1. Cancer
epidemiology
over the life
course
Gianluca Tognon
www.gianlucatognon.com

2. Background
 The incidence of cancer has increased from 12.7
million in 2008 to 14.1 million in 2012, and this trend
is projected to continue, with the number of new
cases expected to rise
 This will bring the number of cancer cases close to
25 million over the next two decades (+ 70%)
 More than 60% of the world’s cancer cases occur in
Africa, Asia, and Central and South America, and
these regions account for about 70% of the cancer
deaths

3.  Among men, the five most common sites of
cancer diagnosed in 2012 were the lung (16.7%
of the total), prostate (15.0%), colorectum
(10.0%), stomach (8.5%), and liver (7.5%)
 Among women, the five most common incident
sites of cancer were the breast (25.2% of the
total), colorectum (9.2%), lung (8.7%), cervix
(7.9%), and stomach (4.8%)
 The worldwide estimate for the number of
cancers diagnosed in childhood (ages 0–14
years) in 2012 is 165 000 (95 000 in boys and
70 000 in girls)

5. Childhood cancer
 Overall annual incidence rates vary between 50 and 200
per million in children and between 90 to 300 per million in
adolescents
 Reliable data on cancer in children and adolescents are
available for only a small fraction of the world’s population
 Over the past 50 years, 5-year survival has improved in
high-income countries from less than 30% to more than
80%
 The growing population of survivors requires specialized
follow-up and care

6. Cancer
etiology

7. The global tobacco
epidemic
 Tobacco use remains an enormous health problem that
kills 6 millions people annually worldwide, mainly for
CVD, COPD and lung cancer
 Use is currently decreasing in most high-income
countries but increasing or persisting at high levels in
many low- and middle-income countries
 More than 80% of all smokers reside in low- and
middle-income countries
 Effective tobacco control strategies such as large
periodic increases in excise taxes and the elimination of
advertising provide opportunities for cancer prevention
worldwide

8. Smokeless
tobacco
 Example of smokeless tobacco products include: loose
leaf for chewing, solid compressed tobacco products in
the form of chunks or sticks, viscous pastes, dry or moist
ground tobacco (snus) for oral or nasal use, tobacco-
smoke water for gargling, ecc.
 Oral smokeless tobacco use delivers nicotine more
slowly than cigarette smoking does
 Over the course of the day, smokeless tobacco users
may ingest twice as much nicotine as smokers
 Smokeless tobacco products (as with many cigarette
brands) usually have an increased pH to promote
availability of nicotine for absorption

9. Chemicals in smoking
products
Tobacco smoke contains > 7,000
chemicals including numerous known
carcinogens: PAH, N-nitrosamines,
aromatic amines, volatile aldehydes
and phenolic amines
Smokeless tobacco contains more than
3,000 chemicals and at least 28
carcinogens, many the same contained
in tobacco smoke products

10. Alcohol
consumption
 Epidemiological and biological research on the
association between alcohol and cancer has
established that alcohol consumption causes
cancers of the mouth, pharynx, larynx, oesophagus,
liver, colorectum and female breast
 Typically a dose-response association has been
established
 For 2010, alcohol-attributable cancers were
estimated to be responsible for 337,400 deaths
worldwide, predominantly among men (liver cancer
showed the largest proportion of deaths)

11. Alcohol content of
selected beverages
Starköl
vol. 5.6%
Lättöl
vol. 2,3%
Red wine
vol. 12%
Port wine
vol. 20%
White wine
vol. 10%
Whisky
vol. 40%
Alcohol in
100 g 4,5 1,8 9,9 16,0 7,9 32
1 standard drink = 10 to 14 g of alcohol

12. Alcohol
metabolism
ADH = Alcol dehydrogenase
ALDH = Aldehyde dehydrogenase Liver enzymes

13. Infections
 Infections with viruses, bacteria, and macroparasites have
been identified as strong risk factors for specific cancers
 2 million (16%) of the total of 12.7 million new cancer
cases in 2008 are attributable to infections
 This fraction varies 10-fold by region: it is lowest in North
America, Australia and New Zealand (≤ 4%) and highest
in sub-Saharan Africa (33%)
 Helicobacter pylori, HBV/HCV and human
papillomaviruses are responsible for 1.9 million cancer
cases globally, including gastric, liver and cervical cancer
respectively
 Infection with HIV substantially increases the risk of virus-
associated cancers, through immunosuppresion

