CANCER & TUMOURS.pptx
- 2. Cancer and Benign Tumours Cancer Epidemiology Cancer is predominantly a disease of middle age and elderly. The varying incidence of cancer in different population may indicate the underlying causes of these tumours Environment and genetics are important ion determining cancer risk. Smoking and diet are major risk predisposing causes
- 3. The Global Cancer Burden WHO publishes annual cancer mortality statistics for most of the countries, and is its subsidiary. It estimated that that about 10 million new cases diagnosed each year and cancer accounts 12% of all deaths worldwide. The annual total is predicted to rise to 15 million per year in 2020 as the population increases and ages. cancer is predominantly a disease of midle-age and elderly
- 4. Taking all forms together, cancer is the second most common cause of death in developed countries and has recently overtaken heart disease to become the major killer in some western word, killing about 25% of some societies. The major malignant human cancer is carcinoma (malignant epithelial tumour), lymphoma (malignant lymphoid tissue), ranks about tents, and sarcomas (malignant connective tissue tumour) are rarer still.
- 5. In men the commonest tumour is bronchial cancer, following stomach, colorectal and prostate. Carcinoma of the breast is the commonest in the women, cervical, colorectal and endometrial carcinomas are relatively common. The risk of development of cancer depend on many factors, among them age, sex, geographical location, race, occupational history, social habits and socio-economic class.
- 6. Age Overall, cancer affects middle age and elderly, but different tumour types have deferent age profiles. Some particularly affect children (some lymphoblastic leukaemia) and adoloscents (osteosarcoma). Hodgkin lymphoma, a from of lymphoma has a bimodal peak affecting young adults and then the middle aged to elderly. Carcinomas, commonest cancers tend to affect the middle age and elderly, incidence increase with age.
- 7. Geographical variation There are striking regional variation in cancer incidence throughout the world. Many of these variations depend on environmental factors such as carcinogens rather than genetic factors. In Asia and Africa hepatocellular carcinoma is very common due to high prevalence of HBV infection and environmental exposure of to carcinogens such as aflatoxins present in mouldy granules.
- 8. Malignant melanoma in mainly disease of white- skinned people and specially common in sunny climates such as Australia. Gastric carcinoma is common in former USSR, in Japan and in china due H. Pylori infection and environmental factors. Breast and colorectal carcinoma is common in western world.
- 9. Diet In general, diet rich in fruit and vegetables are associated with lower risks of many major forms of cancer including the tumours of lung, stomach, breast and colon. In contrast a diet rich in animal fat is statistically linked to increased incidence of cancers of breast, colon, prostate and endometrium.
- 10. The risk of colon carcinoma is directly proportional to the extent of meat consumption. A diet rich in salted fish is associated with high incidence of gastric and nasopharyngeal carcinoma. alcohol consumption is associated breast, colon and liver cancers and acts synergistic manner with smoking.
- 11. Cigarette smoking It is generally acknowledged that cigarette smoking is responsible for at least a quarter of cancer deaths, specially from cancers of the lung, larynx, oral cavity and the lesser extent of urinary tract. There is a direct proportional between the number of cigarette smoked and the risk of lung cancer.
- 12. General Features of Tumours A neoplasm, literally is an abnormal mass of tissue, whose growth is uncoordinated with and exceeds that of the normal tissue. It results from aberrations of the normal mechanisms which control the cell number; these are cell production by cell division and cell loss by the process of apoptosis.
- 13. Classification of Tumours Tumours are divided in to two major groups according to their behaviour, benign and malignant. Benign tumours remain localised at their site of origin. They grow by expansion, pushing normal tissue away, often with the formation of a capsule of compressed fibrous tissue. Benign tumours usually grow slowly.
- 14. Malignant tumours (cancers), grow by infiltrating in to surrounding normal tissue and have the ability to spread to distant sites, to metastases, where secondary deposit takes place. The histological appearance of metastases similar to that of origin tumour. While malignant tumour usually grow rapidly, it must be remembered that not all malignant tumours are not equally malignant.
