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
Endogenous Oxy-radical Damage
Polymerase infidelity
Phase I Activation
Protooncogene Activation
Phase I Activation Promutagenic Adducts Failure to Repair
Depurination
Loss of Detoxification
Chemical Exposure
Endogenous NO
Recombinase Infidelity
Polymerase infidelity
Exogenous Oxyradical Damage
Loss of Suppressor Gene
Loss of Suppressor Gene 186-PS
Radiation Exposure
CANCER EPIDEMIOLOGY A Newish Paradigm •
Traditional Epidemiology (Single Agent) Mycobacterium Tuberculosis
Pneumonia •
•
Unique Disease
Molecular Epidemiology (Multiple Agents) Diet Air
Interindividual variation
Cancer
Occupation Endogenous
•
Same cancers are caused by different agents in different people
EPIDEMIOLOGY Classical Epidemiology:
Molecular Epidemiology:
Exposure
Black Box
Disease outcome (groups)
Less-Black Box Exposure
Adduction Metabolism Repair Mutation Oncogenes Suppressor Genes
Disease outcome (individual)
What is Dose-Response? 45 40 35 30 25
Risk
20 15 10 5 0
Exposure
6
What are some examples of risk?
1 in 1 (100%)
1 in 5 (20%)
• • • • • •
1 in 2 (50%)
1 in 3 (33%)
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 History
Risk Factor History
Exposure Assessment
Medical records Diagnostic Studies
Confirm diagnosis
Literature review: known risk factors and exposure/chemical of concern • Apply causation criteria Exposure history Lifestyle and diet, recreation, occupation, and medications and treatments Family history Previous illnesses Environmental monitoring 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
*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.
2002
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
0 1975
Non-Hodgkin lymphoma
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 Lung & bronchus 80
60
40
2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
1950
1945
1940
0
1935
20
1930
Age-Adjusted Rate Per 100,000
100
• 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 Cohort
Number Lung of Cancer Subjects Association
DoseRisk response 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 Reduction
Risk Reduction Individual
Harm Reduction 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 Risk
Population Risk
Ca. 1970
Incorrect Interpretations from Epidemiology – CPS1 “If you cant quit, switch to lights, just don’t Monograph 13, 2002 – Odds compensate” Ratios
1989 Publication – Lung Cancer Mortality
Baseline Analysis
Baseline Analysis 9/28
Flat CPD and no Quitters
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 Bad
Good
Diet
Intake
PE
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 Cancer
Drinks per day (p trend=0.02) 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 Ethanol
ADH (90%) CYP2E1 (10%)
Acetaldehyde
ALDH
Acetate
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 Carcinogen Exposure
Endogenous Endogenous 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 Cells
Initiated Cells
Preneoplastic Malignant Clone Lesion
Clinical cancer
CARCINOGENESIS AND CANCER RISK Macro Environment • Chemicals • Viruses • Radiation • Physical Agents
Caretaker Genes • DNA Repair • Carcinogen Metabolic Activation • Carcinogen Detoxification
GeneN
Interindividual Variation
Gatekeeper Genes • Cell Cycle Control • Programmed Cell Death
EnvironmentN
Micro Environment • Oxyradicals • Nitric Oxide • 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 Studies
Genotypes Haplotypes
Phenotypes
Genotypes Haplotypes
GWAS
Phenotypes Genotypes Haplotypes
Cancer Risk Replication And Corroboration
Truth
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 S L C 6 A 3
OR=0.45 P=0.001 N=238
OR=1.23 P=0.21 N=180
60 50
SLC6A3 9/* X DRD2 Interaction P=0.01
40 30 20
9/* (%)
10 0
A2/A2
A1/A1, A1/A2
DRD2 Genotype DRD2 Genotype
Nonsmokers Lerman, et al, Health Psychology, 1998
Smokers
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 Bupropion v. placebo
Odds Ratio 95% CI 1.87 1.24 – 2.82
p .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
