Epidemiology

&
Etiology of Cancer

epidemiology is "the study of the distribution

and determinants of disease (cancer)
frequency in human populations

The word comes from the Greek epi-demos

("on people)
Epidemiology can contribute to cancer control
(prevention, early detection, diagnosis,
treatment, rehabilitation and palliation)

Cancer Epidemiology
Historical Perspective

1775
British surgeon, Percival
Pott reported probably
the first description of
occupational
carcinogenesis in the
form of scrotum cancer
among chimney sweeps.

Cancer Epidemiology
Historical Perspective

In 1842 Rigoni-Stern an Italian physician,

observed that married women in the city
were getting cervical cancer, but nuns in
nearby convents werent.
He also observed that nuns had higher rates
of breast cancer, and suggested that the
nuns corsets were too tight.

1. Observational studies
2. Descriptive-cancer statistics
- maps, trends, correlations
3. Analytic=studies the causes of cancer
They can be classieifed

External factors

Internal factors

4.Intervention studies.

Epidemiologic methods

1. Observational epidemiology studies include

populational data
demographic data: age, gender, race,
residency, age & time trend,
They are important for public health: on this bases
hypothesis generating causes of cancer can be
established

Epidemiologic methods

2. Descriptive
epidemiology shows
international
correlation
on a map
Ex. Red meat
eating countries
are also
Colorectal cancer
high risk countries

2. Descriptive epidemiology studies

Studies statistical data:

vital statistics: incidence & mortality for
different age, gender, race, residency, time
incidence/morbidity (I): number of diseases
diagnosed in a specific population,
standardized (100,000) for a determined
period of time (years). Ex. incidence of lung
cancer in Romania, 1999 = 44.4%000

2. Descriptive epidemiology studies

mortality: number of death registered in a given
population, standardized (100,000) in a
determined period of time (years); usually
for different age groups
prevalence: nr. of cancer patients alive
(with/without disease) in a given period of time for
a specific population (type/site)

2. Descriptive epidemiology studies

2000 general statistical data (1):
incidence:
10 millions, > 50% in developing countries
20 millions estimated in 2020
mortality: 8 millions, 50% from only 4 sites:
lung: 1.3 million;

stomach: 1 million;

H&N: 0.9 million;

liver: 0.7 million

2. Descriptive epidemiology studies

2000 general statistical data (2)
mortality: other 6 sites = 25%
intestine: 0.6
breast: 0.4
prostate: 0.3
uterus: 0.3
pancreas: 0,2
bladder: 0.2

2. Descriptive epidemiology studies

2000 general statistical data (3):
estimated mortality for 2020: 12 millions of death
from which 70% in developing world
Trends:
decreasing mortality after 1990 for lung, cervix,
stomach, breast in North America & Western
Europe

2. Descriptive epidemiology studies

Geographical variations (1):

2. Descriptive epidemiology studies

Geographical variations (2):
ethnic groups: Parsi/Bombay, eskimo = breast
Caspian Sea: esophagus
South-East Asia, Northern Africa: nasopharynx
African belt: Burkit Ly
nuns vs prostitutes: breast vs cervix
migratory populations: Japanese in USA
(esophagus/stomach vs prostate, colorectum

Cancer rates in Japanese migrants in Hawaii (1970)

vs Japan (Osaka) and in Hawaiian Caucasians
(1970, 1990)

2. Descriptive epidemiology studies

Temporal variations (1):
age at onset
age: the most powerful risk F: >60 years!!!
developing countries: 50-60% < 60 yrs
children: leukaemias, lymphomas, CNS
adolescents: germinal T. testicle, Hodgkin
distribution patterns: cumulative vs others

2. Descriptive epidemiology studies

Romania 1998:
mortality: 39.293 deaths, 174.6/100,000
males: 22,357
lung: 6451/44.4
stomach: 2594/17.2
colorectal: 1782/11.7
prostate: 1452/9.1
liver: 1235/7.6

2. Descriptive epidemiology studies

Romania 1998:
mortality: 39.293 deaths/%, 174.6/100,000
females: 15,873
breast: 2682/15.7
cervix: 1741/11
colorectal: 1594/8.3
lung: 1337/7.2
stomach: 1320/6.8
ovary: 887/5.0

Epidemiologic methods

Changes with Time ex.: Colon cancer

shows stability
in the UK & in increases in Japan

Epidemiologic methods

Mortality from cervical cancer in 1990

(per 100 000 age standardized world population)
From: Jones: BMJ, Volume 319(7208).August 21, 1999.505-508

3. Analytic epidemiology studies:

individual risk factors
cohort studies: follow individuals from
exposure to the development of disease
= large groups
case-control studies: begins with
individuals (diseased cases vs not
disease casesd)