- 16. Some are highly aggressive and highly metastases early, for example small cell carcinoma of the bronchus. Others although they are slow growing and although they are locally infiltrative, they rarely metastasize. Basal cell carcinoma and adenocarcinoma are good examples of this. The degree of malignancy, described as tumour grade, usually correlates well with survival
- 17. Benign Malignant Growth pattern Expansion, localized infiltrative locally, spread to distant sites (metastaize) Growth rate Slowly Faster Clinical effects Local pressure; horm- Local pressur destruction ne secretion in appropriate hormone secretion; distant metatases Histology Resembles tissue of many differ from tissue of origin origin (less differentiated) Nuclei Small, regular, uniform Large, pleomorphic Mitoses Few, normal Numerous, including atypical forms Treatment Local excision Local excision and systemic therapy therapy if metastasepresent
- 18. Tumour Nomenclature Epithelial Benign Malignant Covering epith. Papilloma Carcinoma Glandular epith. Adenoma Adenocarcinoma Connective tissue Smooth muscle Leimyoma liemyosarcoma Skeletal muscle Rhabdomyoma Rhabdosarcoma Bone forming Osteoma Osteosarcoma Cartilage Chondroma Chondrosarcoma
- 19. Benign Malignant Lymphoid No benign Hodkin & non-Hodkin Melanocytes Moles Malignant melanoma Haemopoietic No benign Leukemia
- 20. Epithelial Tumours Benign tumours may from both covering e.g. squamous type, forming papillomas, and from glandular epithelium, e.g. colon or thyroid forming adenomas. Papillomas Papillomas are warty growths in which the proliferating epithelium is thrown upwards into folds, and does not invade in to underlying connective tiussue.
- 21. Adenomas Adenomas are benign tumours of glandular epithelium. The tumour cells in such tumour glandular structures mimicking the arrangement of the normal tissue. These cells are differentiated and often continue to secrete the normal product of the gland; thus the cells of adenoma of colonic adenoma may produce mucin and the thyroid adenoma thyroglobulin. If the glands become distended by secretion they may be form cysts – resulting in a multiloculated lesion called cystadenoma which may be found in the ovary or pancreas.
- 22. Adenoma of viscera such as the colon tend to grow into lumen, and often adopt a papillary architecture. Some are sessile and are thrown into greatly thickened papillary folds – so called villous adenoma – whereas others become pedunculated with stalk of normal mucosa – these are known a tubular adenomas. In most benign tumours, the cytological features closely resemble those of the normal tissue from which they arise.
- 23. Malignant Epithelial Tumours Carcinoma are the commonest type of malignant tumour in humans. They fall into several subtypes, depending on the form of differentiation they show.
- 24. Squamous carcinomas can arise from pre-existing squamous epithelium for example skin or larynx, but some for example of bronchus and cervical transformation zone, arise sites where there is a normally glandular epithelium, but where there squamous metaplasia has been followed by malignant change. Squamous carcinoma
- 25. Adenocarcinoma These are tumours showing glandular differentiation. They usually arise from glandular epithelium, for example within the stomach, endometrium or colon and may arise metaplastic glandular tissue e.g. in the lower third of esophagus when chronic acid reflux has resulted in metaplasia. Adenocarcinoma may be well differentiated or poorly differentiated.
- 26. Transitional Cell Carcinoma Transitional cell carcinoma arises from the transitional epithelium of the urogenital tract. It too may show considerable variation; well differentiated papillary transitional cell carcinoma resemble papillomas, and may of the underlying stroma, but they arenot show any invasion e regarded as malignant for practical purpose because they have high risk of recurrence, often in more aggressive from. Poorly differentiated cell carcinoma have a more solid architecture and frequently invade deeply within the wall of the bladder or ureter.
- 27. Small Cell Carcinoma Small cell carcinoma is tumour which shows neuroendocrine differentiation in the form of neurosecretory granules. Typically it arises from the bronchus, where is the most aggressive form of lung cancer, but occasionally other sites such as the cervix and esophagus.
- 28. Other types of carcinoma include HCC, the malignant tumour of hepatocytes and BCC, a variety of skin cancer, which is always locally destructive, but seldom metastasizes.
