Etiology of cancer

1. Etiology of Cancer
Mohammed Fathy Bayomy, MSc, MD
Lecturer
Clinical Oncology & Nuclear Medicine
Faculty of Medicine
Zagazig University

2. Classification of
etiological factors
 Extrinsic factors
 Intrinsic factors
 Unknown

3. Extrinsic factors
• Chemical
• Physical (Radiation)
• Biological (Infection)

4. Intrinsic factors
• Genetic
• Hormonal
• Immune

5. Extrinsic factors predominate as
etiologic agents of human cancer
Extrinsic Factors : Intrinsic Factors
85% : 15%
Extrinsic factors <> Intrinsic factors
 
Adult cancer Pediatric cancer

6. Proportions of Cancers Attributed
to Various Etiologic Factors (USA)
Factor Percent
Diet 35
Tobacco 30
Virus 5
Genetic predisposition 5
Occupational hazards 4
Alcohol 3
Radiations 3
Medications 2
Pollution 2
Unknown 11

7. Etiology of cancer is commonly
multifactorial
Interaction of multiple factors occur to determine the
overall susceptibility & risk
Multiple extrinsic factors
 HCC: Chemical + Virus
 Nasopharyngeal cancer: Chemical + Virus
 Cancer cervix uteri: Virus + Smoking + Contraceptive pills

8. Multiple Intrinsic factors
 Familial breast cancer: Genetic + Hormonal
 Familial prostate cancer: Genetic + Hormonal
Multiple Extrinsic + Intrinsic factors
 Cutaneous cancer é Xeroderma pigmentosum:
Genetic factor (defect in DNA repair) + Extrinsic physical factor
(UV)
 Squamous carcinoma é epidermodysplasia verruciformis:
Genetic defect + Immune deficiency + Virus + ultraviolet
radiation

9. Extrinsic Factors

10. Chemical Carcinogen
 Definition: compounds é electron-deficient atoms
(reactive electrophilic centers)  electrophiles
 Character: highly-reactive combine é electron-rich
atoms in nucleic acids & proteins
 Mechanism of carcinogenesis
Reaction of electrophiles é biologically
important molecules (DNA)
Gene mutation

11.  Classification
1- Metabolic activation
2- Organ Specificity
3- IARC Categories

12.  Metabolic activation
Direct-acting carcinogens
Indirect-acting carcinogens
(Procarcinogens)
Electrophilicity Intrinsically electrophilic Not intrinsically electrophilic
Activation Activation independent
Do not require metabolic
activation in body for their
carcinogenicity
Activation dependent
Require metabolic conversion
in liver to produce ultimate
active carcinogens
Potency Weak carcinogens Potent carcinogens
Include Therapeutics alkylating
agents used as anticancer
-Cyclophosphamide
-Chlorambucil
-Melphalan
-Busulfan
-BCNU
-Thiotepa
-Benzo(a)pyrene
-Vinyl-chloride
-2-naphthylamine
-Nitrosamine
-Aflatoxin

13. Factors determine carcinogenicity of chemical: ultimate carcinogenic effect of
chemical depend upon balance of three activities
1- Activation: indirect-acting carcinogen (procarcinogen) is activated in liver by
enzyme cytochrome P450 oxidase into active carcinogen
Polycyclic aromatic hydrocarbon (PAH) Benzo(a)pyrene  oxidation 
epoxide ''carcinogenic''  oxidation  dihydrodiol epoxide ''highly
carcinogenic''
2- Detoxication: detoxication system of carcinogens works by combining these
poorly-soluble compounds to hydrophilic groups (e.g. glucuronic acid or
glutathione)  water soluble products  excreted in urine
3- Repair of DNA damage

15. Biomarkers of exposure
 Biochemical tests to measure
* Carcinogen-DNA adducts or
* Carcinogen metabolites in blood & urine