14. Reproductive and
hormonal factors
 Reproductive and menstrual factors are relevant to the etiology
of breast, endometrial and ovarian cancers although the exact
biological mechanisms are still not known
 Parity is inversely related to the risk of breast, ovarian and
endometrial cancers (for breast, first child before the age of 30)
 Breastfeeding for a longer period is inversely related to breast
cancer
 Breast and endometrial cancers are predicted by early age at
menarche and later age at natural menopause
 Women who had surgical ovary removal are at reduced risk of
breast cancer (taking the surgery before the age of 40 halves
the risk compared to a natural menopause at 55)
 Obesity is inversely related to premenopausal breast cancer
(probably due to anovulation), but is positively associated to
postmenopausal BC

15. Contraceptives and
hormone use
Use of oral contraceptives substantially
reduces the risk of endometrial and ovarian
cancers but appears to increase the risk of
breast and of cervical cancers
Use of menopausal hormones has been
associated with increased risk of ovarian and
endometrial cancer

16. http://www.cancer.gov/bcrisktool/

17. Male cancers
 Breast: the incidence is 1% the rate in women. Increased risk
after gynaecomastia and with Klinefelter syndrome, obesity and
low physical activity, prior bone fractures and cigarette
smoking. The association with endogenous hormones has not
been assessed
 Testicular: height, subfertility and (possibly) exposure to
endocrine disruptors. Other risk factors include: cryptorchidism,
hypospadias, inguinal hernia, low birth weight, short gestational
age and being a twin
 Prostate cancer: these cancers respond well to anti-androgens
therapies and both surgical and medical castration reduce the
risk of metastasis. Any endogenous hormone has been proved
to be a risk factor. However, finasteride use reduces prostate
cancer risk by blocking the conversion of testosterone to
dihydrotestosterone

18. Lifestyle factors
 Excess body fat increases the risk of cancers of the oesophagus
(reflux), colon, pancreas, endometrium and kidney as well as
postmenopausal breast cancer
 Dietary factors associated with weight reduction (low intakes of sodas,
refined sugars, high-calorie foods, etc.) are protective
 High consumption of red meat (especially processed) is associated with
risk of colorectal cancer
 A diet high in fruit and vegetables and whole grains does not appear to
be strongly inversely associated with the risk of cancer
 High intakes of dairy products protect from colorectal cancer but
increases the risk of fatal prostate cancer
 Low levels of vitamin D increases the risk of colorectal cancer and
mortality, but more research is needed
 Additional studies are needed to assess the role of physical activity,
further than those related to weight control

19. Carcinogens in
food
PAHs and heterocyclic amines from
high cooking temperature
N-nitroso compounds which are
result from nitrate or nitrite added
during processing and formed
endogenously from haem iron
Food contaminants
Mycotoxins (aflatoxins)

20. Occupation
 32 occupational agents as well as 11 exposure
circumstances are identified as carcinogenic to humans
 An additional 27 agents and 6 exposure circumstances
primarily relevant to occupational exposure are probably
carcinogenic to humans (list on the WCR 2014)
 Workplace exposure to several well-recognized
carcinogens (asbestos, PAHs, heavy metals, diesel engine
emissions and silica) is still widespread
 Recent estimates have been in the range of 4-8% of all
cancers attributable to occupational cancer risk factors in
developed countries
 Little information is available on occupational cancer risk in
low-income countries

21. Problems…
 Multiple attempts (often controversial) have been performed to
estimate the proportion of cancer cases attributable to occupation
 Estimating attributable fractions is feasible when the exposure
factor is well defined and there is a body of evidence to support
estimates of the magnitude of risk associated with the risk factor
 None of these conditions generally exist for the generic class of
occupational exposures
 Moreover, confounding by SES and smoking status can be strong
 ”Healthy worker effect”
 Common problems include incomplete lists of occupational
carcinogens, meagre information on quantitative relative risks
associated with exposure to known carcinogens and scant
information on the prevalence of exposure

