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Principles of Oncology

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Principles of Oncology

  1. 1. Principles of Oncology 1
  2. 2. 2 CELL NUMBER CONTROL Cell number is the balance of: • cell production (due to proliferation via the cell cycle) and • cell loss via a number of means including cell death by the process of apoptosis
  3. 3. Figure 23-8 Molecular Biology of the Cell (© Garland Science 2008) Small number of stem cells Hard to identify Actually slowly turning over Give rise to other cells which can proliferate extensively (transit amplifying cells) Allows amplification and increase in number of cells Allows for rapid response to changing demands And creation of cells with different phenotypes
  4. 4. 4 GROWTH DISORDERS • Hypertrophy • Hyperplasia • Atrophy • Hypoplasia • Metaplasia • Dysplasia • Neoplasia
  5. 5. 5 Perspective • About 250,000 people every year are diagnosed with cancer in the UK: – about 120,000 die every year – about 1 in 3 of all deaths. • The annual cost of diagnosing and treating cancer is about £1.5 billion for the NHS every year.
  6. 6. 6 Basic definitions Rupert Willis 1930s A neoplasm • is an abnormal mass of tissue, • the growth of which is uncoordinated with that of normal tissues, • and that persists in the same excessive manner after the cessation of the stimulus which evoked the change“ An important additional component is • "the presence of genetic alterations that alter cell growth"
  7. 7. 7 Basic definition An alternative OPERATIONAL definition of neoplasia is; "a growth disorder characterised by genetic alterations that lead to loss of the normal control mechanisms that regulate cell growth, morphogenesis and differentiation"
  8. 8. 8 DYSPLASIA • A spectrum of abnormal growth conditions with many of the morphological and genetic changes of neoplasia BUT without any invasion of spread • Half way to neoplasia
  9. 9. 9 DYSPLASIA IN THE COLON Associated sometimes with the formation of polyps Can be flat Pre malignant Associated with some familial types of colon cancer FAP or Familial Adenomatous Polyposis Also associated with inflammatory bowel disease
  10. 10. 10 DYSPLASIA IN THE CERVIX Abnormal maturation of squamous epithelial cells Associated with HPV infection Varying degrees of abnormality . . . . . . . . . ultimately can become invasive and become a frank CARCINOMA
  11. 11. 11 The purpose of classification • is to provide an aid to diagnosis • to allow the accurate exchange of information • to define clinical sub-groups who have different biological or clinical features – will benefit from particular types of treatment – have different outcomes (prognosis) – to facilitate epidemiological analysis
  12. 12. 12 Why is classification important? PRECISE CLASSIFICATION OF A NEOPLASM FROM A PATIENT IS ESSENTIAL FOR THE CORRECT AND APPROPRIATE PLANNING OF TREATMENT
  13. 13. 13 Two key elements of classification of a neoplasm Behavioural classification • based upon the probable behaviour of a tumour – E.g. benign or malignant Histogenetic classification • based upon the presumed cell of origin a tumour – E.g. epithelium or connective tissue
  14. 14. 14 Behavioural classification • Spectrum of behaviour e.g. benign or malignant • Essentially a prediction of likely natural history • Pathologists use a range of morphological features in an attempt to categorise a tumour as benign or malignant
  15. 15. 15 Benign Malignant Slow growing Variable and may be rapid Few mitoses Variable but may be many mitoses Usually resemble tissue of origin Variable, but may only poorly resemble tissue of origin Nuclear morphology is usually normal Nuclear morphology may be variable and can be very abnormal with hyperchromasia, pleomorphism and nucleolomegaly Usually have a well circumscribed or encapsulated Often poorly defined or irregular Necrosis is rare Necrosis is common Ulceration is rare Ulceration is common Never invade May invade surrounding tissues Never metastasise May metastasise
  16. 16. 16 Histogenetic classification • Histogenesis refers to the presumed cell of origin of a tumour • Tumours from a specific histological tissue often have microscopic features similar too that tissue • The basis of this aspect of classification is HISTOLOGY. • Thus – tumours arising in squamous epithelia have a squamous pattern – tumours arising from the glandular epithelium of the gastro- intestinal tract have a glandular pattern.
  17. 17. 17 Two main histogenetic sub groups of malignant tumours CARCINOMA SARCOMA Derived from epithelium Derived from connective tissue Always malignant Always malignant Common Rare Spread by lymphatics Spread by blood May have a pre-malignant phase (or in situ phase) Not believed to have a pre- malignant phase Older patients Younger patients
  18. 18. 18 PREFIXES Prefix Tissue of origin Adeno- Glandular epithelium Pappilo- Non-glandular epithelium Lipo- Fat Osteo- Bone Chondro- Cartilage Angio- Blood vessel Rhabdo- Skeletal muscle Leiomyo- Smooth muscle
  19. 19. 19 SUFFIXES Suffix Meaning -oma Tumour (benign or malignant) -carcinoma Epithelial malignancy -sarcoma Connective tissue malignancy -aemia malignancy of bone marrow derived cells (exceptions exist eg. anaemia)
  20. 20. 20 Grade • the degree of differentiation of a tumour. • It is the degree to which a tumour cell resembles its presumed normal counterpart as assessed by its morphological appearances by a pathologist. • In general – a low grade [or well differentiated] tumour has a less aggressive course – than a high grade [or poorly differentiated] tumour. • ANAPLASTIC – – This word implies that histological examination shows a very poorly differentiated neoplasm that does not resemble any normal tissue. – These tumours are always malignant and usually behave very aggressively.