16.  Organ specificity (tropism)
 Determined by
* Site of activation
* Site of excretion
* Route of administration
 Carcinogens are grouped into
* Single organs carcinogen
- Site of activation: Aflatoxin, vinyl chloride  HCC
- Site of excretion: 2-Naphthylamine  Bladder cancer
* Multiple organs carcinogen
- Polycyclic Aromatic Hydrocarbons
- Nitrosamine

17.  IARC Categories
IARC (International Agency for Cancer Research) classified human
carcinogens according to degree of evidence of carcinogenicity from
epidemiologic studies
Category a Category b Category c
Sufficient evidence of
carcinogenicity
Limited evidence of
carcinogenicity
Inadequate evidence of
carcinogenicity
Definite causal relation Indefinite causal relation *Few studies
*Inconclusive studies
*Investigations showing
no evidence of
carcinogenicity

18. Major Classes of Human Chemical
Carcinogens
Class Example
Polycyclic aromatic hydrocarbon Benzo(a)pyrene
Aromatic amines 2- Napthylamine
Nitrosoamines & nitrosoureas Dimethylnitrosoamine
Alkylating agents Nitrogen mustard
Cyclophosphamide
Alkyl & aryl halides Polychlorinated biphenyls
Natural products Aflatoxin
Metals Arsenic, Nickel, Cadmium &
Chromates
Fibers & dusts Asbestos, silica & wood dust

19. Chemicals Associated with
Occupational Cancer
Industry Carcinogen Site of Cancer
Miners Radon, silica Lung
Chromate Chromium Lung
Insulators Asbestos Lung, mesothelioma
Petroleum PAH* Lung, skin
Ore smelters Arsenic Lung, Skin
Refiners Nickel Lung, nasal sinuses
Furniture Wood dust Nasal sinuses
Rubber 2-Naphthylamine Bladder
Dye 2-Naphthylamine Bladder
Varnish Benzene Leukemia
Plastic Vinyl chloride Liver, brain

20. Medications which Pose a
Carcinogenic Risk to Humans
Drug Associated Neoplasm
Alkylating agents Bladder, Leukemia
Chlornaphazine Bladder
Phenacetin Renal pelvis
Thorotrast Liver (angiosarcoma)
Androgens Liver
Inorganic arsenic Liver, Skin
Methoxypsoralen Skin
Diethylstilbesterol Vagina (offspring)
Estrogen, postmenopausal Endometrium
Tamoxifen Breast
Immunosuppressants Lymphoma, Kaposi,
Skin squamous cancer

21.  Epidemiology
* 30 % all cancer death in USA
* Risk of lung cancer in smokers = 20 times of that of non smokers
 Site of cancer
Tobacco
* Lung
* Oral cavity
* Pharynx
* Larynx
* Esophagus
* Pancreas
* Renal Pelvis
* Urinary bladder
Nitrosamines
Aromatic Amines
 Carcinogens: 30 carcinogen
* Benzo(a)pyrene
* N-nitrosamine
* 2-naphthylamine
* Vinyl chloride
* Formaldehyde
* Benzene
* Arsenic, Nickel, Chromium
* Nitrogen oxides (oxidants deplete antioxidants)

22.  Consumption
* Smoking
* Chewing
* Snuff
Active (exposed smoker)
Passive (exposed nonsmoker)
Cigarette
Cigar

23.  Epidemiology
* 35 % all cancer
* Cancer incidence in developed countries = 3 times of that of developing countries
 Site of cancer
Diet
* Colon
* Stomach
* Esophagus
* Breast
* Endometrium
 Factors associated with  cancer risk
* Excess dietry components
* Deficiency of dietry components
* Natural procarcinogen/carcinogen
* Contaminants
* Additives
* Lung

