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3. Lecture Outline
Cancer - What is it? What causes it?
Epidemiological evidence for a role of
environment/life-style factors as causes of
cancer
Mechanisms of carcinogenesis
– Carcinogenic agents
– Carcinogen bioactivation, DNA damage/repair
– Molecular targets: oncogenes, tumor suppressor
genes
Multistage nature of carcinogenesis
Prevention of carcinogenesis 3
5. Cancer: The Endpoint
What is it?
– Group of diseases
– Uncontrolled growth
– Spread (invasion, metastasis)
5
6. Carcinogenesis: The Process
What causes it?
– Exogenous: Chemicals, radiation,
viruses
– Endogenous: Hormones, immune
dysfunction,
– Inherited mutations (susceptibilities)
6
7. CANCER ARISES FROM
THE ACCUMULATION
OF GENETIC DAMAGE
(only 5-15 % of cancer is
due to inherited cancer
genes)
7
Public Domain
8. SINGLE AND SUSCEPTIBILITY GENES IN CANCER CAUSE
Single Susceptibility Gene
Definition Necessary & sufficient Alters risk but is neither
for disease necessary nor sufficient
for disease causation
Example BRCA (breast/ovary) CYP1A1 (lung)
APC (polyposis coli) CYP2D6 (lung)
RB (retinoblastoma) GST-M1 (lung, bladder)
Gene prevelence Low Often high
Gene type Mutation Polymorphism or mutation
Study setting Family Gen. population/epi. studies
Strength of association Very high Low to moderate
Absolute risk High Low
Population attributable
risk Low High
Gene-environment
interaction 2° and variable 1° and implicit
Role of environmental
exposure 2° and variable Crucial
8
9. Risk of Breast Cancer Among BRCA1 or BRAC2 Mutation Carriers
JHSPH OpenCourseWare has removed this image
because license for its use could not be secured.
See Figure 1A. King MC, et al. Breast and ovarian cancer
risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003;302:643-646. Free with registration.
9
10. Influence of Birth Cohort on Risk of Breast Cancer
in BRCA1 or BRCA2 Mutation Carriers
JHSPH OpenCourseWare has removed this image
because license for its use could not be secured.
See Figure 1D. King MC, et al. Breast and ovarian cancer
risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003;302:643-646. Free with registration.
10
11. Effect of Physical Activity on Risk of Breast Cancer in
BRCA1 or BRCA2 Carriers
JHSPH OpenCourseWare has removed this image
because license for its use could not be secured.
See Figure 1F. King MC, et al. Breast and ovarian cancer
risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003;302:643-646. Free with registration.
11
12. SINGLE AND SUSCEPTIBILITY GENES IN CANCER CAUSE
Single Susceptibility Gene
Definition Necessary & sufficient Alters risk but is neither
for disease necessary nor sufficient
for disease causation
Example BRCA (breast/ovary) CYP1A1 (lung)
APC (polyposis coli) CYP2D6 (lung)
RB (retinoblastoma) GST-M1 (lung, bladder)
Gene prevelence Low Often high
Gene type Mutation Polymorphism or mutation
Study setting Family Gen. population/epi. studies
Strength of association Very high Low to moderate
Absolute risk High Low
Population attributable
risk Low High
Gene-environment
interaction 2° and variable 1° and implicit
Role of environmental
exposure 2° and variable Crucial
12
13. Progression of Pre-Cancer to Cancer in
Humans: A Multiyear Process
Atypical
Atypical
Breast
Breast 14-18 yrs DCIS 6-10 yrs
6-10 yrs Cancer
Hyperplasia
Hyperplasia 14-18 yrs DCIS Cancer
Cervix CIN I I 9-13 yrs CIN III/
CIN III/ 10-20 yrs
Cervix CIN 9-13 yrs 10-20 yrs
CIS
CIS
Colon
Colon 5-20 yrs
5-20 yrs Adenoma
Adenoma 5-15 yrs
5-15 yrs
Latent
Latent Clin.
Clin.
Prostate
Prostate 20 yrs
20 yrs PIN > 10 yrs
> 10 yrs 3-15 yrs
3-15 yrs
PIN Carc. Carc.
Carc.
Carc.
