1. Neoplasia Neoplasia

2. Epidemiology Aetiology CARCINOGENS Aetiology CARCINOGENS Molecular basis of cancer “Pathogenesis of cancer” “Carcinogenesis” Molecular basis of cancer “Pathogenesis of cancer” “Carcinogenesis”

3. EPIDEMIOLOGY Epidemiology is the study of patterns of health and illness and associated factors at the population level. Identify environmental and genetic causes of cancer E.g. study of colon cancer.

4. CANCER INCIDENCE The number of new cases of specific cancer registered over a specific period in a defined population.

5. MORTALITY The number of death from a given form of cancer during a specified period of time.

6. AGE Most carcinoma occur in the later year of life (55-74 years). Children are affected by certain neoplasms, e.g.: * Leukemias and neoplasm of CNS *Retinoblastoma *Neuroblastoma *Nephroblastoma *Rhabdomyosarcoma

7. Number of all cases of cancer, both new and registered within a defined population at a given point in time. CANCER PREVALENCE

8. GEOGRAPHIC AND ENVIRONMENTAL FACTORS Remarkable difference in incidence and death rate of specific cancer around the world, e.g.: *Skin cancer……………..White skin people *Gastric cancer ……….. Japanese

9. Epidemiology Aetiology CARCINOGENS Aetiology CARCINOGENS Molecular basis of cancer “Pathogenesis of cancer” “Carcinogenesis” Molecular basis of cancer “Pathogenesis of cancer” “Carcinogenesis”

10. Aetiology

11. Direct-Acting Agents Require no metabolic conversion to become carcinogenic e.g., alkylating agents (Anticancer drugs ) Indirect-Acting Agents Chemicals that require metabolic conversion to an ultimate carcinogen before they become active. Chemicals carcinogens

12. Found everywhere in our environment. Occupational, e.g: *Beryllium *arsenic component *benzene *nickel يستخدم البيريليوم لإنتاج سبائك النحاس مما يجعلها تستخدم بشكل واسع بسبب موصليتها الحرارية والكهربائية العالية. زرنيخ قبل عام 1920 كان البنزين يستخدم كمذيب صناعي لإزالة الشحوم من المواد مادة تضاف للوقود السائل ( البنزين المستخدم كوقود ) تم استبدال البنزين الحلقي بالتيترا إيثيل رصاص, عنصرالنيكل من العناصر المكونة لـ السبائك المعدنية بالإضافة إلى أنه مكون أساسي للفولاذ المقاوم للصدأ Chemicals carcinogens

13. Geographic Environmental factors include: *Asbestos يستخدم الأسبست في مجال البناء وتسقيف المنازل والعوازل الداخلية والخارجية وأنابيب صرف المياه والأدخنة والتهوية، mesothelioma

15. Smoking

16. RADIATION CARCINOGENESIS Radiation, whatever its source, UV rays of sunlight, x-rays, nuclear fission, radionuclides is an established carcinogen.

17. Radiation Follow-up of survivors of the atomic bombs dropped in Hiroshima and Nagasaki developed: Leukemia Thyroid, breast, colon and pulmonary carcinomas. Ionizing radiation causes chromosome breakage, translocations, and less frequently point mutations.

18. Radiation (contd) The oncogenic effect of UV. UV radiation derived from the sun can cause skin cancers (melanomas, squamous cell carcinomas and basal cell carcinomas). UV radiation damage DNA by forming pyrimidine dimers. This type of DNA damage is repaired by a complex set of proteins that affect nucleotide excision repair.

19. Radiation (contd) Depleted uranium Thorotrast

20. Viral and Microbial Oncogenesis RNA Viruses DNA Viruses

21. Viral and Microbial Oncogenesis Human T-cell leukemia virus-1 (HTLV-1) T-cell leukemia that is endemic in Japan Hepatitis C Virus Hepatocellular carcinoma RNA ONCOGENIC VIRUSES

22. Human papilloma virus  Benign warts …………………… HPV types 1, 2, 4 and 7  Uterine cervical cancer………HPV types 16 and 18 Epstein-Barr Virus  Burkitt lymphomas,  Nasopharyngeal carcinoma. Hepatitis B Virus  Hepatocellular carcinoma Human herpes virus 8  Kaposi sarcoma Oncogenic DNA Viruses

23. Bacteria Helicobacter pylori Gastric adenocarcinomas and gastric lymphomas.

24. Epidemiology Aetiology CARCINOGENS Molecular basis of cancer “Pathogenesis of cancer” “Carcinogenesis” Molecular basis of cancer “Pathogenesis of cancer” “Carcinogenesis”

25. Typically, the phenotypic attributes characteristic of malignancy develop when multiple mutations involving multiple genes accumulate.

26. Primary or environment (75%) Alterations to the human genome First hitSecond hit Normal genome Normal genome Cancer genome TIME Carcinogenesis is a multistep event with somatic mutations

28. Four classes of normal regulatory genes are the principal targets of genetic damage 1.Growth-promoting proto-oncogenes, 2.Growth-inhibiting tumor suppressor genes, 3.Genes that regulate apoptosis 4.Genes involved in DNA repair.