24. *  dietry fat
 Excess dietry components
- Cooking fat  carcinogen products (Benzo(a)pyrene
- Digestive products (fatty acids   bile salts  promoting agent)
- Fatty acids + bile salts --- anaerobic bacteria  carcinogen
- Obesity   Estrogen
  Sex hormone binding globulin
*  dietry red meat
- High fat content
- Cooking  Heterocyclic Aromatic Amines (HAA)
- Excessive iron  produce mutagenic oxygen free radicals
- Sodium nitrate & nitrite  Nitrosamines

25. *  dietry green vegetables & fruits
 Deficiency of dietry components
 micronutrients,  dietry fiber
- Vit C, Vit E, Vit A, Carotinoids, Selenium
- Vit B12  pernicious Anemia  Gastric cancer
- Iron (♀)  postcricoid carcinoma (Plummer-vinson’s syndrome)
*  dietry fiber (cellulose, pectin, lignin) white bran, vegetables
Inhibitory effect of fibers on colorectal carcinoma
 fecal bulk  prevent constipation   fecal carcinogen
concentration
  period of exposure to
carcinogen

26. * Tannin  Tea
* Hydrazine  Mushroms
* Alkenyl benzene  Spices
* Sodium nitrates & nitrites  Plants, meat, dairy products
 Natural procarcinogen/carcinogen
 Contaminants
* Natural contamination
- Fungal contaminant of stored food (Grain  Aflatoxin  HCC)
- Natural pesticed (toxin produced by plants for protection against
fungi & insects)
* Contamination produced during preparation
- Heterocyclic Aromatic Amines (HAA)
- Polycyclic Aromatic Hydrocarbons (PAH)
- N-nitrosamines compound (NOC)
* Synthetic Pesticides
* Environmental contaminations

27.  Additives
Sodium Nitrate – Bacterial reduction  Nitrite + 2ry or 3ry amines  nitrosamines
(food preservative) 
(Smoked meat, salted fish) Cancer esophagus
Cancer stomach
Cancer nasopharynx
Cancer U.B
 Factors associated with  cancer risk
* Diet rich in oleic , olive, fish oil
* Calcium (potential antidote to bile salts)
* Vit A
* Vit E
* Vit C
* Dietary fibers

28. Radiation
 Epidemiology: 3 % of all cancer
 Character
* Long latency
* Cumulative effect
 Include Ionizing
* Electromagnetic radiation
* Particulate radiation Non-ionizing (e.g. Sun UV rays)

29.  Include
* Electromagnetic radiation
* Particulate radiation
- Charged
- Neutral  neutron
Ionizing Radiation
X-ray
Gamma ray
Alpha
Beta
Proton
 Epidemiology
* Uranium miners suffer tenfold  incidence of lung cancer
* Diagnostic (mammography in young women  breast cancer
* Therapeutic (H & N irradiation during childhood  thyroid cancer
 Mechanism of radiation injury to DNA
* Direct: radiation  ionization of DNA molecule
* Indirect: radiation interact with water  free radical  damage DNA
 Radiation Effects
* Chromosomal damage * DNA damage
 Factors determine carcinogenicity
* Type of radiation: higher with neutrons
* Age: children are more vulnerable

30. Radiation-induced Human Cancers
Exposure Cancer Types
Nuclear Weapons
Blast Leukemia
Solid tumors
Fallout Thyroid
Diagnostic & therapeutic Leukemia
Solid Tumors
Professional Exposure
Early radiologist Leukemia
Skin cancer
Uranium miners Lung cancer
Nuclear industry Multiple myeloma
Radium dial painters Osteosarcoma

31.  Related cancer: UV rays from sun is the major cause of skin cancers
Solar Radiation
 Factors determine effects of UV rays (Degree of Risk)
* Intensity of exposure: skin cancer more common in Newsland
* Quantity of melanin pigment: skin cancer is more common in fair skin,
albinism due to  melanin pigment
* Excision-Repair enzymes of DNA: skin cancer occur in patient with
Xeroderma pigmentosum due to hereditary
deficiency in enzymes