13
14. Epidemiological Evidence
For a role of environmental-life factors
as causes of cancer
– Epidemiology provides important
inferences and helps build hypotheses
about the role of environmental factors
in human carcinogenesis
14
15. Role of Environmental Agents
in Human Cancer
Although overall cancer incidence is
reasonably constant between countries,
incidences of specific tumor types can vary
up to several hundred-fold
There are large differences in tumor
incidences within populations of a single
country
Continued 15
16. Role of Environmental Agents
in Human Cancer
Migrant populations assume the cancer
incidence of their new environment within
one to two generations
Cancer rates within a population can
change rapidly
16
17. Geographic Variation in the
Incidence of Some Common Cancers
High Low Ratio
Type Incidence Incidence (35-64 yrs)
Breast USA Uganda 5
Colon USA Nigeria 10
Cervix Columbia Israeli Jews 15
Rectum Denmark Nigeria 20
Stomach Japan Uganda 25
17
18. Geographic Variation in the
Incidence of Some Common Cancers
High Low Ratio
Type Incidence Incidence (35-64 yrs)
Prostate US Blacks Norway 30
Liver Mozambique Norway 70
Skin Australia India >200
Penis Uganda Israeli Jews 300
18
19. Cancer Around the World
Age Adjusted Mortality per 100,000
Population 46 Countries (1974–1975)
Stomach Breast
60 60
50 Male Female 50
40 40
30 30
20 20
10 10
0 0
Japan (1) USA (44) Japan USA (13) England
(43) (1)
19
20. Mortality from Stomach Cancer
(Japan and California)
60
Mortality/100,000/year
50
Age Standardized
40
M
30
20 F
10
0
In Japan Immigrants Born Caucasians
to CA in CA In CA
Japanese
20
21. Mortality From Colon Cancer
(Japan and California)
60
Mortality/100,000/year
50
Age Standardized
40
30
20
M F
10
0
In Japan Immigrants Born Caucasians
to CA in CA in CA
Japanese
21
22. Mortality From Rectal Cancer
(Japan and California)
60
Mortality/100,000/yr
50
Age Standardized
40
30
20
10 M F
0
In Japan Immigrants Born Caucasians
to CA in CA in CA
Japanese
22
30. Cumulative Cancer Mortality In the Worst
10 States and DC (1979-1998)
Death Age Adjusted
State Name Population
Count Rate
District of Columbia 31,365 12,114,011 272.0
Delaware 28,898 13,174,117 241.1
Louisiana 169,699 86,260,188 236.6
Maryland 187,723 93,374,200 236.1
Kentucky 161,990 74,851,849 230.7
Maine 55,404 23,893,173 230.2
New Jersey 351,681 154,248,561 230.2
Nevada 44,249 23,522,411 226.6
Rhode Island 47,715 19,625,760 225.8
New Hampshire 42,737 21,176,058 225.8
30
31. Maryland Cancer Mortality
1997
MELANOMA LUNG AND
PHARYNX 1.2% OTHER BRONCHUS
1.4% 19.5% 28.7%
LIVER
COLON AND
1.8%
RECTUM
BLADDER 11.7%
2.0%
OVARY BREAST
2.2% 8.5%
ESOPHAGUS NHL PROSTATE
2.5% 3.3% PANCREAS 6.4%
STOMACH LEUKEMIAS
2.6% 3.3% 4.7%
31
32. Cancer Mortality Rates
in Maryland by County, 1983–1987
184 161 184
152 168 185
191 185
236 195
174
163
205 176 s
Significantly higher than
US Rate (171)
194 203 190
176
206 198
Rates are age-adjusted to US 1970
201
population; rates per 100,000 192
population 214 180
So
Data source: Maryland Center for
Health Studies
32
33. Breast Cancer Incidence, 1996-1997
88.9-91.2
91.2-107.7
107.7-116.1
116.1-132.7
132.7-143.8
SEER Incidence Rate: 113.9/100,000; Average 96-97
33
34. Breast Cancer Mortality, 1993-1997
Regions with rates that are statistically
significantly higher than the US average
34
35. Prostate Cancer Incidence,
1996-1997
89-102.7
102.7-116
116-147.5
147.5-169.4
169.4-200
SEER Incidence Rate: 137.4; Average 96-97
35
36. Prostate Cancer Mortality,
1993-1997
Regions with rates that are statistically
significantly higher than the US average
36
37. The Causes of Cancer
Quantitative Estimates
of Avoidable Risks of Cancer in the United States
By comparison of cancer incidence in the
U.S. and the lowest incidence areas of the
world, Doll and Peto concluded that:
– 80% of male cancers and 77% of
female cancers are potentially avoidable
37
38. Proportion of Cancer Deaths
Attributed to Environmental Influences
Diet 35%
Tobacco 30%
Infection 10%
Reproductive and sexual behavior 7%
Occupation 4%
Geophysical factors 3%
Alcohol 3%
Pollution 2%
Medicines & medicinal procedures 1%
