Genes and the Environment
in Cancer Causation
Joseph F. Fraumeni, Jr., M.D.
Third Annual Alan S. Rabson Award
Lecture for Intramural Research
National Cancer Institute
January 9, 2007
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
Genes
+
-
Environment
-
+
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
Prostate
100
70
Hong Kong
U.S. (Black)
U.K.
China
Liver
50
China
Canada
Cervix uteri
28
Brazil
Israel
Stomach
Lung
Colon
22
19
19
Japan
U.S. (Black)
U.S. (White)
Kuwait
India
India
Bladder
Pancreas
Ovary
Breast
16
11
8
7
Switzerland
U.S. (Black)
N.Z. (Maori)
Hawaii (Hawaiian)
India
India
Kuwait
Israel (Non-Jews)
Leukemia
5
Canada
India
RRs of Breast Cancer in Asian-American Women by Migration History
1.8
Relative Risks
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
E // 4E
E // 4E
E // 4E
E // 4E
W // 4E
rural - E urban - E rural - E urban - E
<8 y in W <8 y in W 8+ y in W 8+ y in W
Ziegler, R. et al. JNCI 1993; 85: 1819-27
W//1-2W W//3-4W
Estimated Annual Percent
Increase in Cancer Incidence
SEER 1992-2001
WM
Liver
3.9
Melanoma 3.2
Thyroid
2.8
Kidney
1.4
Testis
1.3
NHL
-0.5
Esophagus 1.9
WF BM BF
5.0 4.8 2.2
3.2 2.2 -3.4
4.8 0.8 3.8
1.4 1.9 2.8
6.4
0.8 -1.5 2.9
-0.2 -5.8 -4.1
Esophageal Cancer, 1973-1998 (Males)
Rate per 100,000
Squamous Cell Carcinoma
Black Males
10
Squamous Cell Carcinoma
White Males
Adenocarcinoma
White Males
1
Adenocarcinoma
Black Males
0.1
73-74
78-80
84-86
90-92
Year of Diagnosis
96-98
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
9p21
1994
Familial breast cancer 1
BRCA1 17q21
1994
Familial breast cancer 2
BRCA2 13q12
1995
Basal cell nevus syndrome
PTC
9q22
1996
Percent Cumulative Incidence
Cumulative Incidence of Second Cancer
After Hereditary Retinoblastoma
40
30
20
10
0
0
10
20
30
40
Survival (Years)
Radiotherapy
No Radiotherapy
50
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.
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
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
Fine Mapping
30 ±20
loci
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