32. Chronic infections
 Bacterial Infection
* Helicobacter pylori  Gastic Carcinoma , MALT lymphoma
Infect stomach  production of endogenous
nitrosamines  cellular hyperplasia (promoting factor)
 Parasitic Infestation
* Schistosoma hematobium  Bladder cancer (in Egypt)
Parasite  inflammatory reaction  production of
potent oxidizing agents  DNA damage
* Chlonorchis sinesis  Biliary cancer (in china)
1/3 world’s cancer

33.  Viral Infection
1- DNA viruses
* Hepatitis B virus (HBV)
* Epstein Barr virus (EBV)
* Human Herpes virus (HHV-8)
* Human Papilloma virus (HPV)
2- RNA viruses
* Hepatitis C virus (HCV)
* Human T cell leukemia virus (HTLV-1)
* Human Immuno deficiency Virus (HIV)
5 % of all cancer
Mechanism of action
- Virus is not sufficient alone to induce cancer except (HTLV-1)
- Virus acting as promoting factors
- Associated carcinogen are necessary (Initiators)

34. Human Oncogenic Viruses
Class Virus type Cancer
DNA Viruses HBV Hepatocellular carcinoma
EBV Burkitt lymphoma
Nasal type T cell lymphoma
Hodgkin’s disease
Nasopharyngeal carcinoma
HHV-8 Kaposi’s sarcoma
HPV-5,8,14 Skin squamous carcinoma
HPV-6,11 Verrucous carcinoma
HPV-19,18,31,33, 35 Uterine cervix carcinoma
Oral carcinoma
HPV-30,40 Laryngeal carcinoma
RNA Viruses
(Retroviruses)
HCV Hepatocellular carcinoma
HTLV-1 Adult T leukemia/lymphoma
HIV Kaposi’s sarcoma
Non-Hodgkin’s lymphoma
Anal carcinoma
Skin squamous carcinoma
Pediatric leiomyosarcoma

35.  Structure: mature virion is spherical enveloped nucleocapsid
1- Envelope: protein, lipid, CHO
2- Capsid: Hexagonal
3- Genome: DNA + polymerase
 Partially double stranded molecule
 Encode proteins  Envelope Surface protein (HBsAg)
Nucleocapsid core protein (HBcAg)
DNA polymerase
Protein from X region (HBX)

Necessary for virus replication
(Transcription Trans-activator)
Hepatitis B Virus

38.  Phases of infection
1- Proliferative phase
- Viral DNA present outside cellular DNA
- Episomal form
- Formation of complete virion
- Marked cell damage (necrosis  cirrhosis)
2- Integrative phase HBX gene
- Viral DNA is incorporated into cellular DNA
Pre S2/S gene
- Incapable of reproduction

39.  Mechanism of carcinogenicity (Weak transforming agent)
1- Proliferative phase
- HBV has indirect role
- HBV  necrosis  cell regeneration cirrhosis (promotion)
- Synergistic initial carcinogen (Aflatoxin) is necessary
2- Integrative phase
- HBV has direct role Transactivate cellular proto-oncogenes
- HBX gene integration into cellular DNA
 P53 protein product
 Associated Cancer: Hepatocellular Carcinoma
* Both occur in Far East & Tropical Africa (10 % are carrier of HBV)
* Viral DNA is identified in nuclei of tumor cells
* HBV infection occur in childhood  HCC occur in adult = 35 Y latent period

40.  Family: Herpes family
 Epidemiology: infect > 90 % of population by age of 20 years
 Virus Strains
* Type I: common in western countries
* Type II: common in central Africa & New Guinea
Epstein Barr Virus
 Mechanism of carcinogenicity (Weak transforming agent)
* Virus has strong tropism to (B lymphocytes & squamous cell of pharynx) as
express surface receptor molecule for EBV
* Infection of cell
* Linear genome  form episome in cell nucleus outside DNA
* Viral genes are transcripted éout viral replication (No symptoms, latent infection)
 Epstein Barr Nuclear Antigen (EBNA-1, EBNA-2)
 Latent Membrane Protein (LMP-1, LMP-2)

