Leicester Warwick Medical School Neoplasia III Why and

Leicester Warwick Medical School Neoplasia III Why and How do Tumours Occur? Professor Rosemary A Walker raw 14@le. ac. uk Department of Pathology

WHY DO TUMOURS DEVELOP? Intrinsic factors Extrinsic factors

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

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.

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

INHERITANCE • • • Alteration in Gene Polyposis coli APC 5 q 21 Hereditary Non Polyposis Colon Cancer (HNPCC) Mismatch repair Li Fraumeni syndromep 53 17 p Familial Breast/Ovarian cancer BRCA 1 17 q 21 BRCA 2 13 q 12 Retinoblastoma Rb 13 q 14 eg 2 p 21 -22

EXTRINSIC FACTORS Radiation Chemicals Viruses

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

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

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

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.

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.

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

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

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.

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

OTHER AGENTS Asbestos Mesothelioma Aflatoxins Liver cancer Schistosoma Bladder cancer Hormones cancer Oestrogens and breast Androgens and liver cancer

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

PREDISPOSING CONDITIONS Ulcerative colitis colorectal carcinoma Cirrhosis liver cancer Adenoma of large intestine adenocarcinoma

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

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

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

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

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

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/p 53

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

RETINOBLASTOMA 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)

p 53 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 17 p Alterations to the gene found in many cancers

p 53 Radiation Free Radicals Chemicals DNA Damage DNA Repair Growth Arrest Apoptosis Increased p 53 protein Cell cycle inhibitor increased

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

INITIATOR PROMOTER

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

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