Industrial products <1%
Food additives <1%
Data Source: Doll and Peto 38
39. Historical Perspective
1713: Ramazzini
– Noted that nuns exhibited a higher
frequency of breast cancer than other
women; attributed it to celibate life
1761: Hill
– Associated the use of tobacco snuff with
cancer of the nasal passages
Continued 39
40. Historical Perspective
1775: Pott
– Noted the occurrence of soot-related
cancer in chimney sweeps
1894: Unna
– Associated sunlight exposure with skin
cancer
Continued 40
41. Historical Perspective
1895: Rehn
– Associated occupational exposure to
aromatic amine dyes with bladder
cancer
1915: Ichikawa
– First experimental production of tumors
in animals (application of coal tar to
ears of rabbit)
Continued 41
52. Mechanisms of Chemical
Carcinogenesis
Activation of carcinogens by
biotransformation
– Molecular targets: DNA
• Types of DNA damage
• DNA repair processes
• Gene targets: cellular and proto-
oncogenes, and tumor suppressor
genes
Multistage carcinogenesis
52
55. Sites for Carcinogen-DNA Adducts
I
O
6 N
HN 5
7
1
8 II
2 4
9
3
III H2N N N
I. Alkylating Agents, Mycotoxins DNA
II. Aromatic Amines
III. Polycyclic Aromatic Hydrocarbons, Alkenylbenzenes
55
57. Examples of DNA Damage
Break
– single strand
– double Strand
Crosslink
– DNA-protein
– intra-protein
– intra-strand
Specific binding
Base alteration
Base detachment
Intercolation
57
58. DNA Repair Processes
Direct damage reversal
– Ex.: Alkyltransferases
Base excision repair
– Ex.: Glycosylases and
apurinic/apyrimidinic
– Endonucleases
Source Pitot & Dragan. In Casarett & Doull, 1996 Continued 58
59. DNA Repair Processes
Nucleotide excision repair
– Ex.: repair of pyrimidine dimers
– Repair of “bulky” adducts
Recombination: Postreplication repair
Mismatch repair
– Ex.: Repair of deaminated 5-
methylcytosine
Source Pitot & Dragan. In Casarett & Doull, 1996 59
62. Genotoxicity
Mutagenesis
– Occurrence of “point” or “gene-locus”
mutation (base pairs), substitution, and
small deletions or additions
Clastogenesis
– Occurrence of chromosomal breaks
resulting in gain, loss, or rearrangement
of pieces of chromosome
Continued 62
64. Genetic Damage and Cancer
Gain of function: (proto-oncogenes and
oncogenes)
– Point mutation
– Translocation
– Amplification
Loss of function: (tumor suppressor genes)
– Deletion
– Translocation
– Mutation 64
65. Ways By Which Different Oncogene Products
May Disrupt Normal Regulation of Cell Growth
Growth
Factors
Receptors
2nd Messengers
DNA Synthesis
Oncogenes
65
66. Functions of Representative
Oncogenes and Tumor
Suppressor Genes
A. Oncogenes
Functions of Gene Product Genes Cell Localization
Growth Factors sis, fgf Extracellular
Receptor/protein tyrosine kinases met, neu Extra cell/cell membrane
Protein tyrosine kinases src, ret Cell membrane/cytoplasmic
Membrane-associated G proteins ras, gip-2 Cell membrane/cytoplasmic
Cytoplasmic protein serine kinases raf, pim-1 Cytoplasmic
Nuclear transcription factors myc, fos, jun Nuclear
Unknown, undetermined bcl-2, crk Mitochondrial, cytoplasmic
Continued 66
75. Promoters Can Determine the
Target Site for Tumors
Initiator Tumor Promoter Target Organ
2-AAF or BBN phenobarbital liver
saccharin bladder
N-methylnitroso- phenobarbital liver & thyroid
urea saccharin bladder
75
76. Neoplasms Associated with Prolonged Contact
With Promoting Agents in the Environment
Agent Resulting Neoplasm
Dietary fat Mammary adenocarcinoma
High caloric intake Increased cancer incidence in general
Cigarette smoke Bronchogenic carcinoma (esophageal and
bladder cancer)
Asbestos Bronchogenic carcinoma & mesothelioma
Halogenated hydrocarbons Liver
(dioxin, PCBs)
Phorbol esters Esophageal cancer (?)
Saccharin Bladder cancer*
Phenobarbital Liver*
Prolactin Mammary adenocarcinoma
Synthetic estrogens Liver adenomas
Alcoholic beverages Liver and esophageal cancer
* Promotion demonstrated in experimental animals, but not in humans 76
77. Lung Cancer
Since 1987, more women have died of lung
cancer than breast cancer
Risk factors: SMOKING, industrial
exposures, radiation exposure
Early detection: Difficult
Prevention: STOP SMOKING!