41.  Pathogenesis
1- Klein model for Burkitt’s lymphoma pathogenesis
EBV Chromosomal translocation
T(8:14)
+ C-myc proto-oncogenes
in B cell
EBNA 2-6 + T cell (CTL)
B cell proliferation
B cell rejection
Defect in
Malaria, AIDS
2- Nasopharyngeal Carcinoma pathogenesis
EBV LMP-1
EBNA-2
+ bcl-2 proto-oncogene
- Apoptosis
Cell
Transformation

42.  Associated Cancer
1- Nasopharyngeal Carcinoma
- Both (EBV infection & NPC) occur in china
- 100 % of NPC cases carry EBV antigen
2- Nasal T cell lymphoma
3- Hodgkin’s lymphoma
4- Burkitt’s lymphoma
- Tropical Africa: 100 % of cases carry EBV antigen
- Sporadic: 20 % of cases carry EBV antigen

43.  Route of infection: sexually transmitted
 Mechanism of carcinogenicity
Human Herpes Virus (HHV-8)
Kapsoi Sarcoma Herpes Virus (KSHV)
 Associated cancer: Kaposi’s Sarcoma

44.  Classification: according to rate of malignant transformation
1- Low Risk Group
* Rate of transformation = 5 %
* Include: HPV-6, 10, 11
* Virus: episomal form (Non-integrated)
* Associated with
- Benign genital warts
- Mild dysplasia
- Low grade squamous intraepithelial lesion (LSIL)
2- High Risk Group
* Rate of transformation = 33 %
* Include: HPV-16, 18, 31, 33, 35
* Virus: integrated form
* Associated with: cancer cervix
Human Papilloma Virus (HPV)

45.  Mechanism of carcinogenicity
1- Proliferative form: acts as promoting factor , so synergistic initial
carcinogen is necessary
2- Integrative form: expression of E6 & E7 genes
 Associated cancer
1- Squamous cell carcinoma of skin
2- Verrucous carcinoma
3- Cancer cervix
4- Oral carcinoma
5- Laryngeal carcinoma

46. RNA Oncogenic Virus
 Family: retrovirus (contain enzyme reverse transcriptase)
 Structure
1- Envelope
2- Capsid
3- RNA (double stranded)
4- Reverse transcriptase
 Phases of infection
1- Cell penetration
2- Capsid is uncoated  release RNA
3- RNA genome is reversely transcribed to double stranded DNA
4- Viral DNA develop at its end regulatory units: Long Terminal Repeat (LTR)
5- Fate of viral DNA
* Replication  budding of new viruses (C type virus particle)
* Integration into cellular DNB (provirus)

48.  Classification: according to transforming activity
Acute Transforming virus Slow Transforming virus
Affect low animals Affect human
Viral genome
• Promotor LTR
• gag gene  viral core protein
• V-onc gene (Viral oncogene)
- Derived from cellular proto-oncogene
- Transduced into viral genome in place of
pol gene
- When integrated again in cellular DNA
induce malignant transformation
• env gene  envelope protein
Viral genome
•Promotor LTR
•gag gene  viral core protein
•pol gene  reverse transcriptase
•env gene  envelope protein
•TAT gene  tax protein  + Viral LTR
& + cellular genes
Potent malignant transformation Produce tumor after long latent period
Deficient viral replication (Deficient in pol
gene) so need helper virus for replication
Viral replication occur
v-onc gene (viral oncogene) Deficient in oncogenes