- 29. Connective Tissue Tumours The connective tissue are fibrous, fat, nerve, muscle, blood vessels, bone and cartilage. Both benign and malignant tumours can be found, which show differentiation towards one of these forms. It is likely that all arise from primitive mesenchymal stem cell which retain the ability to differentiate in many directions.
- 30. Benign Connective Tissue Tumours The nomenclature of the tumours is straightforward – the name consists of a prefix indicating the type of differentiation, for example lipo (fat), chondro (cartilage), haemangio (blood vessel), with the suffix – oma donating a benign tumour. Most are slowly growing encapsulated tumours composed of appropriate differentiated tissue.
- 31. The commonest is the leimyoma, a benign tumour showing smooth muscle differentiation, often occurring in the uterine muscle. Lipomas are also common tumours, usually occurring in the subcutaneous tissues of adults, typically at the back of the shoulder. They consists a encapsulated mass of mature fat.
- 32. Malignant Connective Tissue Tumours These are known sarcomas. They are far less common than carcinomas. Most common within the deep soft tissue of the limbs and trunk although some arise within viscera. There are numerous different types. Like benign tumours, the nomenclature indicates the form of differentiation shown: for example leiomyosarcoma is a malignant tumour showing smooth muscle differentiation. Rhabdosarcoma show skeletal muscle differentiation and are among the commonest tumours of childhood.
- 33. Well differentiated contain myosin and actin myofilaments so well orientated cross-striations similar to those found in normal skeletal muscle can be seen. In poorly differentiated tumours, the diagnosis is made on the basis that proteins found in the skeletal muscle (desmin, myoglobin) or involved in skeletal muscle differentiations (MyoD1) can be demonstrated by immunochemistry.
- 34. Spread of Malignant Tumour Malignant tumours spread in several ways :- Local spread Lymphatic spread Blood (haematogenous spread) Transcoelomic spread Intraepithelial spread
- 35. Local Spread Malignant cells have the ability to insinuate themselves between adjacent normal cells and invade the surrounding tissue, e.g. for epithelial tumours the first step is for tumour cells to breach the basement membrane, i.e. to proceed from the stage of intraepithelial neoplasia to that of invasive tumour.
- 36. It is at this point that the cells can be said to have become malignant, tumour cells can easily spread through loose fibrous tissue and adipose tissue. Dense fibrous tissue such as fascia and periosteum tend to form more barrier, but are eventually also penetrated.
- 37. Lymphatic Spread This is the principal mode by which carcinomas spread. The very thin wall of lymphatics are readily penetrated by tumour tissue, which is carried along in the lymph to the first lymph node in lymph node chain, the sentinel node. Whether this node is involved by tumour is now recognized to be important in planning the extent of surgery, for example melanoma or the carcinoma of the breast
- 38. The malignant cells move from lymph node to other in the lymph chain. Ultimately may reach to thoracic duct and enter the SVC from which further dissemination through the blood stream may occur.
- 39. Blood (haematogenous) spread Tumour cells also able to invade thin walled veins and grow along the venous system or embolize in to the blood stream. The site of initial metastasis (first-pass organ) depends on the venous drainage of the location of the tumour. Most of tumour emboli pass through the right heart and impact in pulmonary capillary bed, whereas many tumours of splanchnic origin, for example of bowel metastasize by blood to the liver along the portal vein.
- 40. Visceral organs also invade blood vessels which communicate with the paravertebral venous plexus of Batson, a complex valveless veins. Retrograde flow occurring, for example when intra- abdominal pressure increases, is responsible for the metastases to the spine seen for example in prostate carcinoma.
- 41. Tumour emboli from the lungs enter the systemic circulation and may be widely disseminated to the brain or elsewhere. In contrast to the thin walled veins, the thick walled arteries are resistant to invasion by tumours. It is not only the anatomical features of blood flow which explain the site of metastases. The term ‘seed and soil’ was coined in the nineteenth century to describe tendency to some cancers to spread specific sites.
- 42. Gastric carcinoma cans spread in a similar fashion, to involve peritoneal cavity, often seeding in the ovaries. When these ovarian metastases are bilateral in premenopausal women they are known as Krukenberg tumours.
