1. Aetiology of Human Cancer
By
Dr. Ihab Samy
Lecturer of Surgical Oncology
National Cancer Institute
Cairo University
2013
2. The etiologic factors responsible for human
cancer are generally classified into 3 main
groups:
• Extrinsic factors
• Intrinsic factors
• unknown
3. Extrinsic factors
• Chemical factors
• Physical factors (radiation)
• Infections (mainly oncogenic viruses)
N.B.: These factors represent 85% of etiologic
factors of cancer and are particularly important
in cancers of adults.
4. Intrinsic factors
• Genetic factors
• Hormonal factors
• Immune causes
N.B.: The intrinsic genetic factors are the main
contributing agents in pediatric malignancies.
5. Proportions of cancers attributed to various etiologic agents
(USA)
Factor Percent
Diet 35
Tobacco 30
Viruses 5
Genetic predisposition 5
Occupational hazards 4
Alcohol 3
Radiation 3
Medications 2
Pollution (mainly polycyclic hydrocarbons from fuel
combustion)
2
Unknown 11
6. Etiology of cancer is multifactorial which is illustrated by the
following examples:
1. Multiple extrinsic factors:
• Chemical + viral factors e.g. HCC and
Nasopharyngeal carcinoma
• Virus + Smoking + Contraceptive pills
Cervical carcinoma
7. 2. Multiple intrinsic factors:
• Genetic + hormonal factors Familial breast cancer.
3. Extrinsic and intrinsic factors:
• Genetic (DNA repair defect) + Physical factor (UV
radiation) Cutaneous cancer in xeroderma
pigmentosum
• Genetic + Immune factor + Virus + UV radiation
SCC in epidermodysplasia verruciformis
8. Chemical carcinogens
They are classified according to:
• The metabolic activation in the body
• The organ specificity
• The degree of evidence of carcinogenicity
9. Metabolic activation
A. Direct acting carcinogens :
• Not requiring metabolic activation in the body
for their carcinogenicity (activation independent).
• Weak carcinogens.
• Includes many therapeutic alkylating agents used
as anticancer drugs (cyclophosphamide,
chlorambucil, melphalan, busulfan, thiotepa and
cisplatin).
10. B. Indirect acting (Procarcinogens):
• Require metabolic conversion in the liver to
produce carcinogenesis on the cells.
• Include most of the known potent carcinogens
which are activated by cytochrome P450
oxidase (benzo(a)pyrene, vinyl-chloride,
nitrosamine, aflatoxin and 2-naphthylamine)
11. The ultimate carcinogenic effect of the chemical will
depend upon the balance between 3 activities:
• Activation
• Detoxication
• Repair of DNA damage
Cancer will only develop as a result of a sublethal
DNA damage which is not repaired while the cell is
viable enough to undergo mitosis.
12. Organ specificity
• Organ tropism of the chemical carcinogen is
largely determined by the sites of their activation
or excretion.
• Accordingly they are grouped into 2 main
categories:
1. Single organ affection aflatoxin, vinyl chloride,
butter yellow liver cancer (activation site).
Naphthylamine
bladder cancer (excretion site).
13. 2. Multiple organ affection nitrosamine and
polycyclic aromatic hydrocarbons (according to
the route of administration).
14. Degree of carcinogenicity (IARC categories)
The international agency for cancer research
(IARC) categorizes human carcinogens into:
1. Sufficient evidence of carcinogenicity
2. Limited evidence of carcinogenicity
3. Inadequate evidence of carcinogenicity
15. Chemical carcinogens definitely proven to be cancer causative
agents
Class Example
Polycyclic aromatic hydrocarbons Benzo(a)pyrene
Aromatic amines 2-Naphthylamine
Nitrosamines and nitrosoureas Dimethylnitrosoamine
Alkylating agents Nitrogen mustard and cyclophosphamide
Alkyl and aryl halides Polychlorinated biphenyls
Natural products Aflatoxin
Metals Arsenic, nickel, cadmium and chromates
Fibres and dusts Asbestos, silica and wood dust
16. Tobacco Smoking
Lung cancer is the number one cause of cancer deaths.
Women’s death rates due to lung cancer have risen 600%
since 1950.
About 90% of all lung cancer deaths are attributable to
smoking.
A long-time cigarette smoker is 2000 times more at risk of
lung cancer than a lifelong nonsmoker
Chewing tobacco and snuff contain 28 different carcinogens
17. • Direct effect of carcinogens in tobacco
Oral, Esophageal and Laryngeal cancers.
• Indirect (Systemic) effects Pancreatic,
Bladder, Renal and Cervical cancers.
• Research shows that smokers infected with human
papillomavirus have greater risk of developing invasive cervical
cancer than nonsmokers with the virus.
• Tobacco is one of the behavioral factors considered to elevate
the risk of cervical cancer.