49.  Incidence: more risk to develop HCC (more associated é hepatitis & cirrhosis
 Associated cancer: Hepatocellular carcinoma
Hepatitis C Virus
Human Immunodeficiency Virus (HIV)
 Route of infection: Blood transfusion, Sexual contact
 Mechanism of carcinogenicity
Strong tropism to T helper cell  failure of immune response (Cellular & humoral)
Superinfection by opportunistic viruses (HHV8, EBV, HPV)  AIDS 
 Malignant transformation
 Associated cancer
1- Kaposi’s sarcoma
2- NHL
3- HD
4- Cervical carcinoma
5- Anal carcinoma
6- Pediatric leiomyosarcoma

50.  Epidemiology: 1 % of seropositive (infection more common than malignancy)
 Route of infection: Blood transfusion, Breast feeding, Sexual intercourse
 Character: slow transforming retrovirus, integrate randomly into host DNA,
preferentially close to cellular proto-oncogenes
 Mechanism of carcinogenicity
1- Promotor insertion
LTR (proviral)  acts as promotor  convert cellular proto-oncogene into cellular
oncogene (C-onc)
2- Enhancer insertion
LTR (proviral)  + cellular enhancer  + cellular proto-oncogene
3- Transactivation
TAT gene  tax protein  + cellular genes responsible for cell proliferation (IL-2,
C-myc, C-fos, C-jun, bcl-2, GMCSF)
HTLV-1  T helper cells  Secrete IL-2  T cell expansion
(polyclonal  monoclonal)
Human T cell Leukemia Virus (HTLV-1)

51.  Associated cancer: T cell lymphoma/Leukemia
* Highly aggressive
* Rapidly fatal in few months
* Endemic in south Japan, Caribbean
* Associated with skin manifestation & Hypercalcaemia

52. Intrinsic Factors

53. Immunosuppression & Cancer
 Mechanism
* Defect in immuno-surveillance against tumors
* Chronic infection or associated virus infection  chronic antigenic
stimulation  malignant transformation
 Cancer in immunosuppressed host
1- Congenital immunodeficiency
2- Therapy-induce immunodeficiency (iatrogenic)
3- Acquired immunodeficiency syndrome (AIDS)
Acquired Immunodeficiency Syndrome
 Caused by: HIV-1
 Associated cancer: Kaposi’s (HHV-8), NHL (EBV), SCC of skin (HPV)
 Mechanism
Strong tropism to T helper cell  failure of immune response (Cellular & humoral)
Superinfection by opportunistic viruses (HHV8, EBV, HPV) 

54.  Definition: genetically determined immunodeficiency disease
 Differ in
* Underlying immune defect
* Extent of cancer risk
* Type of evolving cancer
 Epidemiology: NHL in unusual sites (Brain, GIT) > 50 % of cancer
Congenital Immunodeficiency
Syndrome Cell Defect Risk % Tumors
X-linked lymphoproliferative
syndrome B & T 35 NHL
Wiskott-Aldrich B & T 15-30 NHL, AML
Ataxia telangiectasia B & T 12 NHL, ALL, NS, OV, SK, ST
Severe combined immunodeficiency B & T 1.5 NHL, HD, ALL
Infantile sex-linked
hypogammaglobulinemia B 0.7 NHL, ALL
Thymic hypoplasia (DiGeorge) T Unknown NS

55.  Use: given to patients undergoing organ transplantation
 Include
* Azathioprine
* Cyclosporin A
* Cyclophosphamide
* Prednisone
 Associated cancer
* SCC of skin (20 times expected, more aggressive)
* NHL (50 times expected, involve CNS)
* Kaposi’s sarcoma
* Malignant Melanoma
 No  in incidence of: common cancer (breast, colon)
  risk of: uterine dysplasia  uterine carcinoma
 Time of cancer onset
* 2.5 year: lymphoma
* 4.5 year: non-lymphoma
Therapy Induced Immunodeficiency
A) Immunosuppressive therapy

