Neoplasia III Past Paper 2024-2025 PDF

Session 11 Neoplasia III Why & how do tumour occur Dr Israa A. Kadhim References Robbins Basic Pathology, 10th edition. 2018 Muir’s Textbook of Pathology. 15th edition. 2014 Objectives To understand: 1- Inherited susceptibility to the development of tumours....

Session 11 Neoplasia III Why & how do tumour occur Dr Israa A. Kadhim References Robbins Basic Pathology, 10th edition. 2018 Muir’s Textbook of Pathology. 15th edition. 2014 Objectives To understand: 1- Inherited susceptibility to the development of tumours. -Xeroderma pigmentosum -Ataxia telangectasia 2- The inheritance of certain tumours -Familial adenomatous polyposis -Breast cancer -Retinoblastoma 3- The functions of oncogenes and tumour suppressor genes (TSG) and changes which occur in neoplasia. Objectives 4- The role of certain oncogenes (ras, c-myc, c-erbB-2 (HER- 2) and certain TSG (retinoblastoma, p53). 5- The stages in carcinogenesis -Initiation -Promotion 6- Agents which can result in development of tumours and their mechanisms of action -Radiation (UV, ionizing) -Chemicals (polycyclic hydrocarbons, aromatic amines, nitrosamines). -Viruses (Epstein Barr, hepatitis) -Other factors (hormones, aflatoxins, parasites) Objectives 7- Occupations associated with the development of tumours. -Asbestos exposure -Dye industry 8- Medical conditions associated with an increased risk of malignancy -Ulcerative colitis -Cirrhosis -Hashimoto’s thyroiditis -Chronic atrophic gastritis Objectives 9- Geographical variation in the incidence of malignant tumours. -Gastric cancer -Breast cancer -Burkitt’s lymphoma WHY DO TUMORS DEVELOP? Intrinsic factors Extrinsic factors What causes cancer Cancer is caused by alterations or mutations in the genetic code. Can be induced in somatic cells by: - Extrinsic factors: Carcinogenic, Chemicals, Radiation, some viruses. - Intrinsic factors: Hereditary (5%) Intrinsic factors Inheritance Host factors: -Age -Immune system -Hormones Inheritance Inherited conditions which predispose to the development of tumours related to DNA repair. Inherited susceptibility to the development of tumour or group of tumours due to alteration of one or more genes. Defect in DNA repair mechanisms Retinitis (Xeroderma) Photosensitivity pigmentosa Ataxia telangiectasia Defective response to radiation damage Fanconi’s anaemia Sensitivity to DNA cross linking agents Alteration in genes Polyposis coli APC 5q21 Heriditory non Mismatch repair 2p21-22 polyposis colon genes cancer (HNPCC) Li Fraumeni p53 17p syndrome Familial BRCA1 17q21 breast/ovarian BRCA2 13q12 cancer Retinoblastoma Rb 13q14 Extrinsic factors Radiation Chemicals Viruses  Radiation Evidence  Skin cancer in radiologist  Unprotected miners exposed ionizing radiation- 10 folds increase risk of lung cancer.  Radiotherapy for H&N increases the risk for thyroid carcinoma particularly in children.  Hiroshima, early: Leukaemia, Lymphoma Late: Breast, thyroid  Radiation Causes wide range of different types of damage to DNA including: Single and double stranded breaks. Base damage Note: The effect depend on quality and dose of radiation. Low dose (therapeutic dose): Genomic instability High dose: DS break, translocation and less commonly point mutation. Defective DNA repair mechanism mutation  Chemicals Carcinogens interact with DNA in one of a number of ways:  Causes specific base damage  Single stranded break  Damage is repaired but may be imperfect. Steps involved in chemical carcinogenesis Initiation: Result from exposure of cells to a sufficient dose of carcinogenic agent (initiator); an initiated cell is altered making it potentially capable of giving rise to tumour. Initiation is rapid and irreversible causing permanent DNA damage (mutation). Initiation alone is not sufficient for tumour formation. Steps involved in chemical carcinogenesis Promotion: Promoters can induce tumours in initiated cells; however, they are non tumorigenic by themselves. Note: The tumours would not result if the promoter agent is applied before rather than after the initiating.  Chemicals Directly acting chemical: No metabolic conversion (weak carcinogenesis) e.g. alkylating agent like cyclophosphomide and chlorambucil. Indirectly acting agents: require metabolic enzymatic conversion through cytochrome P 450 e.g. polycyclic hydrocarbons (ultimate carcinogens).  