Aetiology of human cancer


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Aetiology of human cancer

  1. 1. Aetiology of Human Cancer By Dr. Ihab Samy Lecturer of Surgical Oncology National Cancer Institute Cairo University 2013
  2. 2. The etiologic factors responsible for human cancer are generally classified into 3 main groups: • Extrinsic factors • Intrinsic factors • unknown
  3. 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. 4. Intrinsic factors • Genetic factors • Hormonal factors • Immune causes N.B.: The intrinsic genetic factors are the main contributing agents in pediatric malignancies.
  5. 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. 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. 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. 8. Chemical carcinogens They are classified according to: • The metabolic activation in the body • The organ specificity • The degree of evidence of carcinogenicity
  9. 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. 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. 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. 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. 13. 2. Multiple organ affection  nitrosamine and polycyclic aromatic hydrocarbons (according to the route of administration).
  14. 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. 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. 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. 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. 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. 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. 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. 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.
  22. 22. Radiation • Ionizing electromagnetic radiation • Ultraviolet (UV) rays N.B.: Both types represent only 3% of cancer risk factors
  23. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 40. 1. Inherited Cancer Risk • Autosomal dominant. • Appears in every generation. • 50% incidence. • Equal sex affection. • Mainly loss of tumor suppressor gene.
  41. 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. 42. 2. Inherited Precancerous Risk • Autosomal dominant. • Inherited precancerous lesion  Turn malignant or associated with malignancy.
  43. 43. Examples: • Familial Polyposis Coli (APC/5q)  Colon cancer. • Gardner’s syndrome  Colon cancer. • Peutz-Jehgers syndrome  Small intestine. • Von-Reklinghausen syndrome (NF-1/17q)  Neurosarcomas & Gliomas. • Acoustic neuroma (Merlin/22q)  Gliomas. • Genodermatosis: a)Dysplastic nevus syndrome  Melanoma. b) Basal cell nevus syndrome  BCC. c) Multiple trichoepithelioma  visceral malignancy. d) Epidermodysplasia verruciformis  SCC. e) Cowden’s syndrome (PTEN/Ch10) [Multiple hamartoma syndrome]  breast, thyroid and uterine cancers.
  44. 44. 3. Inherited Precancerous Syndromes • Autosomal recessive. • Skipped generations without manifest disease. • 25% offspring affection. • Equal sex affection. • Associated with increased cancer risk.
  45. 45. Examples: • Xeroderma pigmentosum: Skin Cancer. • Bloom syndrome: Leukemia and GIT cancers. • Fanconi anemia: AML • Ataxia Telangiectasia: Lymphoma. • Tuberous sclerosis: Gliomas. • Gonadal dysgenesis: Dysgerminoma and Gonadoblastoma.
  46. 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. 47. Immunosuppression and Cancer • Congenital immunodeficiency • Therapy-induced (iatrogenic) immunodeficiency • Acquired immunodeficiency syndrome (AIDS)
  48. 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. 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. 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. 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. 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. 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. 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.
  55. 55. Prostatic Carcinoma • Testosterone DHT • DHT + Androgen receptors  Hormone-Receptor complex (H-R Complex) • H-Rc Nucleus Proliferation. • Castration,antiandrogens and LHRH-Analogues  Hormonal therapy for Prostatic ca. 5-α-reductase (Prostate) Translocation Transcription
  56. 56. Testicular Cancer • Estrogen excess theory: High levels of estrogen in utero in early pregnancy Germ cell tumors of the testis Cryptorchidism
  57. 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. 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.
  59. 59. Thank you