Genes and the Environmentin Cancer Causation

Joseph F. Fraumeni, Jr., M.D.

National Cancer Institute

January 9, 2007

Third Annual Alan S. Rabson Award Lecture for Intramural Research

A distinguished NIH couple, Alan Rabson (Deputy Director of NCI) and Ruth Kirschstein

(former Acting Director of NIH)

Early Days at the National Cancer Institute

Categories of Cancer Causation

Environment- +

Gen

es+

- Spontaneous

Microbes – 1960s Chemicals – 1970s Lifestyle – 1980s

Hereditary syndromes Low-penetrant variants

Interactions

International Variation in Cancer Incidence

Type of Cancer H/L Highest Rates Lowest Rates

Melanoma 155 Australia Japan

Nasopharynx 100 Hong Kong U.K.

Prostate 70 U.S. (Black) China

Liver 50 China Canada

Cervix uteri 28 Brazil Israel

Stomach 22 Japan Kuwait

Lung 19 U.S. (Black) India

Colon 19 U.S. (White) India

Bladder 16 Switzerland India

Pancreas 11 U.S. (Black) India

Ovary 8 N.Z. (Maori) Kuwait

Breast 7 Hawaii (Hawaiian) Israel (Non-Jews)

Leukemia 5 Canada India

RRs of Breast Cancer in Asian-American Women by Migration History

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

E // 4E rural - E <8 y in W

E // 4Eurban - E<8 y in W

E // 4E rural - E 8+ y in W

E // 4Eurban - E8+ y in W

W // 4E W//1-2W W//3-4W

Re

lati

ve

Ris

ks

Ziegler, R. et al. JNCI 1993; 85: 1819-27

Estimated Annual Percent Increase in Cancer Incidence

SEER 1992-2001

WM WF BM BF

Liver 3.9 5.0 4.8 2.2

Melanoma 3.2 3.2 2.2 -3.4

Thyroid 2.8 4.8 0.8 3.8

Kidney 1.4 1.4 1.9 2.8

Testis 1.3 - 6.4 -

NHL -0.5 0.8 -1.5 2.9

Esophagus 1.9 -0.2 -5.8 -4.1

Esophageal Cancer, 1973-1998 (Males)

Squamous Cell CarcinomaBlack Males

Squamous Cell CarcinomaWhite Males

AdenocarcinomaBlack Males

AdenocarcinomaWhite Males

73-74 78-80 84-86 90-92 96-98

1

10

Year of Diagnosis

Rate per 100,000

0.1

Esophageal Cancer, 1973-1998 (Males)

Squamous Cell CarcinomaBlack Males

Squamous Cell CarcinomaWhite Males

AdenocarcinomaBlack Males

AdenocarcinomaWhite Males

73-74 78-80 84-86 90-92 96-98

1

10

Year of Diagnosis

Rate per 100,000

0.1

Squamous Cell CarcinomaBlack Males

Squamous Cell CarcinomaWhite Males

AdenocarcinomaBlack Males

AdenocarcinomaWhite Males

73-74 78-80 84-86 90-92 96-98

1

10

Year of Diagnosis

Rate per 100,000

0.1

Copper Smelter, Montana

Indoor Air Pollution in China

The Causes of Cancer

• Tobacco +++++• Alcohol ++?• Nutrition, including energy balance +++?• Infection and inflammation ++?• Occupational hazards +?• Environmental pollution +?• Pharmaceuticals, including hormones +?• Ionizing and UV radiation +?• Genetic susceptibility ++???

Note: About 50% of all cancer appears related to modifiable risk factors.

Alfred G. Knudson and Two-hit Model for Retinoblastoma

Proc Natl Acad Sci USA 1971; 68: 820-3

Child with Congenital Aniridia

Li-Fraumeni Syndrome_________________________________

• Dominantly inherited

• Striking variety of early-onset tumors

• Predisposition to second primaries

• Germline mutations of p53

Cloned Familial Tumor Suppressor Genes

Retinoblastoma RB1 13q14 1986

Wilms’ tumor WT1 11p13 1990

Li-Fraumeni syndrome p53 17p13 1990

Neurofibromatosis 1 NF1 17q11 1990

Neurofibromatosis 2 NF2 22q12 1993

von Hippel-Lindau syndrome VHL 3p25 1993

Familial melanoma 1 p16 9p211994

Familial breast cancer 1 BRCA1 17q21 1994

Familial breast cancer 2 BRCA2 13q12 1995

Basal cell nevus syndrome PTC 9q22 1996

0

10

20

30

40

0 10 20 30 40 50

Survival (Years)

Pe

rce

nt

Cu

mu

lati

ve

In

cid

en

ce

Radiotherapy No Radiotherapy

Cumulative Incidence of Second Cancer After Hereditary Retinoblastoma

Susceptibility (Modifier) Genes*

Function ExamplesBehavior OPRMI, LEP

Metabolism ALDH2, NAT2, MTHFR

Hormones COMT, SRD5A2

Growth Factors IGF1, GMCSF

Cell Cycle CHEK2

DNA Repair XRCC1, XRCC3

Apoptosis FAS, CASP8

Telomerase TERT, DKC1

Angiogenesis VEGF, CD14

Immune Regulation CCR5, TNF, IL8

*Role of carcinogens or anti-carcinogens may be inferred by knowing the substrate or pathway of the gene variant.

Moving Toward Large-scale Studies:International Consortia

• Multicenter partnerships that strategically and cost-efficiently utilize separately funded epidemiologic studies with biospecimen collections.

• Cohort, case-control, and family-based consortia that maximize power of genomic and other emerging technologies.

• Replication strategies: Provides rapid confirmation of positive or negative findings from independent datasets.

• Pooling strategies: Combines datasets for statistical power to identify risks from gene variants, exposures, and interactions.

InterLymph (18,000 Cases) International Lymphoma Epidemiology Consortium

Participating Centers

IL1B-511 Variant TNF G-308A Variant

Rothman, et al. Lancet Oncol 2006; 7: 27-38

NCI Consortium of CohortsExploiting the Molecular Revolution for Cancer Discovery and Pre-emption

Follow-up Study #1 3500 cases/3500 controls

Follow-up Study #23500 cases/3500 controls

Fine Mapping

Initial Study1150 cases/1150 controls

~28,000 SNPs

at least 1,500SNPs

30 ±20loci

540,000 Tag SNPs

General Strategy for Prostate & Breast CancerGenome-wide Association Studies

Epidemiology During the Molecular Revolution

• Move with greater speed and force to identify genetic/environmental determinants in cancer induction and progression.

• Probe into causal pathways and mechanisms as possible targets for intervention.

• Foster platforms and strategies of large-scale studies, including consortial initiatives.

• Encourage multidisciplinary research to galvanize discovery and translation to clinical practice and public health.

DCEG Senior Advisory Group Retreat 2006

Robert Warwick Miller, M.D.1921 – 2006