22. ”Dirty” blue-collar jobs
 As a result of many social, economic and
technological forces, in the past 50 years there
have been a decline in the numbers of workers
involved in the ”dirty” blue-collar work in
developed countries
 Unfortunately, the reverse is true in developing
countries, where occupational environment
continues to be poorly regulated
 An increase in the prevalence of occupational
cancers in developing countries is therefore
expected

23. Prevention
Workers’ education
Safer occupational practices
Surveillance

24. Ionizing, UV and
electromagnetic radiations

25. Risks due to
exposure
 Exposure to all types of ionizing radiation, from both natural
and man-made sources, increases the risk of various types of
malignancy
 The risk is higher if the exposure occurs early in life
 There is current consensus on the absence of a threshold for
the induction of cancers by radiation and presumption of a
linear dose-response relationship
 Exposure to UV radiation, both from the sun and from tanning
devices, is established to cause all types of skin cancers,
including melanoma
 Associations between heavy use of mobile phones and certain
brain cancers have been observed, but causal interpretation is
controversial

26. UV exposure
 Over the last 50 years, the incidence of all skin cancer types has
steeply increased in Caucasian populations worldwide, with
highest incidence rates where fair-skinned populations are
exposed to intense UV radiation in countries such as Australia
 The solar radiation is composed of 95% UVA and 5% UVB, since
the latter are more blocked by the ozone layer
 Tanning lamps and beds emit mainly UVA, with less than 5%
UVB
 Powerful tanning equipment may be a source 10-15 times as
intense as midday sunlight on the Mediterranean sea
 Tanning of the skin is predominantly triggered by DNA damage
induced by UV radiation
 UVB is far more efficient than UVA in inducing a deep, persistent
tan and is 1000 times as potent as UVA in inducing sunburn

27. Extremely low-frequency
electromagnetic fields
 Ubiquitous exposure occurs due to power transmission
and use of electrical appliances, as well as to fields in
the radiofrequency range due to communication and
broadcasting
 A small fraction of households located very close to
high-voltage power lines or other sources can have
appreciably higher background exposures
 For most people, the highest exposure to radiofrequency
electromagnetic fields occurs when using mobile
phones, since the source of emission is held close to the
head
 The number of sources continue to increase

28. Pollution of air, water
and soil
 Air pollution can be divided into indoor and outdoor
 Sources of indoor air pollution include tobacco smoking and
burning or solid fuels (coal and biomass)
 Sources of outdoor air pollution include emissions from
vehicles, power generation, household combustion of solid
fuels and a range of industries
 Exposure to indoor pollution is associated with lung cancer,
particularly in low-income countries where solid fuels are
common
 Exposure to outdoor pollution is associated with
cardiovascular disease and lung cancer

29. Asbestos
 One of the best characterized causes of human
cancer in the workplace
 The installation, degradation, removal and
repair of asbestos-containing products in the
context of household maintenance represents
another mode of residential exposure
 Exposure can also occur through contacts with
dust-contaminated clothes
 It causes mesothelioma and lung cancer, the
latter particularly among smokers

30. Particulate matter (PM)
 It is a mix of hundreds of individual chemicals and its
composition varies around the world, reflecting different
sources of pollution and meteorological conditions
 It also contains carcinogens (PAHs, benzene, inorganic
compounds)
 The smaller the particle, the more dangerous it is. The
measurement of PM2.5 levels is generally considered
more informative than PM10
 Increased PM levels are associated with CVD and lung
cancer. These levels are decreasing in high-income
countries, while are still very high in many low-income
countries

31. Pesticides
 A large and diverse number of chemicals designed to kill pests
such as weeds, insects, rodents, algae and moulds for
agricultural, residential and public health purposes
 They are designed for the release in the environment and
exposure can occur occupationally or through the ingestion of
contaminated foods
 Despite widespread potential exposure, cancer risks associated
with long-term exposure to specific pesticides are generally not
well characterized
 Several organochlorine and organophosphate insecticides have
been linked with an increased risk of prostate cancer
 Inorganic arsenic compounds are classified as Group 1 by IARC
 The fungicide captafol and the fumigant ethylene dibromide are
classified as Group 2A (probably cancerogenic)
 Several are listed as Group 3 (not classifiable as carcinogenic)

