1. 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

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

3. Early Days at the National Cancer Institute

4. Categories of Cancer Causation Environment - + Genes + -

5. International Variation in Cancer Incidence

6. RRs of Breast Cancer in Asian-American Women by Migration History Ziegler, R. et al. JNCI 1993; 85: 1819-27

7. Estimated Annual Percent Increase in Cancer Incidence SEER 1992-2001 WMWFBMBF 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

11. Copper Smelter, Montana

15. Indoor Air Pollution in China

16. 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.

17. Alfred G. Knudson and Two-hit Model for Retinoblastoma Proc Natl Acad Sci USA 1971; 68: 820-3

18. Child with Congenital Aniridia

20. Li-Fraumeni Syndrome _________________________________ Dominantly inherited Striking variety of early-onset tumors Predisposition to second primaries Germline mutations of p53

21. Cloned Familial Tumor Suppressor Genes RetinoblastomaRB113q141986 Wilms’ tumorWT111p131990 Li-Fraumeni syndromep5317p131990 Neurofibromatosis 1NF117q111990 Neurofibromatosis 2NF222q121993 von Hippel-Lindau syndromeVHL3p251993 Familial melanoma 1p169p211994 Familial breast cancer 1BRCA117q211994 Familial breast cancer 2BRCA213q121995 Basal cell nevus syndromePTC9q221996

22. Cumulative Incidence of Second Cancer After Hereditary Retinoblastoma

24. 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.

25. 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.

26. InterLymph (18,000 Cases) International Lymphoma Epidemiology Consortium Participating Centers

27. IL1B-511 Variant TNF G-308A Variant Rothman, et al. Lancet Oncol 2006; 7: 27-38

28. NCI Consortium of Cohorts Exploiting the Molecular Revolution for Cancer Discovery and Pre-emption

29. Follow-up Study #1 3500 cases/3500 controls Follow-up Study #2 3500 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

30. 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.

31. DCEG Senior Advisory Group Retreat 2006

32. Robert Warwick Miller, M.D. 1921 – 2006