• Smokeless tobacco risk of Oral, Esophageal and
pancreatic Cancer.
18. • Pipe and Cigar smokers risk of Oral,
pharyngeal,esophageal and laryngeal cancers.
• Passive smokers (environmental exposure) who
live with smokers are 30% -50% at a higher risk for
lung cancer.
• Commercial tobacco contains 4000 chemicals
500 poisons
40 carcinogens
• On a milligram for milligram basis , Nicotine is 10
times more addictive than Heroin.
19. Diet
• Women who are overweight are more likely to:
– Develop breast cancer
– Be diagnosed at a later stage
– Have higher mortality rates
• Obesity increases risk of death from breast cancer about as
much as mammography reduces it.
• Low-fat diet reduces the risk of breast, prostate and
colorectal cancers.
• Intake of saturated and monounsaturated fats colon
cancer risk.
• Dietary fibers risk of colon and rectal cancer.
• B- carotene risk of lung cancer (controversial)
20. • Food additives, pesticides represent less than
1 % of carcinogens found in food.
• Aflatoxins in badly stored grains –> HCC
• Smoked fish (NOCs) naopharyngeal ca.
• HAAs (Frying or grilling high ptn foods), PAHs
(broiling and smoking food) NOCs (Salting and
picking food cured with nitrite or nitrate)
DNA adducts Breast cancer (2.5 folds risk)
and colorectal cancer.
21. Alcohol
• risk of Aerodigestive cancers Oral cavity,
pharynx, larynx and eosophagus.
• Acts synergistically with smoking to cancer risk.
• Also risk of Breast, colorectal, prostate and liver
cancers.
• The exact measure and mechanism is still
unknown.
• Genetic susceptibility among individuals make it
difficult to establish a clear Alcohol-Cancer
relationship.
23. Ionizing radiation
• Electromagnetic X-rays, Gamma rays
• Particulate Alpha and Beta particles,
protons and neutrons
They are all carcinogenic, e.g.:
1. Radioactive miners 10 times incidence of
lung cancer
2. Survivors of atomic bombs (Japan) incidence
of leukemia, thyroid, breast, lung and colonic
cancers.
24. 3. Children exposed to head and neck
radiation Thyroid cancers in 9%
4. Young women (< 35) exposed to
mammography incidence of breast cancer
N.B.: Radiation causes chromosomal breakage,
translocations and point mutations being
highest with neutrons and alpha particles where
children are more vulnerable than adults
25. Ultraviolet radiation
The degree of risk depends on:
• The intensity of exposure
• The quantity of melanin pigment in the skin
(protective role).
Both squamous and basal cell carcinomas as
well as melanoma are the sequelae.
incidence of skin cancer in individuals with fair
skin and albinos.
Hereditary deficiency of excision- repair
enzymes of DNA Xeroderma pigmentosum.
26. Radiation induced human cancers
Exposure Cancer type
Nuclear industry Multiple myeloma
Nuclear weapons ( blast or fall out) Leukemia, solid tumors, thyroid cancer
Early radiologists Leukemia, skin cancer
Uranium miners Lung cancer
27. Chronic infections
• Bacterial:
Helicobacter pylori (13 of stomachs of world
population) major cause of gastric carcinoma
and MALT lymphoma
• Parasitic:
Schistosoma haematobium urinary bladder
cancer (Egypt)
Chlonorchis sinensis biliary cancer (China)
28. Viruses (Oncoviruses)
• 15 % of all human cancers worldwide may be attributed to
viruses.
• Both DNA and RNA [Retroviruses] viruses have been shown
to be capable of causing cancer in humans.
• Epstein-Barr virus, human papilloma virus, hepatitis B virus,
and human herpes virus-8 are the four DNA viruses that are
capable of causing the development of human cancers.
• Human T lymphotrophic virus type 1 and hepatitis C viruses
are the two RNA viruses that contribute to human cancers.
• The path from viral infection to tumorgenesis is slow and
inefficient; only a minority of infected individuals progress
to cancer, usually years or even decades after primary
infection.
29. • The region of the viral genome (DNA in DNA
tumor-viruses or RNA in RNA-tumor viruses) that
can cause a tumor is called an oncogene.
• This foreign gene can be carried into a cell by the
virus and cause the host cell to take on new
properties Transformed cell.
• Viral infection also is generally not sufficient for
cancer, and additional events and host factors,
such as immunosuppression, somatic mutations,
genetic predisposition, and exposure to
carcinogens must also play a role.
• The presence of viral gene products in tumor cells
that require them to maintain their unchecked
proliferation also can provide important targets for
directed therapies that specifically can distinguish
tumor cells from normal cells.
30. Hepatitis B and C viruses
• Hepatocellular carcinoma is an aggressive tumor that
can occur in the setting of liver disease resulting from
infections with hepatitis B and/or hepatitis C virus.
