McCance/Huether: Pathophysiology: The Biologic Basis of Disease in Adults

and Children, 8th Edition

Chapter 13: Cancer Epidemiology

Chapter Summary Review

Genes, Epigenetics, and Tissue

1. Cancers are caused by environmental-lifestyle and genetic factors. Environmental factors

and lifestyle behaviors contribute to a very large number of cancer cases. Biologically,
cancer is driven by genetic alterations and changes in epigenetic regulation. Different
combinations of mutations and epigenetic changes are found in different types of cancer.
Avoiding high-risk behaviors and exposures to individual carcinogens, or cancer-causing
substances, will prevent many types of cancer.
2. Investigators are connecting the intricate web between genotype, phenotype, high-risk
lifestyle behaviors, the environment, and carcinogenesis.
3. Interacting factors that influence cancer risk include detoxifying enzymes, DNA repair
genes, immune/inflammation systems, and the cell’s immediate environment. The cell’s
biologic environment is modified by metabolic requirements, physical activity,
infections, nutrition, carcinogens, air pollution, and many other environmental factors.
4. Cancer development and progression involve the tissue microenvironment or stroma.
5. The microenvironment participates in a complex signaling process that facilitates tumor
promotion and metastases because stromal tissue has immune cells. Chronic
inflammation from infiltrating immune cells can be caused by numerous environmental
factors, for example, inhaling tobacco smoke.
6. Cancer development in the presence of chronic inflammation involves the continuous
presence of cytokines, ROS, COX-2, 5-LOX, MMPs, and essential transcription factors
(e.g., NF-κB).

Incidence and Mortality Trends

1. Cancer is reported to become a major cause of morbidity and mortality in the coming
decades in all regions of the world.
2. Data for the United States from 2003 to 2012 showed incidence of 7 of the 17 more
common cancers in men decreased and overall incidence stayed close to the same for
women. The decline in lung cancer corresponded to a decrease in tobacco use. Cancer
incidence, however, increased among people ages 0 to 19 years. In all racial and ethnic
populations, men had about a threefold higher liver cancer incidence than women.
3. Death rates continued to decrease for men, women, and children. Deaths caused by liver
cancer, however, increased at the highest rate of all reported cancer sites.

In Utero and Early Life Conditions

1. Accumulating data suggest early life events influence later susceptibility to certain
chronic conditions, including cancer.

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Chapter Summary Review 13-2

2. Developmental plasticity is the degree to which an organism’s development is contingent

on its environment. An emerging hypothesis is that persistent epigenetic adaptations that
occur early in development in response to parental nutrition and the environment are
associated with increased susceptibility to cancer and other adult-onset chronic diseases.
3. Epidemiologic and animal studies reveal that small changes in the developmental
environment can alter phenotypic changes, resulting in individual responses in adulthood.

Environmental-Lifestyle Factors

Tobacco Use
1. Cigarette smoking is carcinogenic and the most important cause of cancer and death from
cancer. The risk is greatest in those who begin to smoke when young and continue
throughout the life.
2. Worldwide, tobacco use is a major preventable cause of premature death and disease
where 5.4 million people die each year from tobacco-related illnesses. More than 16
million Americans live with a smoking-related disease.
3. Smoking affects nearly every organ of the body. Since the first Surgeon’s General report
on smoking and health in 1964, more than 20 million Americans have died as a result of
smoking. Smoking causes even more deaths from vascular, respiratory, and other
diseases than from cancer.
4. Smoking tobacco is linked to cancers of the lung, upper aerodigestive tract (oral cavity,
pharynx, larynx, nasal cavity, paranasal sinuses, esophagus), stomach, lower urinary tract
(renal pelvis, penis, bladder), kidney, pancreas, cervix, and uterus, as well as myeloid
leukemia. The new list of disease risks includes liver cancer and colorectal cancer.
5. Secondhand smoke or environmental tobacco smoke (both sidestream smoke [burning
end of cigarette, cigar, or pipe] and mainstream smoke exhaled by the smoker) is a cause
of stroke; it increases the risk of death in people with cancer and cancer survivors, as well
as those with age-related macular degeneration, tuberculosis, ectopic pregnancy, and
diabetes mellitus; it increases inflammation and impairs immunity; and it is a cause of
rheumatoid arthritis.
6. Nonsmokers who live with smokers are at greatest risk for lung cancer, as well as other
noncancerous conditions. Parental smoking is linked to babies who died of sudden infant
death syndrome or complications from low birth weight or other conditions. In utero
effects from maternal or paternal smoking and subsequent disease are being investigated.
7. Regular cigar smoking is associated with increased risk for cancers of the lung,
esophagus, larynx, and oral cavity (lip, tongue, mouth, throat). Heavy cigar smoking
increases the risk for lung diseases, including emphysema and chronic bronchitis. Cigar
smoking is linked to gum disease and tooth loss. Pipe smokers have an increased risk of
dying from cancers of the lung, throat, esophagus, larynx, pancreas, and colorectum.
Compared to nonsmokers, bidi smokers have the same risks of cancer and higher risks of
heart attacks and chronic bronchitis. Kreteks are a tobacco product.
8. An e-cigarette delivers a vapor (aerosol) of nicotine, flavorings, and other chemicals
when puffed. The vapor is inhaled just like smoke from a regular cigarette and absorbed
into the lungs. Colorful “vape pens” or “e-hookahs” are marketed to appeal to youth with
flavors like candy and fruit. The electronic nicotine delivery system (ENDS) is designed

