Causes of Cancer risk

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?

1 in 1 (100%) 1 in 2 (50%) 1 in 3 (33%)

1 in 5 (20%) 1 in 79,451 (0.0000125%)

• The risk for getting into a car accident is 1 in 8
• The risk for lung cancer in smokers is 1 in 10
• The risk of getting cancer is 1 in 2 for men
• The risk for dying from cancer is 1 in 4
• The risk for being struck by lightning is 1 in 2.5 million
• EPA models risk for 1 cancer in 1 million 7
 CARCINOGENESIS ASSESSMENT
REGULATORY, RESEARCH AND
REVIEW ORGANIZATIONS

• Environmental Protection Agency

• American Conference of Governmental Industrial Hygenists
• National Toxicology Program
• Agency for Toxic Substances Disease Registry
• Food and Drug Administration
• Consumer Product Safety Commission
• Occupational Safety and Health Administration
• National Institute for Occupational Safety and Health
• International Agency for Research on Cancer
• Numerous Foreign Government Regulatory Agencies
 Risk Assessment
Risk: 1 in 79,451

Arrowhead Stadium, Kansas City, has 79,451 seats

Environmental Protection Agency
Risk Assessment

Risk less than 1 additional cancer in 1 million people

How is Cancer Causation Determined?
Conflicting studies are part of our lives…..

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

 Literature review: known risk factors

and exposure/chemical of concern
• Apply causation criteria
Risk Factor History  Exposure history
Lifestyle and diet, recreation,
occupation, and medications and
treatments
 Family history
 Previous illnesses

 Environmental monitoring
Exposure Assessment  Biomarkers
 Scientific studies of analogous exposures
and highly exposed persons

Form opinions and provide recommendations

 Cancer Myths
Some people incorrectly believe that:
• What someone does as a young adult has
nothing to do with getting cancer
• Electrical devices, like cell phones and
microwaves cause cancer
• Organic foods must reduce cancer risk
• Taking vitamins must reduce cancer risk
• Injuries, like broken bones and cuts, cause
cancer
• Living in a polluted city is worse than smoking
• Cancer is more common today
 Cancer Incidence Rates* Among Men, US, 1975-2004

Rate Per 100,000

250

Prostate
200

150

Lung & bronchus

100

Colon and rectum

50 Urinary bladder

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

Rate Per 100,000

250

200

150 Breast

100

Colon and rectum Lung & bronchus

50
Uterine Corpus
Ovary
Non-Hodgkin lymphoma
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.
 Smoking and Lung Cancer
An Example of a Human Carcinogen
Risk of dying from
any cancer is
increased 1.97-fold

Hammond and Horn. CA Cancer J Clin 38: 28-58, 1988

 What is in Tobacco Smoke
• Cigarette smoke contains many known and
probably classified human carcinogens:
– Aromatic Amines
– Nitrosamines
– Vinyl Chloride
– Benzene
– 1,3-Budadiene
– Polycyclic aromatic hydrocarbons
– Metals such as cadmium, chromium and
arsenic
– Radioactive chemicals
 Nicotine is a Powerful Drug….
• Dopamine – pleasure, appetite
• Norepinephrine – arousal, appetite
• Acetylcholine – arousal, cognitive
• Vasopressin – memory
• Serotonin – mood modulation, appetite
• Beta-Endorphin – anxiety
 Smoking Causes Lung Cancer:
Cancer Death Rates for Men
Years 1930-2003
100
Age-Adjusted Rate Per 100,000

Lung & bronchus

80

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?

Cancer Statistics, American Cancer Society, 2007

 Lung Cancer and Cigarette Smoking
Consistency and Dose-Response
Number Lung Dose-
of Cancer Risk response
Cohort Subjects Association Estimate relation
MRFIT (1991) 12866 Yes 7 Yes
Swedish Study (2004) 25444 Yes NA Yes
British doctors (1994) 34439 Yes 15 Yes
Iowa Women's Health (1992) 41843 Yes 10 Yes
California Study (1970) 68153 Yes 8 Yes
Norwegian Study (1993) 68825 Yes 16 Yes
Canadian Veterans (2004) 78000 Yes NA Yes
ACS-25 State Study (1989) 120000 Yes 11 Yes
ACS – 9 State Study (1988) 187783 Yes 11 Yes
Japanese Study (1990) 265000 Yes 5 Yes
U.S. Veterans (1995) 293958 Yes 11 Yes
Methods to Reduce Tobacco Mortality
Harm Reduction Paradigm

Exposure Risk Reduction Harm Reduction

Reduction Individual Population

Harm Reduction Methods

• The only known method for harm reduction is complete
cessation and long-term abstinence
 Philip Morris, Inc.