Epidemiologic Method

How to calculate the Relative Risk - RR:

risk for persons with exposure compared with risk of one for
non-exposed

3. Analytic epidemiology
Alias: Risk Factors, Cancer Causes
Definition of carcinogenicity for human beings:
on human & animal evidence!

based

3. Analytic epidemiology
Regulatory bodies:
NTP: National Toxicology Program (USA)
IARC: International Agency for Research on
Cancer
Attributable Risk percentage (AR%): is an
indicator about the proportion of cases that would
be prevented if the agent in the category were
virtually entirely controlled

3. Analytic epidemiology
Causes of Cancer: External factors
I. Environmental: 4 - AR 5%
II. Lifestyle: 6 - AR 45%
III. Occupational: 35 - AR 4%
IV. Pharmacologic: 18 - AR 2%
V. Biologic: 9 AR 4%
External factors: prevention of cancer is possible
in more than 90% of the cases !! - ?

3. Analytic epidemiology
Causes of Cancer: I. Environmental: 4 - AR 5%
Environment is
from the epidemiologists point of view: general or
shared environment, individual behavior & lifestyle
in practice : environment is air, water, ground, food
supplies
Lifestyle: 45% responsible (USA) but >60% from, is
attributable to smoking!

3. Analytic epidemiology
Causes of Cancer: I. Environmental: 4 - AR 5%

3. Analytic epidemiology
Causes of Cancer: II. Lifestyle: 6 - AR 45%

3. Analytic epidemiology
Causes of Cancer: III. Occupational: 35 - AR 4%

3. Analytic epidemiology
Causes of Cancer: IV. Pharmacologic: 18 - AR 2%

3. Analytic epidemiology
Causes of Cancer: V. Biologic: 9 - AR 4%

Helicobacter pylori
Gastric cancer
490,000 cases/year
5.4% of all cancers globally
Hepatitis B/C
Liver cancer
390.000 cases/year
4.3%
Human papilloma
Cervical cancer (+)
550,000 cases/year
6.1%
World Cancer Report 2003
Uneven distribution of burden
between developing and developed countries

The number of viruses, bacteria and parasites that are

recognized cancer causing agents is growing.
The World Cancer Report 2003 estimated that around
1.5 Mill cases annually are caused by helicobacter pylori,
hepatitis viruses and human papilloma viruses alone.
The report notes that the cancer burden
associated with these agents rests heavily on the
developing countries where primary prevention, e.g.
through immunization, early recognition e.g. through
screening for early cervical cancer, or treatment e.g.
for helicobacter through antibiotic drugs may not or less
easily be available.

3. Analytic epidemiology
The main risk factors at the beginning of XXI century:
1. Smoking:
effects on: lung, pancreas, bladder & kidney, larynxmouth-pharynx-esophagus (synergy with alcohol)
more recent evidence for: stomach, liver, cervix,
breast
2. Diet & overweight (1):
consensus: Ca commoner in overweight:
postmenopausal F, endometrium, gall bladder, kidney

3. Analytic epidemiology
2. Diet & overweight (2):
about 1/3rd of British Ca deaths might be avoided
by dietary changes but definitely avoidable only those
due to obesity
about 5% (3% M, 6% F) of all Ca in EU might be
prevented if BMI < 25 kg/m2
USA: about 10% of Ca death among non-smokers
(7% M, 12% F) are caused by overweight

3. Analytic epidemiology
3. Reproductive and hormonal factors:
carcinogenic effects of endo-/exogenous hormones
on breast & ovary: OC, HRT vs late menarche,
early 1st childbirth & increasing parity
HRT: endometrial Ca
ovarian Ca: declines with increasing parity, OC
Western diet: associated with earlier age at
menarche, postmenopausal obesity = increased
endogenous estrogen production

3. Analytic epidemiology

4. Occupational and environmental carcinogens:

Ca risk from long-term hazardous activities: not high
burning fossil fuels indoors & inadequate ventilation
contributes to the high Ca rates in non-smoker
China
sun light: occupational vs lifestyle

3. Analytic epidemiology
Causes of Cancer: Internal factors that can cause cancer
Genetic background & individual susceptibility

3. Analytic epidemiology
Cancer: genetic disease
Mutation lesions on genes (implicated in cancer)
are the most important step in understanding
carcinogenesis
Mutation lesions are cumulated in time: more and
more
monoclonal origin in at least 95% of tumours
The cancerogenesis is a multistep process which
involved:

3. Analytic epidemiology
The step of cancerogenesis
- the

initiation: the lesions appear on genetic

material due to the action of external or internal factors
on genetic material the lesions can be repair
- the promotion: the lesions persist and increase in
presence of some favorable conditions - and the lesions
can not be repaired
- the invasion and metastases