- 43. Intraepithelial Spread This is the process by which tumour cells can infiltrate between cells of normal epithelium, without invading the underlying stroma. It is best seen in Paget’s disease of the nipple in which the cells of ductal carcinoma in situ grow in to nipple skin giving an appearance resembling eczema.
- 44. Premalignancy Three main groups can be considered as premalignancies:- Malignant change in benign tumours Intraepithelial malignancy/dysplasia Malignancy developing in chronic inflammation
- 45. Benign tumours which undergo malignant change, examples include colonic adenomas which may become adenocarcinomas (adenoma-carcinoma sequence), Intraepithelial premalignant condition is the basis of understanding carcinomas. In numerous condition it is possible to identify stage of pre-invasive condition, where epithelial cells show the cytological features of malignancy but not yet developed to invade adjacent normal tissues. This process has been known as dysplasia, carcinoma in situ and more recently ‘intraepithelial neoplasia’.
- 46. It can effect the epithelia of all types- squamous, transitional, glandular, detection of early of these changes can prevent the overt change in to malignancy. This is the basis of cervical screening programmes in which the abnormal cells from cervical intraepithelial neoplasia (CIN) can be seen in cervical smears.
- 47. Major Sites of Intraepithelial Neoplasia Site Terminology Cervix CIN (cervical intraepithelial neoplasia) Vulva VIN (vulval intraepithelial neoplasia) Vagina VAIN (vaginal intraepithelial neoplasia) Prostate PIN (prostatic intraepithelial neoplasia) Skin Carcinoma Breast Ductal & lobular carcinoma in situ
- 48. Breast screening aims to detect the carcinoma in situ and also small invasive carcinomas with the hope of diagnosis before metastases occurred. Dysplastic changes can be seen in metaplastic intestinal epithelium found in the oesophagus in Barret’s oesophagus, an important precursor of adenocarcinoma of the oesophagus.
- 49. Chronic inflammatory conditions can change in to malignancy due to increased proliferation and reparative conditions. Examples include longstanding ulcerative colitis in which there is an increased risk of colonic cancer and Hashimoto’s thyroiditis in which lymphoma may develop. Hepatocellular carcinoma typically arise livers affected by cirrhosis.
- 50. Clinical Effects of Tumours Not all tumours are symptomatic. Many are found accidentally on X-rays or post-mortem and all tumours pass through a stage when they are too small to cause any effects.
- 51. Benign Tumours Despite their name these are not always harmless. As they remain localized at their site of origin, the effects occur into three broad categories:- 1. The presence of palpable lump, often painless, but occasionally causing discomfort. 2. The effects of substance produced by a tumour. The cells of benign tumour are well differentiated and often remain the function of the tissue of origin such as the production of hormones. This usually out with the normal feedback mechanism and over activity may result, e.g. the thyroid adenoma may lead to hyperthyroidism.
- 52. 3- The effect of adjacent tissues due to pressure from expansion of the tumour. This usually seen particularly when tumour arises from confined area e.g. within the cranial cavity. The distortion of the uterine cavity by fibroid (leiomyoma) often results in heavy menstrual bleeding.
- 53. Malignant Tumours Direct Effects Malignant tumours may cause a palpable mass which often grows rapidly and compresses adjacent structures such as nerves with resulting pain. Blood loss due to haemorrhage from an ulcerated carcinoma may be acute or chronic, thus leading to iron deficiency anaemia. Carcinomas cause narrowing (stenosis) or complete obstruction of hollow viscus
- 54. Metastatic Effects Metastases can cause similar mass effects to primary tumours, but because they are usually multiple consequences tend to be more severe.
- 55. Common Sites of Metastases and their Effects Site Effects Lung Haemoptysis, pneumonia, pleural effusion Bone Pain, fracture, spinal cord compression Liver Hepatomegaly, jaundice, hepatic failure Brain Seizures, stroke, raised ICP Bone marrow Anaemia, leucopoenia, thrombocytopenia
- 56. Non-metastatic Effects This is heterogeneous group of disorders, many due to release of cytokines, such as interleukin 1 (IL 1) and tumour necrotizing factor α (TNFα) from tumour cells. Patients with advanced cancer are wasted (cachectic) with weight loss, anorexia and fever. Immunosuppression, abnormalities of coagulation, e.g. thrombophlebitis migrans and neurological disorders, e.g. neuropathy, cerebellar degeneration and Eaton-Lambert syndrome, a syndrome resembling myastenia gravis may be all seen.