30. 1-Oncogenes Are altered versions of normal genes, termed protooncogenes, that regulate normal cell growth, differentiation, and survival. Gain-of-function (dominant) mutations activate protooncogenes to become oncogenes and are positive effectors of the neoplastic phenotype.

31. 1.Growth factors 2.Growth factors receptors 3.Transducing proteins 4.Nuclear transcription factors 5.Entry of the cell in cell cycle 1-Oncogenes

32. 1.Growth factors e.g. platelet-derived growth factor (PDGF) 2.Growth factors receptors e.g. EGF receptor family 3.Transducing proteins e.g. RAS gene mutation found in 30% of all human tumor 4.Nuclear transcription factors e.g MYC gene is dysregulated in 90% of Burkitt lymphoma 5.Entry of the cell in cell cycle e.g. Cyclin D gene is overexpressed in cancers of breast, esophagus, liver and some types of lymphoma Oncogenes and oncoproteins

33. ABL gene Example of Transduction proteins Normal ABL protein localizes in nucleus to promote apoptosis

34. N- MYC gene is amplified in neuroblastomas Example of transcription proteins

35. 2- Tumor suppressor genes Are normal genes whose products inhibit cellular proliferation. Loss-of-function permit unregulated cell growth. Suppressor genes are "recessive" and require loss of both copies of the normal before cancer becomes likely, the "two- hit" model of carcinogenesis.

36. 2- Tumor suppressor genes Retinoblastoma gene works to prevent cells in G1 from advancing to S phase. p53, a protein exclusive to the nucleus, is the most common transformed gene in human cancer, presenting in over 50% of human tumors.

37. Sporadic cases: 60% -2 hits are required. Familial cases: 40% -one hit is required. Patients with familial retinoblastoma also are at greatly increased risk of developing: 1.osteosarcomas 2.breast carcinoma 3.small cell carcinoma of lung 4.some soft tissue sarcomas 5.some brain tumor. Sporadic cases: 60% -2 hits are required. Familial cases: 40% -one hit is required. Patients with familial retinoblastoma also are at greatly increased risk of developing: 1.osteosarcomas 2.breast carcinoma 3.small cell carcinoma of lung 4.some soft tissue sarcomas 5.some brain tumor. RB gene 2- Tumor suppressor genes

39. Rb gene and protein RB serves as a brake in the advancement of cells from G1 to the S phase of the cell type. Quiescent cells (in G0 to G1) contain the active hypophosphorlyated form of RB. RB prevents cell replication by binding and possibly sequestering, the E2F family of transcription factors. RB serves as a brake in the advancement of cells from G1 to the S phase of the cell type. Quiescent cells (in G0 to G1) contain the active hypophosphorlyated form of RB. RB prevents cell replication by binding and possibly sequestering, the E2F family of transcription factors.

40. Retinoblastoma

41. p53

42. Designated "guardian of the genome," acts in the nucleus to stop replication of damaged cells. Following damage, p53 gets rapidly up regulated and its accumulation triggers increased transcription of DNA repair proteins and those that stop the cell cycle. If repair occurs, the cell cycle resumes. If not, p53 plays a role in triggering apoptosis. Loss of both normal alleles of p53 causes the cell cycle to continue with the mistakes in DNA transcription intact.

43. P53 Li-Fraumeni syndrome – – inherited loss of TP53- – 25 fold greater chance to develop cancer – e.g. sarcomas, breast cancer, leukemia, brain tumors and carcinomas of the adrenal cortex Normal TP53 can be rendered nonfunctional by certain DNA viruses: – oncogenic HPVs – hepatitis B virus (HBV) – possibly Epstein-Barr virus (EBV)

44. 3- Gene that regulate apoptosis bcl-2 inhibit apoptosis Transformed in most B cell lymphomas. The bax and bad gene accelerates cell death and opposes bcl-2.

45. Slide 8.35

46. 4- DNA mismatch repair genes Normally maintain the integrity of the genome and the fidelity of DNA replication. Inactivating mutations of these genes allow the successive accumulation of further mutations. E.g. MSH, MLH

47. DNA repair gene Xeroderma pigmentosum are at increased risk to the development of cancers of the skin exposed to the ultraviolet(UV) light contained in sun rays. UV light causes cross-linking of pyrimidine residues, preventing normal DNA replication. DNA damage is repaired by the nucleotide excision repair system. Pt. with xeroderma pigmentosum have inherited loss of these genes.

48. Xeroderma pigmentosa

49. Four classes of normal regulatory genes Oncogenes Tumor suppressor genes Regulate Apoptosis DNA repair RAS MYC ABL Rb p53 Bcl-2 Bax MSH MLH Growth factors Growth factors recep Transducing proteins transcription factors cell cycle Li-Fraumeni syndrome Xeroderma pigmentosum