Chemicals Polycyclic aromatic hydrocarbons Coal tar, cigarette smoke 3,4-Benzbyrene most important converted to active form by hydroxylation e.g. aryl carbonate hydroxylase Lung Cancer, bladder cancer, skin cancer.  Chemicals Aromatic amines B-naphthalamines hydroxylated in liver to 1- hydroxy2-naphtalamine which is conjugated with glucoronic acid. Deconjugated into inactive form in urinary bladder. Bladder cancer in rubber and aniline dye workers.  Chemicals Nitrosamines Conversion of dietary nitrates/nitrites to nitrosamines by gut bacteria lead to gastrointestinal cancer Viruses Hepatitis B Hepatocellular carcinoma Epstein Barr Burkitt’s lymphoma, Nasopharyngeal carcinoma Human papilloma Cervical carcinoma Other agents Asbestos: Mesothelioma Aflatoxins: Liver cancer Schistosoma: Bladder cancer Helicobacter: Gastric cancer and lymphoma Hormones: Oestrogen and breast cancer Androgen and liver cancer Geographical variation in the incidence of malignant tumour Genetic: Tight family cluster Viruses: Hepatitis B, EB virus Parasites: Schistosoma Diet: Gastric cancer in Japan Other factors: Reproduction and breast cancer, cervical cancer. Predisposing factors Ulcerative colitis Colorectal carcinoma Liver cirrhosis Liver cancer Adenoma of the large Adenocarcinoma intestine  Host factors Age: Incidence of cancer increases with age. Cumulative exposure to carcinogens. Latency Accumulating genetic lesions Innate defence Immune factors Hormones Molecular bases of cancer  Cancer is a genetic disease Tumour cells contain genetically altered DNA with point mutation, deletion and translocation. Cancer cells must evade natural defence mechanisms i,e DNA damage repair and apoptosis. Which genes are involved Oncogenes Tumour suppressor genes DNA repair genes  Oncogenes Proto-oncogenes present in all normal cells, involved in normal growth and differentiation. DNA sequence is identical to viral oncogenes. Alteration (mutation, amplification and translocation) oncogenes.  Oncogenes c-myc binds to DNA and stimulate synthesis Amplified (over-expressed) in breast cancer and neuroblastoma. Translocation 8,14 (inappropriate transcription) in Burkitt’s lymphoma.  Oncogenes Ras (Intracellular signalling mutation) Mutation in colon and lung cancer c-erbB-2 (HER-2): Growth factor receptor Amplification in breast cancer  Tumour suppressor genes In normal cells, the protein encoded by these genes suppresses growth. Loss/alteration of these genes leads to loss of growth suppression. Retinoblastoma, p53 genes  Retinoblastoma Tumour of retina in children. 40% of the cases are familial. Familial cases occur in younger children (1 year) and can be bilateral. Familial cases can develop osteosarcoma in teens. Familial vs. Sporadic retinoblastoma  p53 Gene encode a nuclear protein which binds to and modulate expression of genes important for DNA repair, cell division and cell death by apoptosis.  It’s the guardian of the genome p53 transcription factor is located on Chromosome 17q p53 is mutated in > 50% of cancers DNA repair genes These genes ensure that each strand of DNA is accurately copied during cell division. Mutation of DNA repair genes increases the frequency of mutations affecting other genes like TSG and oncogenes.  DNA repair genes i.e. Breast cancer susceptibility genes (BRACA1 and BRACA2 ). Hereditary non polyposis coli susceptibility have DNA repair functions. Their mutation will cause tumorigenesis.  DNA repair genes Individuals born with such inherited defects of DNA repair proteins have greatly increased risk of developing cancer. DNA repair genes themselves are not oncogenic, but their abnormalities allow mutations in other genes during the process of normal cell division.  DNA repair genes Defects in three types of DNA repair system (mismatch repair, nucleotide excision repair &recombination repair) contribute to different types of cancer. Importance of DNA repair  Mechanisms in carcinogenesis Long period of time elapses between exposure to stimulus and the emergence of clinical cancer. Initiation Promotion Progression  Mechanisms in carcinogenesis Initiating stimulus-effect modified by genetic factors, DNA repair. Promotion-local tissue response, immune response. Progression-number and type of genes modified allows development of neoplastic cells.  Tumour development and progression Not just an alteration to one gene Its ACCUMULATION of alterations with many factors involved. Hallmarks of cancer Thank you