Genes and the Environment in 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 - + Genes + -

International Variation in Cancer Incidence

RRs of Breast Cancer in Asian-American Women by Migration History Ziegler, R. et al. JNCI 1993; 85:

Estimated Annual Percent Increase in Cancer Incidence SEER WMWFBMBF Liver Melanoma Thyroid Kidney Testis NHL Esophagus

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 RetinoblastomaRB113q Wilms’ tumorWT111p Li-Fraumeni syndromep5317p Neurofibromatosis 1NF117q Neurofibromatosis 2NF222q von Hippel-Lindau syndromeVHL3p Familial melanoma 1p169p Familial breast cancer 1BRCA117q Familial breast cancer 2BRCA213q Basal cell nevus syndromePTC9q221996

Cumulative Incidence of Second Cancer After Hereditary Retinoblastoma

Susceptibility (Modifier) Genes* FunctionExamples BehaviorOPRMI, LEP MetabolismALDH2, NAT2, MTHFR HormonesCOMT, SRD5A2 Growth FactorsIGF1, GMCSF Cell CycleCHEK2 DNA RepairXRCC1, XRCC3 ApoptosisFAS, CASP8 TelomeraseTERT, DKC1 AngiogenesisVEGF, CD14 Immune RegulationCCR5, 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 Cohorts Exploiting the Molecular Revolution for Cancer Discovery and Pre-emption

Follow-up Study # cases/3500 controls Follow-up Study # cases/3500 controls Fine Mapping Initial Study 1150 cases/1150 controls ~28,000 SNPs at least 1,500 SNPs 30 ±20 loci 540,000 Tag SNPs General Strategy for Prostate & Breast Cancer Genome-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 – 2006