What causes Cancer?

1. What causes Cancer?

2. What causes Cancer? • Cancer is caused by alterations or mutations in the genetic code • Can be induced in cells by: • Chemicals • Radiation • Viruses • Heredity - 5%

3. Carcinogenesis: Pathogenesis of cancer • Oncogenesis: Pathogenesis of neoplasm (cancer!) • Carcinogen - agent causing cancer. • Mutagen - agent causing mutation. • Oncogenes – genes causing cancer

6. Incident Cancer Cases in India

7. Cancer

8. Nonlethal genetic damage - environmental - inherited • Clonal expansion of a single precursor cell that has incurred the genetic damage

9. Nonlethal genetic damamge • Radiation • Chemicals • Viruses Environmental Inherited in germline

10. Inherited cancer syndromes Familial cancers Syndromes of defective DNA repair Three categories of hereditary cancer

11. Hereditary Causes: Due to inherited abnormal genes. Autosomal Dominantly inherited • FAP – gene polyposis  Adenocarcinoma colon • Retinoblastoma – Rb gene • Neuroblastoma

12. RB gene • First tumour suppressor gene discovered • Discovered in retinoblastoma • Retinoblastoma occurs in1 in 20000 infants & children • 60% sporadic • 40% inherited as autosomal dominant trait

13. Patient with retinoblastoma

14. Eye with retinoblastoma

15. APC (Adenomatous polyposis Coli) • APC gene is mutated in FAP (familial adenomatous polyposis) of colon

16. Familial adenomatous polyposis

18. DNA REPAIR DEFECTS & GENOMIC INSTABILITY • “genomic instability syndromes”. inherited mutations of DNA repair proteins • greatly increased risk of developing cancer. • DNA repair genes - not oncogenic, but their abnormalities allow mutations in other genes during the process of normal cell division. • genomic instability occurs when both copies of these genes are lost.

21. Defects in three types of DNA repair systems: • mismatch repair, • nucleotide excision repair • recombination repair .

22. DNA repair defects • Hereditary non polyposis colon (HNPCC) syndrome – mutation in mismatch repair gene • BRCA-1 and BRCA-2 genes

23. Syndromes of defective DNA repair Autosomal Recessively inherited Xeroderma pigmentosum Ataxia telangiectasia Bloom syndrome Fanconi anemia

24. Xeroderma pigmentosum

25. Familial cancers Most common sporadic cancers have familial forms too Familial clustering of cases but no clear inherited predispoisition Breast, colon, ovary, brain Occur earlier Two or more close relatives are affected Multiple and bilateral tumours

26. Acquired Preneoplastic Syndromes (Precancerous) Persistent regenerative cell replication Chronic skin fistula → squamous cell carcinoma Cirrhosis → Liver cancer Hyperplastic and dysplastic proliferations Atypical endometrial hyperplasia → endometrial cancer Dysplastic bronchial mucosa → lung cancer

27. Acquired Preneoplastic Syndromes Chronic atrophic gastritis → stomach cancer Chronic ulcerative colitis → colon cancer Leukoplakia → squamous cell carcinoma Villous adenoma → colonic cancer

28. RADIATION CARCINOGENESIS1.ULTRAVIOLET LIGHT2.IONISING RADIATION

29. Radiation Carcinogenesis • UV rays – Skin Cancers • Ionizing radiation - many neoplasms

30. 1.ULTRAVIOLET LIGHTMain source of UV light is sunlightothers are UV lamps and welder’s arcsUV light penetrates only few millimetres of the skin

31. MELANIN PIGMENT PROTECTS Cause various forms of skin cancers 1.Squamous cell carcinoma2.Basal cell carcinoma3.Malignant melanoma

32. White racethose living close to the equator who receive more sunlight (Australia,New Zealand) farmers & outdoor workers due to the effect of actinic light radiation

33. MECHANISM OF ACTION OF UV LIGHTDNA damage –mutationnormally damaged DNA gets repaired

34. Hereditary diseases characterised by a defect in DNA repair mechanism associated with increase risk of cancer

35. Radioactivity • The spontaneous emission of ionizing radiations–alpha rays, beta rays, gamma rays – from radioactive materials

36. IONISING RADIATIONX – RAYSβ – RAYSGAMMA RAYSRADIOACTIVE ISOTOPESPROTONSNEUTRONSHE RISK INCREASES WITH HIGHER DOSAGE

37. X ray workers,radiotherapist-skin cancerswatch workers engaged in painting the dials with luminous radium- osteosarcomaminers working with radioactive elements

38. The Principal Hazards ofIonizing Radiation • Genetic effects • Carcinogenic effects • Effects on the developing embryo/fetus

39. Early Experience • Skin cancer in early x-ray workers • Lung cancer in underground uranium miners • Bone cancer in radium dial painters • Liver cancer in Thorotrast patients

40. Japanese atom bomb survivers of the twin cities of Hiroshima & Nagasaki after World War 2

41. CHERNOBYL NUCLEAR POWER LEAKAGE-USSR-(1985)

42. Damage to DNA directly or by formation of highly reactive free radicals which bring about DNA damage

43. NONRADIATION PHYSICAL CARCINOGENSMECHANICAL INJURY LIKESTONES IN THE GALL BLADDER,URINARY TRACT

44. Mechanical injury likestones in the gall bladder,urinary tractHealed scars, asbestosisimplants of inert materials such as plastic, glass in prosthesis

45. Second Cancers in Radiotherapy • If radiation causes cancer, are we harming patients by using radiation to treat existing cancers? Examples: • Prostate, Cervix, Hodgkin’s Disease