Chapter 12: Cancer Epidemiology

Question 1

Genetics, Epigenetics, and Tissue

Answer 1

1. Cancer arises from a complicated and interacting web of multiple etiologies. Avoiding high-risk behaviors and exposure to individual carcinogens will prevent many types of cancers.
2. Risk factors for cancer include lifestyle behaviors (smoking, alcohol intake, diet), lack of physical exercise and obesity, certain infections, environmental factors (exposure to sunlight or ionizing radiation), occupational exposure to carcinogens, and certain medications.
3. Cancers are caused by environmental-lifestyle factors and genetic/ epigenetic factors. Interacting factors are weaker immune systems, variations in detoxifying enzymes or DNA repair genes, differences in hormone levels, and metabolic factors. Altogether the biologic environment is modified by metabolic and hormonal factors, inflammation, and disordered glucose and lipid metabolism.
4. Cancer-causing factors are influenced by the surrounding microenvironment or stroma. Once malignant phenotypes have developed, complex interactions occur between the tumor, the surrounding stroma, and the cells of the immune and inflammatory systems.
5. Globally cancer is reported to become a major cause of morbidity and mortality in the coming decades.
6. In the United States, cancer incidence rates decreased for men and stayed about the same for women from 2003 to 2012. During this same time period, cancer incidence rates increased in children 0 to 19 years of age.
7. Overall, cancer death rates have continued to decline in men, women, and children. However, deaths caused by liver cancer increased at the highest rate of all reported cancer sites, and liver cancer incidence rates increased sharply

Question 2

In Utero and Early Life Conditions

Answer 2

1. Emerging data suggest early life events influence later susceptibility to chronic diseases.
2. Developmental plasticity is the degree to which an organism’s development is contingent on its environment. Plasticity refers to the ability of genes to organize physiologically or structurally in response to environmental conditions during fetal development.
3. The developmental origins’ hypothesis suggests that nutrition and other environmental factors affect cellular pathways during gestation, enabling a single genotype to produce a broad range of adult phenotypes. Maternal nutrition, as well as environment factors, are proposed as significant biological influences.
4. Undernutrition in utero is linked to increased heart disease, metabolic disorders, and possibly breast cancer decades later. Early versus late undernutrition in pregnancy indicated that the first trimester of pregnancy is particularly vulnerable to disease outcome in adulthood.

Question 3

Environmental-Lifestyle Factors

Answer 3

Tobacco Use

1. Cigarette smoking is carcinogenic and the most important cause of cancer. Tobacco smoking causes cancer in more than 15 organ sites, and exposure to secondhand smoke and parental smoking causes cancer in children and in other nonsmokers. The risk is greatest in those who begin to smoke when young and continue throughout life. Smoking is, however, pandemic affecting all ages.
2. Worldwide, tobacco use causes more than 7 million deaths per year.
3. Environmental tobacco smoke (i.e., secondhand smoke) is a cause of stroke; increases the risk of death in people with cancer and cancer survivors as well as those with macular degeneration, tuberculosis, ectopic pregnancy, and diabetes mellitus. Secondhand smoke exposure increases inflammation, impairs immunity, and is a cause of rheumatoid arthritis.
4. Smoking tobacco is linked to cancers of the lung, upper aerodigestive tract, stomach, lower urinary tract, kidney, pancreas, cervix, uterus, and myeloid leukemia. Recently added to the list are liver cancer and colorectal cancer. Smoking causes even more deaths from respiratory, vascular, and other diseases than from cancer.
5. Cigar or pipe smoking is related to cancers of the oral cavity, oropharynx, hypopharynx, larynx, esophagus, and lung. Pipe smokers have an increased risk of cancers of lung, lip, throat, esophagus, larynx, pancreas, and colon and rectum.
6. Electronic cigarettes can contain harmful and potentially cancercausing substances.

