Leicester Warwick Medical School

1. Leicester Warwick Medical School Neoplasia III Why and How do Tumours Occur? Professor Rosemary A Walker raw14@le.ac.uk Department of Pathology

2. WHY DO TUMOURS DEVELOP? Intrinsic factors Extrinsic factors

3. INTRINSIC FACTORS Inherited susceptibility Host factors • age • Immune status • hormones

4. INHERITANCE Inherited conditions which predispose to the development of tumours – relate to DNA repair. Inherited susceptibility to development of a tumour or a group of tumours due to alteration of one or more genes.

5. INHERITANCE Defects in DNA repair mechanisms Retinitis (xeroderma) pigmentosa – photosensitivity Ataxia telangiectasia – defective response to radiation damage Fanconi’s anaemia – sensitivity to DNA cross-linking agents.

6. INHERITANCE Alteration in Gene • Polyposis coli APC 5q21 • Hereditary Non Polyposis ColonCancer (HNPCC) Mismatch repair eg 2p21-22 • Li Fraumeni syndrome p53 17p • Familial Breast/Ovarian cancer BRCA1 17q21 BRCA2 13q12 • Retinoblastoma Rb 13q14

8. EXTRINSIC FACTORS Radiation Chemicals Viruses

9. RADIATION Evidence Skin cancer in radiologists (1920s) Thyroid carcinoma in children irradiated for thymic asthma. Hiroshima – early: leukaemia, lymphoma later: thyroid, breast Chernobyl - thyroid carcinoma in children (ret)

10. RADIATION Causes a wide range of different types of damage to DNA Single and double stranded breaks Base damage Effects depend on quality of radiation and dose DNA repair mechanisms important Incorrect repair of DNA damage mutation

11. CHEMICALS Evidence Epidemiological studies eg. cigarette smoking and lung cancer. Occupational eg. bladder cancer and rubber industry. Carcinogenic effects in laboratory animals. Mutagenicity testing.

12. CHEMICALS Carcinogen interacts with DNA in one of a number of ways. eg. causes specific base damage or single strand breaks. Damage repaired but may be imperfect.

13. CHEMICALS Some act directly. Others require metabolic conversion to active form. If enzyme required for conversion is ubiquitous, tumours occur at site of contact/entry. Others require enzymes confined to certain organs.

14. CHEMICALS Polycyclic aromatic hydrocarbons • coal tar, cigarette smoke • 3,4-benzpyrene most important • converted to active form by hydroxylation eg. aryl carbonate hydroxylase Lung cancer,bladder cancer, skin cancer

15. CHEMICALS Aromatic amines • Beta-napthylamine hydroxylated in liver to 1,hydroxy-2napthylamine, which is conjugated with glucuronic acid • Deconjugated to active form in urinary tract Rubber and dye workers Bladder cancer

16. CHEMICALS Nitrosamines Animal evidence that conversion of dietary nitrates/nitrites to nitrosamines by gut bacteria lead to GI cancer. Alkylating Agents Bind directly to DNA – Nitrogen mustard.

17. VIRUSES Hepatitis B Hepatocellular carcinoma Epstein Barr Burkitt’s lymphoma, Nasopharyngeal carcinoma Human Papilloma Cervical carcinoma

18. OTHER AGENTS AsbestosMesothelioma Aflatoxins Liver cancer Schistosoma Bladder cancer Hormones Oestrogens and breast cancer Androgens and liver cancer

20. GEOGRAPHIC VARIATION • Genetic Tight family clusters • Viruses Hepatitis B, Epstein Barr • Parasites Schistosoma • Diet Gastric cancer in Japan, Fibre content • Other factors Reproduction and breast cancer Carcinoma of cervix

21. PREDISPOSING CONDITIONS Ulcerative colitis colorectal carcinoma Cirrhosis liver cancer Adenoma of large adenocarcinomaintestine

22. HOST FACTORS Age - incidence of cancer increases • cumulative exposure to carcinogens • latency • accumulating genetic lesions • innate defence Immune factors Hormones

23. WHICH GENES ARE INVOLVED The function of the genes which are modified by radiation/chemicals/viruses is critical for the development of neoplasms Growth Differentiation Proto-Oncogenes Tumour Suppressor genes

24. PROTO-ONCOGENES Present in all normal cells, involved in normal growth and differentiation. DNA sequence identical to viral oncogenes. Alteration (mutation, amplification, translocation) oncogene

25. ONCOGENES • c-myc binds to DNA, stimulates synthesis amplified (over-expressed ) in e.g. neuroblastoma, breast cancer translocation 8 to 14, adjacent to immunoglobulin (inappropriate transcription) in Burkitt’s lymphoma

26. ONCOGENES • Ras intracellular signalling mutation (altered function) colon, lung cancer • c-erbB-2 growth factor receptor(HER-2) amplification (over expression) adenocarcinoma

27. TUMOUR SUPPRESSOR GENES In normal cells the protein encoded by the gene suppresses growth Loss/alteration to the gene results in loss of growth suppression Retinoblastoma/p53

28. RETINOBLASTOMA Tumour of retina in children. 40% of cases familial. Familial cases occur younger (» 1yr age) and can be bilateral. Familial cases can develop osteosarcoma in teens.

29. Familial Inherit defect of Rb gene on one allele Deletion/mutation Rb gene other allele RETINOBLASTOMA(ONE HIT) Sporadic Normal Rb gene Deletion/mutation Rb gene one allele Deletion/mutation other allele RETINOBLASTOMA(TWO HIT) RETINOBLASTOMA

30. p53 Gene encodes a nuclear protein which binds to and modulates expression of genes important for DNA repair, cell division and cell death by apoptosis Located on chromosome 17p Alterations to the gene found in many cancers

31. Radiation Free Radicals Chemicals Increased p53 protein DNA Damage Cell cycle inhibitor increased DNA Repair Growth Arrest Apoptosis p53

32. MECHANISMS IN CARCINOGENESIS Long period of time elapses between exposure to stimulus and the emergence of a clinical cancer. Initiation Promotion Progression

33. INITIATOR PROMOTER

34. MECHANISMS IN CARCINOGENISIS Initiating Stimulus - Effect modified by genetic factors, DNA repair. Promotion - Hormones, local tissue responses, immune responses. Progression - Number and type of genes modified allows development of neoplastic cell

35. TUMOUR DEVELOPMENT AND PROGRESSION Not just an alteration to one gene Accumulation of alterations Many factors involved