32. Water disinfection
 In drinking water, inorganic arsenic is a recognized
carcinogen
 Arsenic is often a natural water contaminants, which
causes cancer of the skin, bladder and lung
 Other contaminants include disinfection by-products
(chloroform and other trihalomethanes), organic
solvents, nitrates, nitrites and some pesticides
 Consumption of chlorinated drinking water is
associated with an increase in bladder cancer
 Alternative/complementary methods include UV
irradiation, microfiltration, oxygen

33. Soil contaminants
 A variety of toxic agents, including heavy metals,
solvents, and persistent organic pollutants (POPs)
contaminate the soil
 In some regions, such pollution occurs by substances
produced as waste or as other consequences of a
particular mining or industrial process
 Soil contaminants present a carcinogenic risk as a
result of being vaporized and consequently inhaled, or
being leached from the soil to contaminate water
supplies
 Accordingly, risk of cancer is generally evaluated in
relation to water or air pollution

34. Pharmaceutical
drugs
Pharmaceutical drugs may have the potential to
induce or prevent cancer development
Antineoplastic agents used in cancer therapy can
induce second cancers, mostly because of the
genotoxicity of these agents
A few drugs have been approved for cancer
preventive therapy (for instance in breast receptor-
positive women), and several others are being
evaluated as preventive agents, including
aromatase inhibitors, aspirin, statins and metformin

35. Tamoxifen
 Indicated as adjuvant therapy for treatment of
postmenopausal estrogen-receptor-positive or
progesterone-receptor-positive breast cancer in men
and women
 Approved as a breast cancer preventive agent among
women at high risk of breast cancer
 Observational epidemiological studies and RCT have
consistently shown that use of tamoxifen increases the
risk of endometrial cancer
 There is also some indication that it may be
associated with an increased risk of some types of
gastrointestinal cancer (not conclusive evidence)

36. Mycotoxins
 Mycotoxins are secondary metabolites produced by
molds in appropriate microclimate conditions of
temperature and humidity (hot/humid)
 They constitutes a heterogeneous group both
chemically and biologically
 Their growth is influenced by the level of moisture,
the temperature and the pH and can be made:
 directly on the plant
 during transfer to storage sites
 during storage

37. Main toxic effects
Genotoxicity, Carcinogenicity, Mutagenicity
Nephrotoxicity
Teratogenicity
Immunotoxicity
Endocrine disruption

38. Common strains and
mycotoxins
Aflatoxins (Aspergillus sp.)
Fumonisins (Fusarium sp.)
Griseofulvin (Penicillium sp.)
Ochratoxin A (Aspergillus and Penicillium
sp.)
Sterigmatocystin (Aspergillus sp.)

39. Products that can
be contaminated
Raw materials (grains, seeds, fruits and
vegetables, dried fruits, coffee, cocoa,
spices)
Food items (products made from
cereals, oils, sweets made of
chocolate, beer, products containing
spices, fruit juices, etc.).
Even meat and dairy products may be
contaminated!

40. Cancer
biology

41. TP53
 The tumour suppressor gene TP53 has been studied for
20 years and encodes a protein called p53
 p53 plays an important role in the maintenance of cell
integrity by repressing proliferative signalling, enhance
the effects of growth suppressors, sensitize cells to
apoptosis, suppress replicative immortality through
senescence and many others
 IARC maintains a database that documents all TP53
gene variations reported in the literature
 > 30 000 somatic mutations are known, mostly single-
amino-acid substitutions in the DNA-binding domain
which disrupt p53 function

42. Epigenetics

43. Epigenetic therapy
Epigenetic changes are revesible and,
therefore, a potential target for therapy
DNA methylation can be reversed by DNA
demethylating agents (two have been approved
by the FDA for haematological disorders)
Histone deacethylation can be reversed by
histone deacetylase inhibitors (two drugs
approved for cutaneous lymphoma)
DNA methylation can be revesed by DNA
demethylating agents