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Chapter Summary Review 13-3

to deliver nicotine, which is addictive. Many questions have been raised as to the safety
of e-cigarettes because ENDS cartridges are not labeled with their ingredients.

Nutrition, Obesity, Alcohol Consumption, and Physical Activity

1. Abundant evidence exists that dietary factors are related to cancer development.
Emerging is the interaction of dietary factors with genomics, epigenomics, transcription
factors (transcriptomics), proteomics, and metabolic factors (metabolomics) and how
they influence cancer risk. Nutrigenomics is the study of the effects of nutrition on the
phenotypic variability of individuals based on genomic differences.
2. What people eat, how much they weigh, and how much they move influence their risks of
developing cancer and other chronic diseases. Everyday choices impact their chances of
getting or preventing cancer. Lifestyle and nutrition are associated with development or
progression, or both, of major human cancers, including some of the most common (e.g.,
breast, prostate, colorectal, and others).
3. Researchers are studying types of diet that either prevent or reduce mortality rates for
cancer and other chronic diseases. Much attention is the research on the Mediterranean
diet.
4. Examples of food components reported to have cancer-preventive potential include
polyphenols, selenium, methyl group donors, retinoids, isothiocyanates, allyl compounds,
and mono- and poly-unsaturated fatty acids. Several dietary factors alter the expression of
many miRNAs in animals and humans.
5. Various food components can influence DNA repair.
6. Sources of carcinogenic substances include compounds produced in the cooking of fat,
meat, or protein, and naturally occurring carcinogens associated with plant food
substances, such as alkaloids or mold byproducts.
7. Dietary components can act directly as mutagens or interfere with the elimination of
mutagens.
8. Dietary factors may affect the cell cycle, differentiation, DNA damage and repair, stem
cell renewal, hormonal axes, the balance of cellular proliferation and cell death, the
microenvironment, cell signaling, inflammation, and immunity.
9. Xenobiotics that include toxic, mutagenic, and carcinogenic chemicals are found in the
human diet.
10. Food and nutrition modify carcinogen metabolism and include the examples selenium,
allyl sulfur, sulforaphane, and isoflavonoids.
11. Diets high in red meat and processed meat are linked to an increased risk of developing
colorectal cancer. Several mechanisms are proposed for effects of meat and cancer, for
example, N-nitroso compounds can increase nitrogenous residues in the colon and cause
DNA damage.
12. Undernutrition can be a factor in cancers caused by infectious agents, for example,
cancers of the liver and cervix.
13. Future research is needed to define robust biomarkers of cancer risk.
14. Obesity has been increasing in most developed countries and in urban areas of
developing countries. Obesity in the United States is an epidemic.
15. Childhood obesity has been increasing. There is considerable concern for children with
early onset of obesity.