Diet

1. The influence of diet on cancer development is complicated. Cancer
   risks in older adults may depend as much on diet in early life as
   on current eating practices.
2. Nutrigenomics is the study of the effects of nutrition on the phenotypic variability of individuals based on genomic differences.
3. Nutrition, Obesity, Alcohol Consumption, and Physical Activity: Impacts on CancerDiet, weight, and activity level all influence risks for cancer development.
4. The implementation of dietary patterns, for example, the Mediterranean dietary pattern, and the promoting of specific dietary recommendations, is
   becoming more widespread.
5. The importance of diet has been illustrated by data showing changes
   in cancer risk among migrants in low-risk countries compared with those in high-risk countries. With geographic migration, risks
   and cancer patterns change, particularly with the adoption of the Western diet.
6. Bioactive components have a profound effect on differentiation, potentially including differentiation of cancer stem cells. Intake of specific food compounds may suppress cancer stem renewal.
7. A variety of food compounds may influence DNA repair.
8. Xenobiotics are toxic, mutagenic, and carcinogenic chemicals that humans are constantly exposed to. The body has defense systems for counteracting these effects. Many foods enhance the efficiency and degree of detoxification of xenobiotics and thus serve a protective role in metabolizing carcinogens.
9. Diets high in red meat or processed meat may lead to increased risks of development colorectal cancer. Means containing nitrites, nitrates, or other preservatives can leave residues in the colon that cause DNA damage.
10. Obesity has been increasing in developed countries and in urban
    areas of developing countries. Obesity in the United States is epidemic. Obesity impacts energy balance, cancer risk, cancer recurrence, and survival.
11. Obesity is a risk factor for 11 cancers: liver, advanced prostate, ovarian, gallbladder, kidney, colorectal, esophagageal, breast (postmenopausal), pancreatic, endometrial, and stomach.
12. The mechanisms of obesity-associated cancer risks are evolving and vary by type of tumor and distribution of body fat. Emerging data point to are three main factors:

(a) Insulin-insulin-like growth
factor (IGF-1) axis
(b) Sex hormones
(c) Adipokines.

13. Metabolic changes in adipose tissue from obesity result in several
    alterations and include insulin resistance, hyperglycemia, dyslipidemia, hypoxia, and chronic inflammation. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment, so stromal compartments that are rich in adipose tissue can promote the development of tumor cells.
14. Alcohol is classified as a human carcinogen. Strong data link alcohol with cancers of the mouth, pharynx, larynx, esophagus, liver, colorectum, and breast.
15. Evidence does not show any safe limit of alcohol and the health effects are from ethanol regardless of the type of drink.
16. Alcohol-related carcinogenesis involves acetaldehyde, reactive oxygen species (ROS), pro-carcinogen activation, cellular regeneration,
    nutritional deficiencies, and enzyme and metabolic dysfunction.
17. Physical activity, independent of weight changes, reduces the risk for breast cancer, colon cancer (in men), and endometrial cancer.
18. Biologic mechanisms for the protective effects of physical activity include decreasing insulin and IGF levels, decreasing obesity, increasing free radical scavenger systems, altering inflammatory mediators, decreasing levels of circulating sex hormones and metabolic hormones, improving immune function, decreasing oncogenes, enhancing cytochrome P-450 activity (thus modifying carcinogen activation), increasing gut motility, and increasing release of myokines (proteins from contracting muscles with antitumor
    effects).
19. Many unanswered questions remain regarding frequency of exercise,
    intensity, and duration.
20. Recent data encourage 150 minutes of moderate-intensity aerobic or 75 minutes of vigorous-intensity aerobic physical activity each week for adults. Children and adolescents should get at least 60 minutes of physical activity daily.

Air Pollution

1. Air pollution, indoor and outdoor, is the leading environmental
   cause of death worldwide. Long-term exposure to air pollution
   increases mortality and morbidity, and shortens life expectancy from
   cardiovascular, respiratory disease, and lung cancer.
2. There is a significant association between increased rates of lung
   cancer and exposure to particulate matter, a mixture of small particles
   and liquid droplets. Primary particles are emitted directly from a
   source, for example, construction sites, unpaved roads, fields, or
   smokestacks. Secondary particles are emitted from power plants,
   industries, and automobiles.
3. Diesel exhaust is carcinogenic and causes lung cancer. Acute exposure
   to diesel exhaust that contains particles is linked to lung, throat,
   and eye irritations; asthma attacks; and myocardial ischemia.
4. The mechanisms of adverse effects of particulate matter include

(a) Oxidative stress
(b) ROS generation
(c) DNA oxidative damage,
(d) Mutagenicity
(e) Stimulation of proinflammatory factors
(f) Induction of senescence.