56.  Action: * Immunosuppressive *Mutogenic
 Effect: pt é cancer  treated é chemotherapy  second primary cancer
 Associated cancer
* AML
* Lymphomas
* Urinary bladder carcinoma
 Latent period: 2-7 years
B) Chemotherapy
C) Radiotherapy
 Action: * Immunosuppressive * Late somatic effect
 Effect: pt é cancer  treated é radiotherapy  second primary cancer
 Associated cancer
* Leukemia
* Thyroid cancer
* Breast cancer
* Osteosarcoma
 Latent period: 10-15 years

57. Hormones & Cancer
 Epidemiology: neoplasia of hormone target tissues
* > 40 % of female cancer
* 35 % of male cancer
 Mechanism
* Excessive hormonal stimulation of particular target organs
* Hormones act as promoting factors
Breast Carcinoma
 Underlying factor: hormonal imbalance (estrogen > progesterone)
 Cause of  estrogen
* Early menarche & late menopause
* Obesity
Androstenedione -- Aromatase enzyme  Estrone  Estradiol (potent)
 Action of estrogen
Estrogen  + Production of TGF-α Tumor promotion

58. Endometrial Carcinoma
 Underlying factor: hormonal imbalance (estrogen > progesterone)
 Cause of  estrogen
* Hyperestrinism (80 % of endometrial carcinoma / premenopausal)
* Estrogen-secreting granulosa cell tumors (endometrial carcinoma regress after
excision of ovarian tumor)
* Oral contraceptive pills containing estrogen only (combined pills   risk)
 Antiestrogenic effect of progesterone
*  Conc. estradiol receptor
*  activity of enzyme system that convert estradiol to estrone (less potent)
Ovarian Carcinoma
 Underlying factor: Incessant ovulation theory (repeated ovulation  traumatize
surface epithelium  proliferation)
Carcinogenic effect of Gonadotropins is indirect by  ovulation
 Theory is supported by: rare incidence of ovarian cancer in
* Nulliparous women * Women é Anovulatory cycle * Users of OCP

59. Prostatic Carcinoma
 Underlying factor: hormonal imbalance
*  Testosterone (testicular)
*  Androstendione (Adrenal)
*  Androgen level due to high dietary meat & fat
 Mechanism
Testosterone Dihydrotestosterone
(DHT)
5 α reductase
testis
Bound to Androgen
receptor
Hormone-receptor
complex translocated to
nucleus
Act as transcription
factor
+ Genes responsible for prostate
epithelium proliferation
 Application: basis of hormonal treatment (castration, Anti-androgens, LHRH)

60. Testicular Cancer
 Underlying factor
* Hormonal imbalance (Estrogen Excess Hypothesis)
* Cryptorchidism
 Age: peak incidence in early adulthood
Inutero exposure to estrogen
Cryptorchidism Germ cell
tumors
Thyroid carcinoma
 Underlying factor:  TSH level (pituitary adenoma, iodine deficiency)
± female sex hormone (more common in females)
 Application: basis of use thyroxin to  TSH level
(Follicular type)
Osteosarcoma
 Underlying factor:  growth hormone (somatotropin) level
 Age: adolescent (age of maximal growth)
 Sit: metaphysis of long bone (site of maximal growth)

61. Hereditary Cancer
 Definition: familial clustering of cancer of definite genetic cause that follows
Mendelian laws of inheritance
Hereditary Cancer Familial cancer Cancer in inborn
chromosomal abnormalities
Familial  in cancer
incidence
Familial  in cancer
incidence
(2 cases close relative)
Mendelian pattern of
transmission
No Mendelian pattern of
transmission
Not hereditary
= not transmitted
Definite genetic cause Indefinite genetic cause
Related to
* Environmental factor
* Hormonal factor
* Chance coincidence
Examples
* Down syndrome (Trisomy
21 )  Leukemia
* Klinefelter’s (XXY) 
Breast cancer, Leukemia