3. Analytic epidemiology
The gene that are implicated in cancerogenesis are:
1. oncogenes: the normal component of genomic
material which are a normal role in the growth of cells
- in cancer: the oncogenes have a increased
function or are supraexpressed, increase its protein
product (GF,GFR), so, the growth of cells are in exces
- The GF, GFR are implicated in signals growth
transmision from external medium of cells to nucleus

3. Analytic epidemiology
The gene that are implicated in cancerogenesis are:

2. Tumor suppression genes: the normal genes which

suppress the growth of cells: p53 (implicated in
apoptosis process), Rb
- in cancer: the tumor suppress genes can be
deleted

3. Analytic epidemiology
3. DNA repair genes: the normal component of
genomic material which have a normal role to repair the
genetic material lesions
- in cancer: a defect of repair genes can conduct to
cumulate lesions; when exist many lesions in genetic
material, even if exist a normal function of repair genes,
these genes cant repair the lesions.
- Types: excision repais, DRP, for recognition of lesions,
topoisomerases I, II, ERCC

3. Analytic epidemiology
4. The apoptosis = the controlled death cells
- p53 dependent
- p53 independent
In apoptosis routes are implicated proteins:
1) Proteins that stimulate apoptosis
a) bcl-XS, bcl-2
b) p53
2) Proteins that inhibit apoptosis
a) bcl-2, bcl-XL

3. Analytic epidemiology
Observation: in normal situation: it exist a normal
equilibration between oncogenes and tumor suppress
genes, an equilibration between the growth and the
inhibition of growth
If there are not this equilibration, the growth can be
abnormal stimulated and the cells abnormal proliferate
and tumor appear
separate genetic changes required for tumor
invasion and metastases
genetic instability:

3. Analytic epidemiology
INVASION AND METASTASES
separate genetic changes required for tumor
invasion and metastases
1. INVASION steps:
- the tumour cell attachement at EM (external matrix)
- the activation of specific receptors and the ricognition of
molecules from EM,
- secretion of ensimes
- locomotion

3. Analytic epidemiology
INVASION AND METASTASES
1. Metastases steps:
- the vascular invasion
- trombs formations
- endothelial lesions
- NAG is a central step in metastases process
- the proliferation in new invadated viscer

3. Analytic epidemiology

It exist an exponential increase of cancer

incidence with age:
- frequency of spontaneous mutations: 10-6 - 10-7
The growth of tumors can be:
- exponentials: in leukemia, limfoma
- gompertzian: in the most majority of solid tumors

3. Analytic epidemiology

The clinical implications of tumor growth

models
1) Subclinical perioud tumor evolution
- detect tu at 10 9 cells (tu=1gr, 1ml, 1cm )
- 10 12 cells (1 kg) = death
Sub-clinical perioud > clinical period Dt (for breast cc = 4 years)
In subclinical perioud = metastases
2) Tumor volum high = efficacy of treatment (RT, PCT) low
3) Recognition of subclinical perioud is important for adjuvant CT
or RT
4) The risk of metastases is direct prop. with tumor volum
ex : In breast cancer cc mamar: T=3.5 cm =10 6 10 8 = > 50% of
ptc have metastaze; they will have metastases in the future

3. Analytic epidemiology
Mechanisms of cancer predisposition:
1. germline T suppr gene inactivation: retinoblastoma/Rb
2. germline oncogene activation:
MEN 2a syndroms (medullary Thyr Ca + pheocgromocytoma)
MEN 2b syndroms(mucosal neuromas, blubbery lips, marfanoid
habitus) = defect on ret gene

3. DNA repair defects:

Ataxia-telangiectasia: AT
BrCa: BRCA1/BRCA2, 5% of all

3. Analytic epidemiology

Mechanisms of cancer predisposition:

4. Abnormal tissue architecture: ex Juvenile polyposis =
germline mutation in PTEN gene
5. Humoral Tu. promoters & repressors
polycistic ovary syndr: cronic anovulation can conduct to
endometrial & Ovary Cancer

3. Analytic epidemiology

3. Analytic epidemiology
1. Clinical characteristics of cancer families
onset of cancer at earlier age
frequent multiple primary tumors
positive familial history
associated with congenital defects & malformations

3. Analytic epidemiology

3. Analytic epidemiology

Five Criteria for a Cause Effect Relationship

Criteria

Risk Factor for Disease

1) Timing

Exposure occurs before

2) Strength

Is dose-dependent
Cessation of exposure can modify

development
of disease or during its progression

disease
3) Prevalence
4) Relationship
to
other risk
factors
5) Plausibility

Occurs in multiple populations

Is independent
Can also act synergistically
Produces structural or functional

changes
which are events in mechanism of
disease