- 57. Inappropriate Hormone Production Many tumours produce hormones not only produced by their tissue of origin. These include ADH, ACTH typically secreted by small cell carcinoma of the bronchus. Many tumours including squamous carcinoma produce parathyroid hormone related which has parathormone-like action and results in humoral hypercalcaemia of malignancy.
- 58. Common Cancers and their Effects Lung Cough, haemoptysis, chest pain, pneumonia, PE, obstruction of SVC, metastases to bone, brain, Breast Lump, early spread to nodes, bone, lung & liver Prostate Urinary symptoms, metastases to bone (spine) Colon Altered bowel habit, obstruction, anaemia, metastases to the liver Pancreas Obstructive jaundice, back pain esophagus Dysphagia, anaemia, early local spread and metastaes
- 59. Pathological Diagnosis of Tumours Although clinical, radiological and biochemical findings all contribute towards the diagnosis of tumour, the final diagnosis is made in almost all cases by microscopic examination: a so-called tissue diagnosis. Depending on the procedure used to obtain a sample for examination, the entire lesion, a large or small sample, or few cells may be studed.
- 60. Biopsies for Histopathological Assessment These allow assessment both of the appearance of the tumour cells and their relationship to normal tissues, i.e. the tissue architecture. Excisional biopsy In this procedure, usually performed for relatively small tumours, the lesion is removed and submitted for examination.
- 61. Incisional Biopsy In this procedure, the surgeon exposes the tumour and removes a wedge of tissue of fairly large and hopefully representative specimen. On the basis of the biopsy result, either immediately by frozen section or after a day or so, the appropriate therapy can be instituted.
- 62. Needle Biopsy Many tumours, including deep-seated ones under radiological control, can be sampled by needle biopsy in which a thin core of tissue is removed. This technique provides small amounts of tissue. This may not representative of the entire lesion, i.e there is potential for sampling error.
- 63. Cytology In recent years there has been a explosion in the use of cytology, to obtain the cells for study. The technique relies largely on interpretation of the appearance of the individual cells, although the degree of cohesion of the tumour cells (a feature of epithelial tumours) can also be assessed.
- 64. Cells can be easily found in body fluids, eg. Aspiration from pleural or peritoneal cavities by needle and syringe or saliva or sputum. Fine needle aspiration of solid tumours is now routine. It does not need anaesthesia and other preparation and it is simple procedure for superficial lesion. E.g. Breast lump and deeply located lesion can be sampled under imaging control.
- 65. Conventional Diagnosis and Additional Techniques In most cases, for example carcinomas of breast, colon or lung the diagnosis is made on stained sections applying the conventional criteria of malignancy. Simple histological techniques, for example for the detection of glycogen, much polysacharides and the pigments such as melanin help in some cases.
- 66. Immunochemistry, using antibodies to cell constituents, contributes much to the diagnosis of poorly differentiated tumours and often allows a precise diagnosis to be made on small needle biopsies. Immunostaining has largely superseded electron microscopy in this regard.
- 67. Tumour Markers These substances are produced by tumour cells, are detectable in the blood, and are of value in diagnosis and in monitoring progress following treatment. Many are onco-fetal antigens, proteins that are usually produced by fetal cells but not by normal mature adult cells.
- 68. Marker Tumour α-fetoprotein Teratoma, Hepatocellular carcinoma hCG Choriocarcinoma; teratoma PSA Prostatic carcinoma CA125 Ovarian carcinoma Carcinoembryonic antigen Carcinoma of the gut, lung Calcitonin Medullary carcinoma of the thyroid Thyroglobulin Follicular and pupillary carcinoma of thyroid
- 69. Tumour Staging & Grading Once the diagnosis of cancer is made, it is important to predict the likely behaviour of a tumour, both to decide the appropriate therapy and to estimate the patient’s survival. The two main factors are the biological nature of the tumour, the grade and its extent, the stage.