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16. The substantial suffering and long-term human and societal costs of obesity underlie the
urgency to accelerate progress in obesity prevention.
17. Studies have significantly improved the understanding of the relationship between
overweight/obesity, energy balance and cancer risk, cancer recurrence, and survival.
18. Consensus now exists that obesity is a risk factor for developing the following cancers:
liver, advanced prostate, ovarian, gallbladder, kidney, colorectal, esophageal
(adenocarcinoma), postmenopausal breast, pancreatic, endometrial, and stomach (cardia)
(see Fig. 13.13). The IARC identified additional cancers with sufficient evidence that the
absence of body fatness lowers cancer risk for thyroid and multiple myeloma.
19. Obesity is recognized as a poor prognostic factor for several cancers.
20. The mechanisms of obesity-associated cancer risks are unclear and may vary by type of
tumor and distribution of body fat. Three main factors related to obesity and cancer are
the insulin–insulin-like growth factor axis, sex hormones, and adipokines.
21. Metabolic changes in adipose tissue from obesity result in several alterations and include
insulin resistance, hyperglycemia, dyslipidemia, hypoxia, and chronic inflammation.
22. Obesity leads to adipocyte dysfunction and immune cell recruitment leading to cytokine
production, inflammation, and, ultimately, fibrosis and reduced response to
chemotherapy. Adipocytes function as endocrine cells and critically shape the tumor
microenvironment.
23. Obesity can increase aromatase expression, resulting in increased estradiol levels, which
can promote the growth of estrogen-dependent cancers.
24. Cancers have altered metabolism. Tumors consume large quantities of glucose to make
cellular building blocks, called the Warburg effect.
25. Food metabolism and circadian cycles are linked, and impairment of inner clock
regulation results in dysregulated metabolism.
26. Overall, there are strong data supporting alcohol as a cause of cancers of the mouth,
pharynx, larynx, esophagus, and liver; colorectal cancer in men; and postmenopausal
breast cancer.
27. Factors contributing to alcohol-induced cancer development include acetaldehyde,
oxidative stress, and nutritional deficiencies, especially folate, a B vitamin.
28. Variations in several genes modulate the risk of alcohol-induced carcinogenesis, and
increasing evidence suggests aberrant patterns of DNA methylation also contribute.
29. Physical activity reduces the risk for breast cancer, colon cancer, and endometrial cancer,
independent of weight changes.
30. Biologic mechanisms for the protective effects of exercise include decreasing insulin and
IGF levels, decreasing obesity, increasing free-radical scavenger systems, changing
inflammatory mediators, decreasing oncogenes, decreasing the levels of circulating sex
hormones and metabolic hormones, improving immune function, and enhancing
cytochrome P-450 function, thus modifying carcinogen activation and increasing gut
motility.
31. Several reports suggest that implementing a physical activity program after a cancer
diagnosis is associated with better cancer-specific outcomes and overall survival with
early-stage breast, prostate, and colorectal cancers.
32. Many unanswered questions remain regarding the frequency, intensity, and duration of
exercise required for optimal health benefits.

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Chapter Summary Review 13-5

Air Pollution
1. Ambient air pollution increases mortality and morbidity and shortens life expectancy
from cardiovascular, respiratory disease, and lung cancer.
2. Air pollution is a leading cause of global disease burden. Long-term exposure to fine
particle air pollution (PM2.5) caused 4.2 million deaths and 103.1 million lost years of
healthy life in 2015. An additional 254,000 deaths were linked to exposure to ozone.
3. The IARC concluded that exposure to outdoor air pollution and to particulate matter
(PM) in outdoor air is carcinogenic to humans and causes lung cancer. Fine or ultrafine
particles are easily absorbed by the lungs and phagocytosed by macrophages and
neutrophils that release tissue-damaging inflammatory mediators.
4. The mechanisms of adverse cellular effects of PM include (1) cytotoxicity through
oxidative stress, (2) ROS generation, (3) DNA oxidative damage, (4) mutagenicity, (5)
stimulation of proinflammatory factors, and (6) induction of cell senescence.
5. The indoor air pollution environmental tobacco smoke (ETS; passive smoking) can cause
the formation of reactive oxygen free radicals and thus DNA damage. The IARC has
classified ETS as a human carcinogen.
6. In 2012, diesel exhaust was classified as a carcinogen in humans by the IARC.
7. The central hypothesis for cancer pathogenesis is that insoluble particles cause
pulmonary inflammation (e.g., cytokine release, ROS) which leads to oxidative stress and
oxidation of DNA, proliferative response, and tissue remodeling progressing toward
fibrosis and tumor development.