77
79. Relative Risk for Developing Lung Cancer
Compared with the Risk of Dying from Lung Cancer for a
Nonsmoker not Exposed to Asbestos
Nonsmoking asbestos worker 5
Smokers not exposed to asbestos 11
Smoking asbestos workers 53
Asbestos workers smoking 1
87
pack/day
0 20 40 60 80 100
Times Higher
Source: Report of the Surgeon General, 1985 79
80. EFFECT OF SMOKING CESSATION ON MORTALITY
FROM LUNG CANCER
(former smoker/never smoker)
30
MORTALITY RATE RATIO
40+ # cigarettes per day
25
20
15 21-39
20
10
10-19
5
1-9
0
5 10 15 20 25
Duration of Cessation (years)
80
84. Morphological and Biological Characteristics of
Initiation, Promotion, and Progression
INITIATION PROMOTION PROGRESSION
Irreversible Operationally reversible Irreversible
both at the level of gene
expression and at the
cellular level
Initiated “stem cell” not Promoted cell population Morphologically
morphologically dependent on continued discernible alteration in
identifiable administration of cellular structure
promoting agent resulting from karyotypic
instability
Efficiency sensitive to Efficiency sensitive to Growth of altered cells
xenobiotic and other aging and dietary and sensitive to environ
chemical factors hormonal factors mental factors during
early phase of this stage
Spontaneous Endogenous promoting
(endogenous) agents may effect
occurrence of initiated “spontaneous”
cells promotion Continued 84
85. Morphological and Biological Characteristics of
Initiation, Promotion, and Progression
INITIATION PROMOTION PROGRESSION
Requirement for cell
division for “fixation”
Dose-response not Dose response exhibits Benign or malignant
exhibiting a readily measurable threshold neoplasms observed in
measurable threshold and maximal effect this stage
Relative potency of Relative potency of “Progressor” agents
initiators dependent on promoters measured by advance promoted cells
quantitation of their effectiveness in into this stage
preneoplastic lesions causing an expansion of
after defined period of the initiated cell
promotion population
85
86. Some Cellular and Molecular Mechanisms in
Multistage Carcinogenesis
INITIATION PROMOTION PROGRESSION
Simple mutations Reversible enhancement Complex genetic
(transitions or repression of gene alterations
transversions, small expression mediated via (chromosomal
deletions, etc.) involving receptors specific for the translocations, deletions,
the cellular genome individual promoting gene amplification,
agent recombination, etc.)
resulting from evolving
karyotypic instability
In some species and Inhibition of apoptosis Irreversible changes in
tissues point mutations by promoting agent; gene expression,
in protooncogenes selective cytotoxicity to including fetal gene
and/or oncogenes non-initiated cells expression, altered
major histocompatibility
complex (MHC) gene
expression, and ectopic
hormone production
Continued 86
87. Some Cellular and Molecular Mechanisms in
Multistage Carcinogenesis
INITIATION PROMOTION PROGRESSION
Mutations in genes of No direct structural Selection of neoplastic
signal transduction alteration in DNA from cells for optimal growth
pathways that may action or metabolism of genotype phenotype in
result in an altered promoting agent response to the cellular
phenotype environment and
including the evolution
of karyotypic instability
87
88. Classification of Chemical Carcinogens
In Relation to Their Action on One or More
Stages of Carcinogenesis
Initiating agent (incomplete carcinogen): A
chemical capable only of initiating cells
Promoting agent: A chemical capable of
causing the expansion of initiated cell
clones
Continued 88
89. Classification of Chemical Carcinogens
In Relation to Their Action on One or More
Stages of Carcinogenesis
Progressor agent: A chemical capable of
converting an initiated cell or a cell in the
stage of promotion to a potentially
malignant cell
Continued 89
90. Classification of Chemical Carcinogens
In Relation to Their Action on One or More
Stages of Carcinogenesis
Complete carcinogen: A chemical
possessing the ability to induce cancer
from normal cells, usually with properties
of initiating, promoting, and progressor
agents
90
92. Prevention
Elimination of carcinogenic influences
(e.g., industrial carcinogens, cigarette
smoking, radiation
– Knowledge of identity of carcinogen is
essential
92
93. Protection
Measures designed to interrupt the
carcinogenic process without specific
efforts to identify or eliminate carcinogenic
influences (e.g., dietary measures)
– Knowledge of identity of carcinogen is
desirable
93
94. Key Points
Environmental factors may contribute to
3/4 of all human cancers
Chemicals, viruses, and radiation can be
carcinogenic
DNA is a major target for carcinogens
– With damage leading to gain or loss of
function of key genes
Continued 94
95. Key Points
Carcinogenesis is a long, multistage
process yielding a heterogeneous family of
diseases: Cancer
Most cancer is, in theory, preventable
95
