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

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

Page 34: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

RR trend-p

< 0.001

< 0.001

< 0.001Testosterone

Androstenedione

Estrone

12345

12345

12345

12345

<0.001Estradiolo

0.5 1 2 4

Androgens levels and subsequent breast cancer relative risk:Pooled cohort study

Endogenous Hormones and Breast Cancer Collaborative Group, JNCI, 2002; 94: 606

Page 35: Elio Riboli MD, MPH, ScM  Head, Nutrition, Hormones and Cancer Group I.A.R.C.-W.H.O.

Kaaks / IARC / 98

Available IGF-I

IGFBP1 in plasma, target-tissues

Plasma insulin

Insulin resistance

Plasma SHBG

Ovarian androgen production

Plasma testosterone

Estrogen binding to SHBG

Free estrogen

Regulation of plasma steroid hormones by insulin & IGF- I