- 70. Grade: degree of malignancy of a neoplasm usually judged from its histological feature (nuclear size and regularity, mitotic frequency). Stage:- a recognized phase in the development (progression) of disease usually neoplasm. Different grading systems have been developed for the various tumour types.
- 71. The parameters are: - Mitotic activity - Nuclear pleomprphism - Degree of differentiation - Extent of necrosis The tumour staging can be assessed in number of ways. The TNM system, developed by the Union of International Cancer Centre (UICC) is applied in many tumour types specially carcinomas.
- 72. In this scoring system an increasing number is described to more extensive disease, at the primary site T, in draining lymph nodes N and distant sites of metastasis M. Other systems include Duke’s staging system for colonic carcinoma.
- 73. TNM Staging of Gastric Carcinoma Stage Explanation T1 Tumour in Mucosa or submucosa T2 Tumour penetrates muscularis mucosa propria T3 Tumour erodes through serosa T4 Tumour involved adjacent organs N0 No nodal metastases N1 Metastases in 1 – 6 lymph nodes N2 Metastases 7 – 15 regional lymph nodes N3 Metastases in more than 15 lymph nodes M0 No distant metastases M1 Distant metastases
- 74. Carcinogenesis Cancer is not a single disease, and different cancers have different causes. In some tumours a single major factor is implicated, but in most tumours multiple factors are involved. The clues or our understanding of the causes of cancer come from several sources, but it is clear that environment, genetic predisposition and inter- individual variability in coping with toxic injuries are all important.
- 75. Environmental Factors Chemical Carcinogens Many chemicals have been implicated in causing cancer in humans. Sometimes this is based on strong epidemiological evidence, for example lung cancer and cigarette smoking or bladder cancer in aniline dye worker, but it may also assumed from animal experiments.
- 76. Chemical Occurrence Tumour Alkyl ting agents Chemotherapy Leukemia Asbestos Insulation Mesothelioma Benzene Solvents Leukemia Nickel Mining Lung cancer Nitrosamines Dietary Gastric Carcinoma Polycyclic hydrocarbons Burning of organic material Carcinoma Radon Mining Lung cancer Vinyl chloride PVC monomer Angiosarcoma of liver
- 77. From animal studies it become apparent that chemicals acted in different ways to cause cancer. Some acted directly, while others required metabolic conversion to an active from. Many chemicals are weakly carcinogenic but that potency is much increased when chemicals are given in combination or subsequently.
- 78. Multistep theory of carcinogens is observed. Initiation leads to DNA damaged mutation of cells followed by promotion where there is clonal expansion of the abnormal cell eventually giving rise to cancer. Some chemicals appear to be initiators and promoters, so-called complete carcinogens but not all of these cause DNA damage
- 79. Human and rodents have markedly different metabolic pathways in some respects and may therefore cope with a potential carcinogen in quite different ways. The capacity of human cells to repair damage may be differ. Animal experiments tend to rely on constant, relatively high exposure to one or few agents whereas human context exposure to potential carcinogens occurs intermittently, frequently at low dose, and ad complex mixture rather than single agent.
- 80. Radiation There is evidence that ionizing radiation can induce cancer. Radiation induced cancers were seen in early radiologists, who used there own hands to calibrate their equipment. Many of the survivors of atomic bombs in Nagasaki & Hiroshima in 1945 later succumbed to tumours, especially carcinomas and leukemia.
- 81. An increased incidence of thyroid cancer is seen after the Chernobyl nuclear explosion in 1986. Therapeutic irradiation can cause an other cancer after several years, both carcinomas and sarcomas. Ionizing radiation acts by damaging the DNA. Both single & double cleavage is seen. Breaks in single strand of DNA repaired but, specially in rapidly growing cells this may be inaccurate leading to single base mutaion
- 82. In contrast, double strand damage leads to chromosomal rearrangement such as translocation and deletion. Ultraviolet radiation is strongly implicated in the aetiology of skin tumours especially malignant melanoma of which 90% of cases can be attributed to exposure.