• Hepatitis C virus is an enveloped RNA virus of the
flavivirus family.
• The hepatitis B virus of the family hepadnaviridae is, by
contrast, a DNA virus.
• HBsAg carriers have a risk of HCC that is 217 times that
of a non-carrier. 51% of deaths of HBsAg carriers are
caused by liver cirrhosis or HCC compared to 2% of the
general population.
31. Epstein-Barr virus (EBV) and human
herpesvirus 8 (HHV-8)
• Both herpesviruses that possess large double-stranded DNA
genomes.
• As with all herpesviruses, they encode enzymes involved in DNA
replication and repair and nucleotide biosynthesis.
• EBV is most commonly known for being the primary agent for
infectious mononucleosis. Up to 95% of all adults are estimated to
be seropositive, and most EBV infections are subclinical.
• EBV also is associated with a number of malignancies: B and T cell
lymphomas, Hodgkin’s disease, post-transplant lymphoproliferative
disease, leiomyosarcomas, and nasopharyngeal carcinomas.
32. • The primary site of infection is the oropharyngeal
cavity, and EBV is capable of infecting both B cells
and epithelial cells and switching between the
two.
• In 1994, HHV-8 DNA was identified in biopsies
from tumors of a patient with Kaposi sarcoma.
• HHV-8 also is believed to have a role in
Castleman’s disease and primary effusion
lymphoma.
• The viral genome is expressed in these tumors and
encodes transforming proteins and anti-apoptotic
factors. The virus is also able to enhance the
proliferation of microvascular endothelial cells.
33. Human Papillomavirus (HPV)
• HPV are small non-enveloped DNA tumor viruses that commonly
cause benign papillomas or warts in humans.
• Persistent infection with high-risk subtypes is associated with the
development of cervical cancer.
• HPV infects epithelial cells, and, after integration in host DNA, the
production of oncoproteins, mainly E6 and E7, disrupts natural
tumor suppressor pathways and is required for proliferation of
cervical carcinoma cells.
• HPV also is believed to play a role in other human cancers, such as
head and neck tumors, skin cancers in immunosuppressed patients,
and other anogenital cancers.
34. • In 2006, an effective prophylactic vaccine against HPV
16 and 18 based on virus-like particles (VLP) was
approved for use by the FDA based on clinical trials
that demonstrated nearly 100 percent protection from
persistent infection through the generation of high
levels of neutralizing antibodies.
• Since these types are the causative agent of
approximately 70% of cervical cancers, development
of such an effective vaccine holds much promise for
the prevention of cervical cancer.
• However, the vaccine currently costs $360 for a
complete course of three injections given over six
months, does not provide protection against other
high risk HPV types, will presumably have limited
benefit to women already infected, and has an
unknown duration of protection.
35. Human T lymphotropic virus type I
(HTLV-1)
• Single stranded RNA retrovirus and is associated with adult T-cell
leukemia.
• Estimated 12 to 25 million people infected. However, disease is only
observed in less than 5 percent of infected individuals.
• HTLV-1 infection has a very long latency period of 20 to 30 years, but once
tumor formation begins, progression is rapid.
• Transmitted through blood transfusions, sexual contact, and during
parturition.
• A special tropism for CD4 cells, which clonally proliferate in adult T cell
leukemia.
36. Human immunodeficiency Virus (HIV)
A variety of malignant tumors may develop in AIDS
patients:
• Kaposi’s sarcoma
• NHL, HD
• Cervical carcinoma
• Anal carcinoma
• Leiomyosarcoma in children
Pathogenesis of these tumors is related to opportunistic
viral infections (HHV-8, EBV and HPV) rather than HIV
virus
37. Intrinsic factors : Hereditary cancer
• Hereditary cancer is defined as familial clustering
of cancer of definite genetic cause that follows
Mendelian laws of inheritance.
• Familial cancer in which there is also familial
increase in cancer incidence (at least 2 cases in
close relatives), but no Mendelian pattern of
tumor transmission, indefinite genetic bases and
the cause may be related to environmental or
hormonal factors or just coincidence.
38. 7 Cardinal features of Heriditary cancer:
1. Familial clustering of the same type of cancer (site specificity).
2. Mendelian pattern of tumor transmission.
3. Identification of specific abnormal gene.
4. Early age of onset (<40 years).
5. Multicentricity and Bilaterality of tumors.
6. Multiple 1ry cancers at different sites.
7. Associated congenital abnormalities.
39. Hereditary cancer is classified into 4 main
groups (according to underlying hereditary
defect and type of Mendelian transmission)
1. Inherited Cancer Risk.
2. Inherited precancerous lesions.
3. Inherited precancerous syndromes.
4. Inherited immunodeficiency.
40. 1. Inherited Cancer Risk
• Autosomal dominant.