Ionizing Radiation, Ultraviolet Radiation, and Electromagnetic Radiation

1. Much of the knowledge of the effects of ionizing radiation (IR) on human cancer has
stemmed from observations of the Hiroshima and Nagasaki atomic bomb exposures,
particularly the Life Span Study. Other evidence is derived from groups exposed for
medical reasons, underground miners exposed to radon gas, and other occupational
exposures.
2. The atomic bomb exposures in Japan caused acute leukemias in adults and children and
increased frequencies of thyroid and breast carcinomas. Lung, stomach, colon,
esophageal, and urinary tract cancers and multiple myeloma have been added to the list.
3. Recent models of radiation carcinogenesis show ionizing radiation (IR) acts not only as
an initiator of premalignant cell clones but also as a promoter of preexisting premalignant
cell alterations.
4. Health risks from IR involve cancers, cardiovascular diseases, respiratory diseases, birth
defects, and eye maladies.
5. In 2009 the National Council on Radiation Protection and Measurements reported
Americans were exposed to more than seven times as much IR from medical procedures
compared to IR exposure in the 1980s.
6. Ionizing radiation is a mutagen and carcinogen and can penetrate cells and tissues and
deposit energy in tissues at random in the form of ionizations.
7. The past two decades have focused on cellular and molecular mechanisms that relate to
the induction of cancer, including dose-response relationships for chromosome
aberrations and for cell transformation; gene expression (genetic and epigenetic);
alternative targets, such as membranes; mutagenesis in somatic cells; the biologic effects

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Chapter Summary Review 13-6

that occur in nonirradiated cells (i.e., nontargeted effects); and effects on the
microenvironment.
8. Exposure to ionizing radiation induces apoptosis and senescence. Emerging data are
identifying these effects in endothelial cells and the biology of radiation-induced
cardiovascular disease.
9. Because models and underlying assumptions of IR and cell damage are incomplete,
investigators are working hard to understand induced repair, adaptive responses,
hormesis, low-dose hypersensitivity, nontargeted effects, signaling, exosomes, and long-
term persistence of radiation damage and clonal heterogeneity.
10. A long-held assumption is that cellular alterations—mutations and malignant
transformation—occur only in cells directly radiated. It is now known that radiation may
induce a type of genomic instability to the progeny of the directly irradiated cells over
many cell generations and can affect the so-called innocent bystander cells.
11. Epigenetic events after radiation include alterations in pathways affecting cell adhesion,
extracellular matrix interactions, and cell-to-cell communication.
12. The principal source of UV radiation is sunlight. Solid evidence shows sun and
ultraviolet (UV) radiation causes basal cell carcinoma and squamous cell carcinoma. Fair
evidence showing intermittent acute sun exposure leading to sunburn is associated with
an increased risk of melanoma. The most preventable cause of skin cancer is exposure to
UV light from the sun or from artificial sources, such as tanning beds.
13. The degree of damage in skin depends on the intensity and wavelength content—
ultraviolet A (UVA) or ultraviolet B (UVB).
14. The pathogenesis of nonmelanoma skin cancers involves specific gene mutations, DNA
methylation and histone modifications, oxidative stress, inflammation, and reduced
immune surveillance. The relationship between sun exposure and the risk of melanoma
remains complex.
15. ROS can induce a number of transcription factors (e.g., activator protein 1 [AP-1] and
NF-κB) and increase the levels of regulating genes that induce inflammation.
Inflammation is a critical component of tumor progression.
16. The incidence of melanoma in the United States has been increasing annually. Because
mortality rates have not risen as rapidly, however, controversy exists as to whether the
incidence increase is a true increase in clinically significant melanoma or is a result of
overdiagnosis.
17. Health risks associated with electromagnetic radiation (EMR) are controversial. Exposure
to electric and magnetic fields is widespread. EMRs are a type of nonionizing and low-
frequency radiation.
18. EMRs generated by radiofrequency sources couple with the body and result in induced
electric and magnetic fields with associated currents inside tissue.
19. Microwaves, radar, mobile and cell phones, mobile phone base stations, appliances,
power frequency radiation associated with electricity and radio waves, fluorescent lights,
computers, and other electric equipment create EMRs of varying strength.
20. Data measuring the relationships between EMR exposure and cancer are limited because
of inadequate methods to accurately measure exposure, lack of clear dose-response
relationships and reproduction of effects, financial interests, and other priorities such as
convenience.