- 83. Viruses and Cancers It has been recognized that viruses are responsible for some cancers. Viruses cause the development of cancers in different ways, some RNA viruses contain gene (viral oncogenesis) – which are directly responsible for transforming cells to malignancy. The viral RNA genome is copied into DNA by the enzyme reserve transcriptase and this is then inserted in to the host genome. Viral genes can thus influence the expression of adjacent cellular genes.
- 84. Other viruses e.g. HCV can cause direct tissue injury, leading to increased proliferation and an increased risk of mutation. The final common pathways of many of these precipitating factors is mutation of DNA. Other such as chronic infection or hormonal stimulation caused increased cell turnover and may therefore make mutations more likely. Immunosuppression is associated with an increase particularly of lymphoma, a common complication of AIDS.
- 85. Viruses Implicated in Human Cancers Virus Human tumour HPV especially types 16 & 18 Cervical carcinoma, Anal carcinoma & penile carcinoma Epstein-Barr VIRUS Nasopharyngeal carcinoma Burkitt’s lymphoma Hodgkin lymphoma HBV/HCV HCC Herpes 8 Kaposi sarcomas
- 86. Genetic Factors Undoubtedly there are individuals with significant genetic predisposition to various tumours including the common cancers of breast, lung and colon. There are three broad categories of familial cancers. .
- 87. Familial Cancer Syndromes In this group of disorders the increased risk of cancer is due to transmission of a single gene which appears to act in an autosomal dominant manner, although in fact both copies of the gene must be inactivated before a tumour develops The familial adenomatous polyposis coli is characterized by the growth of numerous adenoma in the colon and is inevitable development of colonic carcinoma in the middle age.
- 88. The responsible gene (APC) - on the long arm of chromosome 5 - has been identified and its function as an inhibitor of growth promoting signal transduction molecules established. The normal APC protein binds β-catenin and promotes its proteolytic destruction; mutations of APC tend therefore to increase the concentration of β-catenin, which is important in carcinogens.
- 89. In the Li-Fraumeni syndrome family members have an increased propensity of premature development of a variety of different tumour types (sarcomas, brain tumours & breast cancer); for example the early development of breast cancer and childhood sarcoma, typically in mother and child. It is due to change of P53 gene.
- 90. Familial retinoblastoma is characterized by almost inevitable development, usually bilaterally, of the rare retinal tumour retinoblastoma. This is due to inheritance of one abnormal copy of the retinoblastoma (Rb) gene.
- 91. Familial Cancers In some families there is a striking increase in the incidence of a common cancer, for example of breast, colon or ovary. In some cases the responsible gene can be discovered, for example the BRCA1 (on chromosome 17) and BRCA2 (on chromosome 13) genes associated with familial breast carcinoma.
- 92. Familial Recessive Disorders due to Defects in DNA Repair In ataxia-telangiectasia, an autosomal recessive condition, there is an increased risk of developing lymphoma or leukemia. This related excessive fragility of the chromosomes, either spontaneously or following radiation. The responsible gene (AT) thought to act as a sensor of DNA damage which activates the p53 gene causing the cell enter Go until DNA repair is complete.
- 93. In its absence, the mutated cell continues to proliferate increasing the chance of malignancy. Hereditary non-polypous colon cancer is an other disorder due to impaired DNA repair. The relevant genes are known as ‘mismatch repair genes’; they detect point mutations where the nucleotides on complementary DNA strands do not match correctly (A:T, C:G) and excise the abnormal base.
- 94. Failure of these mismatch repair genes can be detected by the accumulation of variable microsatellites, short sequence which are normally identical in any individual; microsatellite instability is an indication of mismatch repair. Xeroderma pigmentosum is due to loss of the genes involved in excision of so-called primidine dimers caused by ultraviolet damage. It leads to greatly increased risk of skin cancer.
- 95. The topic of oncogenes and tumour suppressor genes can be difficult and confusing. Is simple terms the cancer is due to excessive and uncontrolled proliferation or insufficient loss of cells, i.e. it results from defects in the normal control mechanism for cell population. Normal genes switches on when cell division cell in needed and which when expressed promote cell division are known as cellular proto-oncogenes.
- 96. Thank you for your attention