• Appears in every generation.
• 50% incidence.
• Equal sex affection.
• Mainly loss of tumor suppressor gene.
41. Examples:
• Familial Retinoblastoma (Rb/13q) Retinoblastoma,brain
tumors,pineoblastoma,melanoma and breast cancer.
• Familial Wilm’s tumor (WT1/11p) Wilm’s tumor.
• Li Fraumeni syndrome (p53/13q) Breast cancer and
sarcomas.
• Von Hippel-Lindau (VHL/3p) Renal cell ca. and pheo.
• MEN-2 (Ret/10q) TMC and Pheo
• Cancer Family Syndromes:
a) BRCA-1 (17q) Breast and ovarian cancer.
b) BRCA-2 (13q) Breast cancer only.
c) Lynch 1 (3p) HNPCC-1 Colon cancer only.
d) Lynch 2 (2p) HNPCC-2 Colon + Extracolonic cancers
(Breast, Endometrium and urothelial).
42. 2. Inherited Precancerous Risk
• Autosomal dominant.
• Inherited precancerous lesion Turn
malignant or associated with malignancy.
46. 4. Inherited immunodeficiency
• X-linked genetic transmission.
• Increased risk of lymphoma (NHL) and
leukemia.
Examples:
• Wiskott-Aldrich syndrome.
• Infantile agammaglobulinemia.
• Severe combined immunodeficiency.
47. Immunosuppression and Cancer
• Congenital immunodeficiency
• Therapy-induced (iatrogenic) immunodeficiency
• Acquired immunodeficiency syndrome (AIDS)
48. • Chronic antigenic stimulation from recurrent
infections may be responsible for increased
cancer risk.
• Non-Hodgkin’s lymphoma accounts for over one
half of malignancies regarding Congenital
immunodeficiency and tend to arise in unusual
extranodal sites e.g brain and GIT.
• Azathioprine (Immuran), Cyclosporin A,
Cyclophosphamide and prednisone are the most
commonly used immunosupressants after organ
transplantation.
49. • The 4 most common cancers due to therapy-
induced immunosuppression are:
1. Sq.C.C. of the skin (20%)
2. NHL (14.5%)
3. Kaposi’s sarcoma (3.3%)
4. Malignant Melanoma (1.5%)
• Time of onset is 2.4 years for lymphoma and
4.5 years for non-lymphomatous tumors from
the start of therapy.
50. • Chemotherapy and Radiotherapy also have
immunosupressant effects causing 2nd primaries
after the treatment of the initial cancer.
• Latent period is 2-7 years for chemotherapy and
10-15 years for radiotherapy.
• The most common malignacies are:
1. AML (50%)
2. Lymphomas (13%)
3. Carcinoma of the urinary bladder (9%)
51. Hormones and Cancer
• Endogenous hormones play a major role in
etiology of several human cancers:
1. Breast Cancer
2. Endometrial Cancer
3. Ovarian Cancer
4. Prostatic Carcinoma
5. Testicular Cancer
6. Thyroid Cancer
7. Osteosarcoma
52. Breast Cancer
• Predominance of Estrogen over Progesterone.
• Early menarche and late menopause.
• Obesity: Androstenedione Estrone
Estradiol
(more potent)
• TGF-alpha (tumor promotor) production is
mediated by Estrogen.
Aromatase
(in adipose tissues)
53. Endometrial Cancer
• 80% of premenopausal Endometrial Cancers
are related to hyperestrenism.
• Granulosa cell tumors Estrogen secretion
(regression of endometrial ca. after excision of
ovarian ca.).
• Progesterone concentration of Estradiol receptors.
enzymatic conversion of Estradiol to less
potent Estrone.
54. Ovarian Cancer
• Incessant ovulation theory:
Repeated ovulations traumatize the ovarian
surface epithelium Proliferations.
• Gonadotropins thus have an indirect effect by
increasing ovulation.
• Rare incidence of ovarian cancer in:
1. Nulliparous women.
2. Women with anovulatory cycles.
3. Contraceptive pills inhibiting ovulation.
56. Testicular Cancer
• Estrogen excess theory:
High levels of estrogen in utero in early
pregnancy Germ cell tumors of the testis
Cryptorchidism
57. Thyroid Cancer
• Well differentiated thyroid carcinoma especially
follicular carcinoma is a TSH-dependent tumor.
• Iodine deficient diet TSH.
• Sex hormones may theoretically play a role
regarding female predominence.
• TSH Suppression via Eltroxin is an important goal
in treatment of well differentiated thyroid
carcinoma.
58. Osteosarcoma
May be related to Somatotropin (growth)
Hormone:
• Age most common in adolescents.
• Site Commonly affecting the metaphyses of
long bones.
Age and site of maximal skeletal growth.