44. Cancer prevention
The reversibility of epigenetic changes could
be used also for prevention, although long-
term effects needs to be considered
However, it is now possible to identify
individuals at extremely high risk of some
cancers by assessing accumulation levels of
aberrant DNA methylation
These individuals would certainly benefits from
effective chemoprevention
Multiple studies are strongly required

45. Cancer
prevention

46. Lifestyle changes
Stop smoking
Improve diet
Control weight
Participate in cancer
screening

47. Vaccination
 A notable fraction of human cancers (16%) are caused by
infections
 Hepatitis B virus, human papillomavirus (HPV) and the
helicobacter pylori are the three most important infections
associated with cancer (liver, anogenital tract and stomach)
 HPV is considered a necessary cause of cervical cancer and
vaccines exists: bivalent (against HPV16 and 18) as well as
quadrivalent (also against HPV6 and 11) both give almost
100% to cancer
 The quadrivalent vaccine costs more but also offers protection
to anogenital warts as well as to the majority of vulvar and
vaginal HPV infections
 They are recommended for girls before initiation of sexual
activity (i.e. 12 yr-olds) with additional «catch-up» programs for
young women (13-18 yr-olds) in some countries

48. Hepatitis B virus
 Hepatitis B virus (HBV) causes chronic hepatitis,
cirrhosis and a large fraction of liver cancer cases
 HBV is a very common infection in some areas of the
world
 Among people chronically infected, about 25% die from
liver disease, including cancer
 HBV is responsible for 50-90% of liver cancer cases in
high-risk areas
 Most countries include HBV vaccination in their
childhood immunization programs

49. Cancer by
organ site

50. Lung cancer
 The most common cancer in men and the third most
common in women
 Risk factors: tobacco smoking (including second-hand),
radon exposure, occupational exposure to PAHs, certain
metals, asbestos and silica, outdoor air pollution
 The distinction between small and non-small cell lung
carcinoma has been replaced by the distinction between
adenocarcinoma and squamous cell carcinoma because of
major differences in genetics and response to therapy
 Lung cancer is one of the most aggressive human cancers
with a 5-year overall survival of 10-15%
 Screening by CT-scan is under development

51. Colorectal cancer
 One of the most common cancers in both men and women,
representing almost 10% of the global cancer incidence
 Third most common cancer in men and second in women
 Fourth most common cause of death from cancer worldwide
 > 65% of cases occurs in highly-developed countries (half of
new cases in Europe and Americas)
 Diet, obesity and lack of physical activity are known risk
factors, but the underlying causative biological processes
are not defined
 Inflammatory bowel disease, when long-standing,
predisposes to colorectal cancer

52. Pancreatic cancer
 A majority of pancreatic cancers occurs in
highly-developed countries
 It is the 7th cause of cancer death worldwide,
with a 5-year survival rate of 5%
 The most common type (90%) is the infiltrating
ductal adenocarcinoma
 The leading known risk factor is cigarette
smoking
 Body fatness is another established risk factor

53. Future prospects
 Although ductal adenocarcinomas of the pancreas have seemed
to present an impenetrable barrier to progress, several recent
advances provide hope
 Personalized therapy is slowly becoming a reality with poly(ADP-
ribose) polymerase (PARP) inhibitors or mitomycin C for cancers
with BRCA2 or PALB2 mutations
 Recent studies suggest that it takes many years for a genetically
altered cell in the pancreas to invade and eventually metastasize
 This suggests a large window of opportunity for the early
detection of curable neoplasia
 The discovery of some genes responsible for the familiar
aggregation of pancreatic cancer is another good news
 Finally, a small % of the genetic changes identified are targetable
with existing therapeutical agents

54. Final considerations
 Cancer is still a huge problem for the humankind
 Increasingly, cancer is a particular burden for low-
and middle-income countries
 Better cancer control can be achieved by
implementing screening as well as by continuing
investing in research
 Detailed knowledge of how individuals and
communities are affected and the implementation of
policies whose efficacy have already been proved in
other countries can increase the success in
preventing and treating this disease

55. Thank you!
Gianluca Tognon
www.gianlucatognon.com