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

Baseline Analysis Flat CPD and no Quitters

9/28
Smoking Machines do not Mimic Human
Smoking Behavior

≠
 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

Diet Energy Balance

 Alcohol Drinking

• Alcohol drinking is a risk factor for

oropharyngeal, liver, esophagus,
breast, gastric and pancreatic
cancer
• The type of alcohol that causes
cancer is unknown
• Some alcohol drinking per day
prevents cardiovascular disease
 Alcohol Drinking
Risks and Benefits

Cancer
Cardiovascular
Health
 Women

Breast Drinks per day (p trend=0.02)

Cancer None <1 1 2-3 >4
Death rate 30.3 33.3 37.6 45.8 29.1
Relative risk 1.0 1.1 (0.9, 1.3) 1.2 (1.0, 1.6) 1.5 (1.2, 1.9) 1.0 (0.7, 1.4)
Alcoholic Beverages and Cancer
ADH (90%) ALDH
Ethanol Acetaldehyde Acetate
CYP2E1 (10%)

Carcinogenesis mechanism unknown:

• Effects on estrogen metabolism and response
• Acetaldehyde is a mutagen and carcinogen in
experimental models
• Free-radicals
• Folate metabolism and methylation
• Contaminants are direct acting mutagens and
carcinogens (N-nitrosamines, urethane)
 Alcohol Drinking and Breast
Cancer
• Wide consistency among published
studies
• About 1.4-fold increased risk
• Most consistent for >3 drinks/day, but
good studies show risk at 1-2 drinks/day
• Causes about 14,000 cases in U.S.
• No consistent relationship with a
particular type of beverage
 Multistage Carcinogenesis
Exogenous Endogenous Endogenous
Carcinogen Exposure Carcinogen Exposure Mutational Mechanisms
Metabolic Activation
Detoxification
Genetic and Epigenetic Damage
Caretaker genes
Gatekeeper genes

Failure to repair DNA or Apoptosis

Cancerization through accumulated genetic events

Normal Initiated Preneoplastic Malignant Clone Clinical cancer

Cells Cells Lesion
 CARCINOGENESIS AND CANCER RISK
Caretaker Genes Macro Environment
• DNA Repair • Chemicals
• Carcinogen Metabolic Activation • Viruses
• Carcinogen Detoxification • Radiation
• Physical Agents

Interindividual
GeneN EnvironmentN
Variation

Gatekeeper Genes Micro Environment

• Cell Cycle Control • Oxyradicals
• Programmed Cell • Nitric Oxide
Death • Hormones
• Growth Factors

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

Functional Genotypes Cancer Risk

Studies Haplotypes Replication
And Truth
Phenotypes Genotypes Corroboration
Haplotypes

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

Wray, et al. Current Opinion in Genetics and Development, 2008

 8q24 and Cancer Risk

• The 8q24 region associates with many cancers

• A “gene desert” – no characterized genes
• Found in different races
Ioannidis, et al Nat Rev Genet 2009
 Genetic Markers for Risky
Behaviors and Cancer Risk
• Risky Behaviors – Do we need genetics?
– Target those at most risk for best interventions to
groups
– Tailor interventions to the individual
– Develop new prevention methods
– Understand the biology
• Cancer Risk – Moving toward personalize medicine
– Target early detection strategies to groups
– Tailor early detection strategies
– Develop new prevention methods
– Understand the biology
 Nicotine and Dopamine Reward
Mechanisms in the Brain

Nicotinic receptor

Leshner, NEJM, 1996

 Genetic Basis for Addiction:
Dopamine Pathways
OR=0.45 OR=1.23
S P=0.001 P=0.21
L N=238 N=180
C 60
6 50
SLC6A3 9/* X DRD2
A 40 Interaction
3 30 P=0.01
20
9/* 10
(%) 0

A2/A2 A1/A1, A1/A2

DRD2 Genotype
DRD2 Genotype
Nonsmokers Smokers

Lerman, et al, Health Psychology, 1998

 Predictors of Smoking
Progression Among Adolescents

• CES-D significant predictor of smoking at baseline

Audrain, et al. Am J Psychiatry 2004
 Bupropion Smoking Cessation Trial
SLC6A3 and DRD2 Genotypes
Variable Odds Ratio 95% CI p
Bupropion v. placebo 1.87 1.24 – 2.82 .003
Gender .51 .34 - .78 .002
Nicotine Dep. .83 .75 - .92 .000
SLC6A3 .67 .36 – 1.2 .20
DRD2 .54 .30 - .96 .04
SLCA3* DRD21 2.4 1.07 – 5.48 .03
1EOT only, not at 6 months; Logistic Regression with variables p>0.10

• Pooled analysis with data from Brown University (Niura/David) shows similar
results

Lerman, et al Health Psychology, 2003

• Genetics don’t drive smoking, society does
 GWAS and Smoking
• Genetics of risk phenotypes
– Initiation, cigarettes per day, nicotine
dependence, withdrawal severity and quitting
• Targets in the nicotinic receptor identified
in several studies, also linked to lung
cancer
• Tailoring therapies
– Nicotine replacement therapy
– Chantix or Zyban
– Denicotinized cigarettes
– Others, e.g., vaccine therapies?
GWAS and Obesity

Davies, et al. Nat Rev Genet 2009

How to Prevent Cancer

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