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Chapter Summary Review 13-7

21. Most exposure to EMFs from occupational sources comes from near-field sources; the
highest exposure to the general population comes from transmitters close to the body,
such as hand-held devices like mobile telephones.
22. The WHO International Agency for Research on Cancer Monograph Working Group
reported that the INTERPHONE and Swedish studies were judged susceptible to bias, the
findings could not be dismissed because of bias alone, and a causal relationship between
phones and glioma is possible. The National Institute of Environmental Health Sciences
is doing a large-scale study on rodents exposed to radiofrequency energy (cell phone
type). Early preliminary data have been reported.
23. The outcome of the Working Group was to classify RF-EMF as “possibly carcinogenic to
humans” (Group 2B). The mechanisms included genotoxicity, effects on immune
function, gene and protein expression, cell signaling, oxidative stress, apoptosis, and,
possibly, the blood-brain barrier.
24. There are no studies of adults who have used cell phones as children or adolescents.
Concern is for children in whom the effects may be compounded because of increased
vulnerability to radiation and their longer use of cell phones into adulthood.

Infection
1. Infections with certain viruses, bacteria, and parasites are an important contributor to
cancer worldwide. Of the 14 million new cancer cases in 2012, 2.2 million (15.4%) were
attributable to carcinogenic infections.
2. Infection and cancer rates vary widely between countries and level of socioeconomic
development.
3. The top notable infections and new cancer cases include Helicobacter pylori (H. pylori),
human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and
Epstein-Barr virus (EBV).
4. Hepatitis B and hepatitis C can infect the liver and together account for the large majority
of liver cancer diagnoses. HPV caused more than half of the total infection-attributable
cancers in women worldwide. HPV is the most common viral infection of the
reproductive tract. Most sexually active women and men will be infected at some point in
their lives and some may be repeatedly infected. H. pylori accounts for an estimated 75%
of all stomach cancers. EBV is associated with a subset of Hodgkin lymphoma and
Burkitt lymphoma, and other types of cancer.
5. HPVs are a group of more than 200 related viruses of which 13 are cancer causing. High-
risk or oncogenic HPVs (types 16 and 18) cause about 70% of cervical cancers and
precancerous cervical lesions. HPV has been linked with cancers of the anus, vulva,
vagina, and penis. Prospective studies have confirmed that infection with HPV-16
precedes by several years the diagnosis of oropharyngeal cancer (OPC).
6. Factors that may increase the risk of developing cancer following a high-risk HPV
infection include smoking, decreased immunity, having many children (for increased risk
of cervical cancer), long-term oral contraceptive use (for increased risk of cervical
cancer), poor oral hygiene (for increased risk of oropharyngeal cancer), and chronic
inflammation.

Chemicals and Occupational Hazards as Carcinogens

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Chapter Summary Review 13-8

1. An estimated 100,000 synthetic chemicals are used in the United States. Of those, only
about 7% have been tested for their health effects and another 1000 are added each year.
2. Chemicals are present in air, soil, food, water, personal care products, toys, household
products, medications, workplaces, and homes. The list of chemicals has expanded and
added to other cancer risks related to the workplace, including ergonomic, organizational,
and biologic factors.
3. An extensive list of potential occupational carcinogens is published by the NIOSH, and
known and probable carcinogenic agents are updated by the International Agency for
Research on Cancer (IARC).
4. Chemical carcinogenesis involves genotoxic and nongenotoxic mechanisms. The
nongenotoxic mechanisms include inflammation, immunosuppression, oxidative stress
(ROS), receptor activation, and epigenetic silencing.
5. Work-related stress may indirectly lead to cancer because coping strategies include
smoking, alcohol, drug intake, and excessive high-risk diets.
6. A substantial percentage of cancers of the upper respiratory passages, lung, bladder, and
peritoneum are attributed to occupational factors; however, fewer studies of nonsmokers
exist.
7. Disentangling data related to lung cancer, air pollution, and occupational factors is
complex, especially in combination with active and passive smoking, environmental
factors, and multiple interacting genes.

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