5. Fine particle pollution also is linked to
   (a) Premature death in people with heart or lung disease
   (b) Nonfatal heart attacks
   (c) Irregular heartbeat
   (d) Aggravated asthma
   (e) Decreased lung function, and
   (f) Respiratory symptoms.
6. Indoor air pollution is generally considered worse than outdoor
   pollution. Sources of indoor air pollution include tobacco smoke,
   heating and cooking combustion sources, radon, and coal use.

Question 4

Ionizing Radiation (IR)

Answer 4

1. Much of the knowledge of the effects of ionizing radiation on
   human cancer has come from Hiroshima and Nagasaki atomic
   bomb exposures, particularly the Life Span Study. Other evidence
   is from exposure to radiation for medical reasons, underground
   miners, and other occupational exposures. Human exposure includes
   emissions from the environment, x-rays, CT scans, radioisotopes,
   and other radioactive sources.
2. Atomic bomb exposures in Japan caused acute leukemias and
   increased frequencies of thyroid, breast, lung, stomach, colon,
   esophageal, and urinary tract cancers and multiple myeloma.
3. Excess relative risks (ERRs) for radiation-induced cancers at a given
   age are much higher for individuals exposed during childhood, and
   decreased at the ages of 30-40 years. The ERR of developing solid
   tumors increased again for exposure ages higher than 40 years.
4. The bimodal age distribution reflects that radiation exposure in
   early ages is related to initiation of cancer processes, whereas exposure in later ages is associated with promotion of pre-existing
   premalignant cells.
5. Other health risks from radiation include cardiovascular effects
   and somatic mutations that may contribute to other diseases. These
   effects may manifest years after radiation exposure.
6. There is concern about the increased IR exposure from medical
   procedures, particularly CT scans.
7. IR is a potent mutagen and carcinogen; it can penetrate cells and
   tissues and deposit energy in tissues at random in the form of
   ionizations.
8. IR affects DNA by causing cross-linking, nucleotide base damage, and
   single- and double-strand DNA breaks. Disrupted cellular regulation processes can lead to carcinogenesis. The double-strand break
   is considered the hallmark lesion associated with IR.
9. It is now known that radiation may induce genomic instability to
   the progeny of the directly irradiated cells over many generations
   of cell divisions and can affect so-called innocent bystander cells.
   Investigators are studying genomic instability as it may contribute
   to secondary cancers.
10. The risks from low-dose radiation are constantly debated. Determining risks from low doses of radiation are statistically difficult
    because they require such large populations.

Question 5

Ultraviolet Radiation (UVR)

Answer 5

1. Ultraviolet (UV) radiation comes from sunlight, electric lights, black
   lights, and tanning lamps. Most of the UV radiation received on
   earth is UVA and some UVB. UVA radiation is weaker than UVB,
   but UVA penetrates deeper into the skin and is more constant
   throughout the year despite the weather.
2. The incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is strongly correlated with lifetime sunlight exposure.
   Intense intermittent recreational sun exposure has been associated
   with melanoma and BCC. Chronic occupational sun exposure has
   been associated with SCC. Tanning bed use has been associated with
   an increased risk of BCC, especially in women.
3. Skin cancer risk factors include cumulative sun exposure (the additive effects of intermittent sun exposure, chronic sun exposure, or
   both), ionizing radiation, chronic arsenic ingestion, immunosuppression, and genetic factors.
4. The pathogenesis of nonmelanoma skin cancers involves specific
   gene mutations, epigenetic alterations, oxidative stress, inflammation, and reduced immune surveillance.

