Documentos de Académico
Documentos de Profesional
Documentos de Cultura
and Responsibility
Peter G. Shields, MD
Deputy Director
Professor of Medicine and Oncology
Lombardi Comprehensive Cancer Center
Georgetown University
Washington, DC 20057
Overview
• How does cancer develop
• Examples of smoking, drinking, obesity
and environmental risk factors
• Gene finding for cancer risk and risky
behaviors
• Examples of genetic studies for smoking
and obesity
• Best methods to reduce cancer risks
THE ETIOLOGY OF CANCER
Chemical
Exposure Polymerase Endogenous
infidelity Oxy-radical
Damage
Phase I
Activation Proto- Exogenous
oncogene Oxy-
Phase I radical
Activation Activation
Damage
Promutagenic
Adducts
Loss of Chemical
Failure Detoxification Exposure
to Repair Depurination
Recombinase Endogenous
Infidelity NO
Loss of
Suppressor Loss of
Polymerase Gene Suppressor Radiation
infidelity Gene Exposure
186-PS
CANCER EPIDEMIOLOGY
A Newish Paradigm
• Traditional Epidemiology (Single Agent)
Mycobacterium
Pneumonia
Tuberculosis
• Unique Disease
• Molecular Epidemiology (Multiple Agents)
Diet
Interindividual
Air variation
Cancer
Occupation
Endogenous • Same cancers are caused
by different agents in
different people
EPIDEMIOLOGY
Classical Black Disease outcome
Epidemiology: Exposure
Box (groups)
Less-Black
Molecular Box
Epidemiology: Exposure Adduction Disease outcome
Metabolism (individual)
Repair
Mutation
Oncogenes
Suppressor
Genes
What is Dose-Response?
45
40
35
30
25
20
Risk
15
10
5
0
Exposure
6
What are some examples of risk?
11
Bradford-Hill Guidelines
• Consistency among epidemiology studies (how
many good quality studies say the same thing?)
• Dose-response (does more exposure cause
more disease?)
• Timing of exposure (does the cancer come after
the exposure and a believable period of time?)
• Strength of Association (are results believable?)
• Specificity (is the disease unique?)
• Biologically plausible (does it make sense?)
• Coherence (does it agree with laboratory data?)
• Structural similarities to other toxins
What Not to Do For Risk Assessment
• Don’t make assumptions
– What might make sense may not have
a science base
• Most cancer patients do not have an
obvious cause, but that does allow for
one to conclude that some chemical
caused it
• It is not appropriate to conclude that if a
person was exposed to a chemical at any
dose, then they might get cancer
The Steps for Determining Individual
Causation
Medical records
Medical History Diagnostic Studies Confirm diagnosis
Environmental monitoring
Exposure Assessment Biomarkers
Scientific studies of analogous exposures
and highly exposed persons
Prostate
200
150
Non-Hodgkin lymphoma
Melanoma of the skin
0
1975 1978 1981 1984 1987 1990 1993 1996 1999 2002
*Age-adjusted to the 2000 US standard population and adjusted for delays in reporting.
Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database:
SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2004, National Cancer Institute, 2007.
Cancer Incidence Rates* Among Women, US, 1975-2004
200
150 Breast
100
*Age-adjusted to the 2000 US standard population and adjusted for delays in reporting.
Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database:
SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2004, National Cancer Institute, 2007.
Smoking and Lung Cancer
An Example of a Human Carcinogen
Risk of dying from
any cancer is
increased 1.97-fold
60
40
20
0
1955
1960
1965
1970
1975
1980
1985
2000
1930
1935
1940
1945
1950
1990
1995
• Lung, a mostly fatal disease, increased with smoking
• Before smoking, lung cancer was a rare disease
Source: National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.
What are the most common cancers
that people get?
RJ Reynolds.
Liggett Lorillard
Is “Less Ought to Be Better”?
• Less is better if the reduction in risk is measurable,
and does not adversely affect known ways to
reduce smoking and tobacco control measures
Individual Population
Risk Risk
Ca. 1970
Incorrect Interpretations from Epidemiology – CPS1
“If you cant quit, switch to lights, just don’t
compensate” Monograph 13, 2002 – Odds
Ratios
1989 Publication – Lung Cancer Mortality
Baseline Analysis
≠
Obesity
• 64% of US is obese or overweight in 1999-2000
(children and adults) (NHANES)
– 58% in1994
– 33% are currently obese (27% in 1994)
• Cause: sedentary lifestyle and high calorie/fat diets
• Obesity linked to cancers of the colon, breast
(postmenopausal), kidney, and esophagus
• The biological link of obesity to cancer is unclear
• Unknowns
– Does losing weight reduce cancer risk?
– Does increasing physical activity reduce cancer
risk?
Diet, Weight, Physical Activity
and Cancer Risk
Good Bad Intake PE
Cancer
Cardiovascular
Health
Women
Interindividual
GeneN EnvironmentN
Variation
Cancer
The Interindividual Variation In the Binding Levels of
Benzo[a]pyrene to DNA in Human Bronchial Explants
Human Genetic Variation
• Estimated: 11 million SNPs with minor alleles ≥ 1%
– 1 SNP < 300 bp
• Common genetic variation (alleles ≥ 5%) accounts for
>90% of human genetic diversity
• Two theories:
– A large number of rare alleles underlie common
diseases
• <<1% allele frequencies
– Alleles underlying common diseases are common
(>5%)
• Most common diseases have late-onset
• Alleles are expected to have only subtle effects
• Under neutral selection - alleles will be common
The Fast Track to Truth
Candidate SNPs
Haplotypes
Phenotypes
GWAS Phenotypes
Genotypes
Haplotypes
Approaches for Tagging Common Variation:
Haplotype Block-based methods
Genome-Wide Association Studies
Genome Wide Association Studies
Risk Estimates of SNPs
Nicotinic receptor
• Pooled analysis with data from Brown University (Niura/David) shows similar
results
Don’t Eat
Don’t Drink
Don’t have Sex
Don’t Smoke
Don’t Breathe
Don’t drink Water
Don’t get Old
Don’t have Parents
Have a nice day…….
Preventing Cancer Guidelines
• Do not smoke
• Eat a variety of healthful foods
• Eat 9 or more vegetables and fruits per day
• Eat whole grains rather than refined grains
• Limit consumption of red meats
• Choose foods that maintain a healthful
weight
• Be physically active and have a healthy
weight
• Limit alcohol consumption
Thank you