62.  Mechanisms
* Loss of tumor suppressor genes (Rb, p53, WT1)  cellular growth
* Deranged signal transduction (Men-2, NF-1, AEC)  cellular proliferation
* Loss of cell adhesive molecule (E-cadherin) & cytoskeleton defect  cell
dissociation  loss of contact inhibition
* Loss of differentiation signal (NF-2)
* Defective DNA repair mechanisms (xeroderma & HNPCC)
* Hypersensitivity to DNA damaging agents (Bloom syndrome, Fanconi anemia,
ataxia telangiectasia)
* Congenital immunodeficiency
Loss of tumor surveillance or opportunistic infection with oncogenic viruses

63.  Cardinal Features
* Site specificity (familial clustering of same type of cancer)
* Mendelian pattern of tumor transmission
* Identification of specific abnormal gene.
* Early age of onset (<40 years)
* Multicentricity & Bilaterality of tumors
* Multiple primary cancers at different sites
* Associated congenital abnormalities
 Classification: according to underlying hereditary defect
Group Mendelian transmission
Inherited cancer risk Autosomal dominant
Inherited precancerous lesions Autosomal dominant
Inherited precancerous syndrome Autosomal recessive
Inherited immunodeficiency X-linked

64.  Autosomal dominant: appearance of disease in every generation, 50% incidence &
equal sex affection
  risk due to: loss of tumor suppressor gene
Inherited Cancer Risk
Disease Gene/ch Tumors
Familial retinoblastoma
Rb/13q
Retinoblastoma, Brain, Pineoblastoma,
Melanoma, Breast
Familial Wilm's tumor WTl/11p Nephroblastoma
Li-Fraumeni syndrome p53/13q Breast, Sarcomas
Von-Hippel -Lindau VHL/3p Renal cell carcinoma, Pheochromocytoma
MEN-2
Ret/10q
Thyroid medullary carcinoma,
Pheochromocytoma
Breast cancer type 1 BRCA-l/17q Breast, Ovarian
Breast cancer type 2 BRCA-2/13q Breast
Hereditary Nonpolyposis
cancer colon (HNPCC-1) Lynchl:hMLH/3p Colon
Hereditary Nonpolyposis
cancer colon (HNPCC-2) Lynch2:hMS/2p
Colon, Breast, Endometrium, Urothelial
Cancerfamily
syndromes

65.  Autosomal dominant
Precancerous lesion  cancer
Inherited Precancerous lesion
Disease Gene/ch Tumors
Familial polyposis coli or
adenomatous polyposis APC/5q
Colon
Gardner's syndrome Colon
Peutz-Jegher syndrome Small intestine
Von-Recklinghausen NF-l/17q Neurosarcoma, Gliomas
Acoustic neuroma Merlin/22q Gliomas
Dysplastic nevus syndrome Malignant melanoma
Basal cell nevus syndrome Basal cell carcinoma
Multiple trichoepithelioma Visceral malignancy
Porokeratosis of Mibelli Squamous carcinoma
Epidermodysplasia verruciformis Squamous carcinoma
Tylosis Esophageal
Cowden's disease (multiple
hamartoma syndrome) PTEN/10
Breast, Thyroid, Uterine
Genodermatosis

66.  Autosomal recessive: skipped generations without manifest disease, affection of 25%
offspring & equal sex affection
Inherited Precancerous Syndrome
Disease Gene/ch
Tumors
Xeroderma pigmentosum ERCC/ 8 Skin cancer
Bloom, syndrome Leukemia, Gastrointestinal
Fanconi anemia FACC/4 Acute myeloid leukemia
Ataxia telangiectasia ATM/11q Lymphoma
Tuberous sclerosis Gliomas
Gonadal dysgenesis Dysgerminoma,
Gonadoblastoma

67.  X-linked inheritance: male are affected by disease, female act as carrier
Inherited Immunodeficiency
Disease Tumors
X-linked lymphoproliferative
syndrome
Leukemia
Lymphoma
Wiscott-Aldrich syndrome
Severe Combined
immunodeficiency
Infantile agammaglobulinemia