Genes and the Environment in Cancer Causation Joseph F. Fraumeni, Jr., M.D.

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Genes and the Environmentin Cancer
CausationJoseph F. Fraumeni, Jr., M.D.
Third Annual Alan S. Rabson Award Lecture for
Intramural Research

• National Cancer Institute
• January 9, 2007

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A distinguished NIH couple, Alan Rabson (Deputy
Director of NCI) and Ruth Kirschstein (former
Acting Director of NIH)
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Early Days at the National Cancer Institute
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Categories of Cancer Causation
Environment -
Genes -
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International Variation in Cancer Incidence
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RRs of Breast Cancer in Asian-American Women by
Migration History
Ziegler, R. et al. JNCI 1993 85 1819-27
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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
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Copper Smelter, Montana
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Indoor Air Pollution in China
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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.

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Alfred G. Knudson and Two-hit Model for
Retinoblastoma
Proc Natl Acad Sci USA 1971 68 820-3
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Child with Congenital Aniridia
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• Li-Fraumeni Syndrome
• _________________________________
• Dominantly inherited
• Striking variety of early-onset tumors
• Predisposition to second primaries
• Germline mutations of p53

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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 9p21 1994 Familial breast cancer
1 BRCA1 17q21 1994 Familial breast cancer
2 BRCA2 13q12 1995 Basal cell nevus
syndrome PTC 9q22 1996
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Cumulative Incidence of Second Cancer After
Hereditary Retinoblastoma
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Susceptibility (Modifier) Genes
Function Examples Behavior 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.
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Moving Toward Large-scale StudiesInternational
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.

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InterLymph (18,000 Cases) International Lymphoma
Epidemiology Consortium
Participating Centers
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IL1B-511 Variant
TNF G-308A Variant
Rothman, et al. Lancet Oncol 2006 7 27-38
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NCI Consortium of Cohorts
Exploiting the Molecular Revolution for Cancer
Discovery and Pre-emption
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General Strategy for Prostate Breast
Cancer Genome-wide Association Studies
Initial Study 1150 cases/1150 controls
540,000 Tag SNPs
Follow-up Study 1 3500 cases/3500 controls
28,000 SNPs
Follow-up Study 2 3500 cases/3500 controls
at least 1,500 SNPs
30 20 loci
Fine Mapping
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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.

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DCEG Senior Advisory Group Retreat 2006
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Robert Warwick Miller, M.D. 1921 2006