Question 6

Electromagnetic Radiation (EMR)

Answer 6

1. EMR is energy in the form of magnetic and electric waves. Health
   risks associated with EMR are controversial. Exposure to electric
   and magnetic fields is widespread. Wireless telecommunication
   devices (e.g., cell phones, wireless laptops, smart meters) are the
   most common source of radiofrequency electromagnetic radiation
   (RF-EMR).
2. of the impact of EMR has not been fully assessed. Competing priorities (convenience, financial interest, and health necessity) may
   make a consensus on the risk/benefit ratio difficult to achieve.
3. Low-frequency electromagnetic fields (EMFs) have been classified
   as possible carcinogens.
4. The most extensively studied exposure is from use of wireless
   telephones.
5. Children are a main concern since the effects of exposure may be
   compounded because of increased vulnerability to radiation and
   their longer use of cell phones into adulthood.

Question 7

Infection, Sexual and Reproductive Behavior

Answer 7

1. Infection with certain viruses, bacteria, and parasites are an important
   contributor to cancer worldwide. The most notable infections implicated in new cancer cases include Epstein-Barr virus (EBV), Helicobacter pylori, hepatitis B and C viruses (HBV and HCV), and
   human papillomavirus (HPV).
2. H. pylori is the cause of about 75% of stomach cancers. EBV is
   linked to nasopharyngeal carcinoma, Hodgkin lymphoma, diffuse
   large B-cell lymphoma, Burkitt lymphoma, EBV-associated malignant
   B-cell lymphoma, other lymphomas, and gastric adenocarcinoma.
   HBV and HCV infect the liver and together account for the large
   majority of liver cancer cases.
3. HPV is the most common sexually transmitted virus in the United
   States. HPV accounts for more than half of the total infection attributable cancers in women worldwide. HPV types 16 and 18 are
   responsible for the majority of cancers. Persistence of infection with
   high-risk HPV is a prerequisite for the development of cervical
   intraepithelial neoplasia, lesions, and invasive cancer.
4. HPV infection has been identified as a definite carcinogen for several
   types of cancer: cervical, penis, vulvar, vaginal, anal, and some oropharyngeal (including the base of the tongue, tonsils, and pharynx).
5. The incidence of HPV-associated oropharyngeal cancer has increased
   during the past 20 years, especially among men.
6. Biologic factors that may interact with HPV infection to increase
   cancer risk include smoking, decreased immunity, having many
   children, long-term oral contraceptive use, poor oral hygiene, and
   chronic inflammation.
7. HPV may be transmitted by genital contact (oral, touching, or sexual
   intercourse). The possible modes of transmission in children are
   controversial, however it is thought that newborn babies can be
   exposed to cervical HPV infection from the mother.
8. Although the HPV vaccine reduces the risk for cervical cancer,
   women should still get Pap tests and HPV screening at regular
   intervals.

Question 8

Other Viruses and Microorganisms

Answer 8

1. Human herpes virus type 8 is linked to Kaposi sarcoma, and human
   T-cell lymphotropic virus type 1 is linked to leukemia and lymphoma.
2. Microorganisms involved in carcinogenesis include parasites such
   as Opisthorchis viverrini (bile duct cancer) and Schistosoma haematobium (bladder cancer).

Question 9

Chemicals and Occupational Hazards as Carcinogens

Answer 9

1. An estimated 100,000 synthetic chemicals are used in the United
   States. Only 7% have been fully tested for their impact on health
   and another 1000 are added each year.
2. Exposure to chemicals occurs from air, soil, food, water, personal
   care products, toys, household products, medications, workplaces,
   and homes
3. A large number of chemicals are known carcinogens in experimental
   animals, and it is suspected that most of these are potentially carcinogenic in humans.
4. Chemical carcinogenesis involves genotoxic mechanisms (create
   genetic damage) and nongenotoxic mechanisms (alter signal
   transduction.
5. A substantial percentage of cancers of the upper respiratory passages,
   lung, bladder, and peritoneum are attributed to occupational factors.
   Notable occupational hazards include dyes, rubber, paint, aromatic
   amines, benzol, heavy metals, silica, polycyclic aromatic hydrocarbons,
   sulfuric acid, and chloromethyl ether. Asbestos is linked to an epidemic of mesothelioma and asbestos usage has been banned in most
   developed countries.