Leicester Warwick Medical School Neoplasia III Why and How do Tumours Occur? Professor Rosemary A Walker 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 – sensitivity to DNA cross-linking agents.

INHERITANCE Alteration in Gene Polyposis coliAPC 5q21 Hereditary Non Polyposis Colon Cancer (HNPCC) Mismatch repaireg 2p21-22 Li Fraumeni syndromep5317p Familial Breast/Ovarian cancerBRCA117q21 BRCA213q12 RetinoblastomaRb 13q14

EXTRINSIC FACTORS Radiation Chemicals Viruses

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)

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-2napthylamine, 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 Hepatocellular carcinoma Epstein Barr Burkitt’s lymphoma, Nasopharyngeal carcinoma Human Papilloma Cervical carcinoma

OTHER AGENTS AsbestosMesothelioma AflatoxinsLiver cancer SchistosomaBladder cancer HormonesOestrogens and breast cancer Androgens and liver cancer

GEOGRAPHIC VARIATION Genetic Tight family clusters VirusesHepatitis B, Epstein Barr ParasitesSchistosoma DietGastric cancer in Japan, Fibre content Other factorsReproduction and breast cancer Carcinoma of cervix

PREDISPOSING CONDITIONS Ulcerative colitiscolorectal carcinoma Cirrhosisliver cancer Adenoma of largeadenocarcinoma intestine

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 Rasintracellular signalling mutation (altered function) colon, lung cancer c-erbB-2growth 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/p53

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.

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)

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

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

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

PROMOTER INITIATOR

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