  21. 21. 21 Stage Stage refers to the extent of spread of a tumour. Stage is informed by both • clinical and radiological assessment (clinical stage) as well as • pathological examination of surgical specimens (pathological stage)
  22. 22. 22 Classification of epithelial tumours • Benign tumours of epithelium – Adenoma benign tumour of glandular epithelium – Papillomas benign tumour of non-glandular epithelium • Malignant tumours of epithelium – These are always carcinomas. – Qualifying terms needed like • Adeno-carcinoma • Transitional cell carcinoma
  23. 23. 23 Classification of connective tissue tumours Connective tissue Benign tumour Malignant tumour Cartilage Chondroma Chondrosarcoma Bone Osteoma Osteosarcoma Blood vessel Angioma Angiosarcoma Skeletal muscle Rhabdomyoma Rhabdomyosarcoma Smooth muscle Leiomyoma Leiomyosarcoma Fat Lipoma Liposarcoma
  24. 24. 24 THE PROBLEMS OF EXCEPTIONS . . . . . . • For example – MELANOMA – MESOTHELIOMA – LYMPHOMA • EPONYMS – Hodgkin's disease (a kind of lymphoma) – Ewing's sarcoma (a malignant tumour of bone in children and young people) – Burkitt's lymphoma (a kind of lymphoma)
  25. 25. 25 Relevance • Classification, grade and stage • are important as they enable the clinician to make some prediction of the likely prognosis of a patient AND • are essential information for the logical planning of treatment.
  26. 26. 26 A case history • A 48 year old man presents with a history of blood in his stool. • He has lost weight (2 stone over 8 months). • His brother had colon cancer a the age of 35.
  27. 27. 27 • On examination middle aged man with evidence of weight loss, pale skin. • Abdominal examination: ? Irregular liver edge and suggestion of mass in lower abdomen • Rectal examination: blood on finger but no mass • Differential diagnosis: – Piles – Inflammatory bowel disease – Diverticular disease – Tumour • Referred to Consultant Surgeon. • Sigmoidoscopy shows a mass at 20 cm which is biopsied
  28. 28. 28 • Flexible sigmoidoscopy: – mass in colon – biopsy taken • Histology of mass – Glandular neoplasm – Pleomorphism – Invasion • Surgery planned – Resection of colon
  29. 29. 29
  30. 30. 30 Evidence of metastatic spread Liver deposits
  31. 31. 31 Why epidemiology is useful • It allows you to gauge what is common and what is rare • It can provide clues to aetiology • Can guide the provision of scarce resources • Can facilitate planning of preventative measures • It underpins the development of screening methods for early diagnosis
  32. 32. 32 A range of factors can influence the epidemiology of a disease • Age variation • Gender differences • Historical variation • Geographic variation • Social and economic factors • Occupational factors • Dietary factors • Genetic factors etc . . . . . . . .
  33. 33. 33 EPIDEMIOLOGY examples • Ultraviolet light and skin cancer • Asbestos and mesothelioma • Smoking and lung cancer • HPV, sexual activity and cervix cancer • Malaria and Burkitt’s lymphoma • Meat consumption and colon cancer • Radiation and thyroid cancer • Aniline dyes and bladder cancer • Family history and many cancers • Alcohol and cancer • Hepatitis virus, aflatoxins and liver cancer
  34. 34. 34 Colorectal cancer as an example Age Incidence increases rapidly with increasing age Gender Affects both men and women Historical variation Is becoming more common Geographic variation Associated with developed nations rather than developing nations Social and economic factors Can occur in all groups Occupational factors None known Dietary factors Associated with a low fibre, high fat, high red meat diet Genetic factors Familial forms well described including:- 1. Familial Adenomatous Polyposis or FAP (APC gene) 2. Hereditary non polyposis cancer (HNPCC) DNA repair genes BUT ALSO 3. Genes whose products are involved in metabolism of carcinogens can increase the risk of neoplasia
  35. 35. 35 MIGRATION STUDIES CAN ILLUMINATE THE ROLE OF ENVIRONMENTAL AND GENETIC FACTORS
  36. 36. 36 Mortality statistics the big 5 in men and women Males Females Lung Lung Prostate Breast Colorectal Colorectal Stomach Ovary Oesophagus Pancreas
  37. 37. 37 CHANGING PATTERNS OF NEOPLASIA
  38. 38. 38 Why tumours cause problems • grow • press on structures • ulcerate • bleed • cause loss of organ function • invade locally • spread to distant sites (metastasise) • produce substances – appropriate for the site – inappropriate for the site
  39. 39. 39 • It is implicit from our definition of neoplasia that neoplastic (or tumour) cells have lost normal regulation of cell number control • Tumours are usually clonal in origin • From this single transformed cell tumours grow • 1 cm3 of tumour = ~ 1 gram = ~ 109 cells
  40. 40. 40 Clonality • Tumours are usually clonal in origin (that is they arise from neoplastic change in a single initial cell), • But there are exceptions • BUT NOTE not all cell populations that are clonal are tumours!
  41. 41. 41 Growth of tumours
  42. 42. 42 How tumours present • A consequence of local disease – (eg. grow, compression, ulcerate, bleed, destroy adjacent structures) • A consequence of distant spread – (eg. grow, compression, ulcerate, bleed, destroy adjacent structures) • A non-metastatic manifestations of malignancy – (paraneoplastic effects) including anaemia, skin changes, neurological effects, inappropriate hormone production, weight loss and fatigue. - CACHEXIA or severe weight loss and debility. • An incidental finding – (eg. on screening or on routine medical examination)
  43. 43. 43 When thinking about a tumour at a given anatomical site, it might be A primary tumour that can be either benign or malignant or be a a secondary deposit (a metastasis) from another site
  44. 44. 44 Spread of tumours • Metastasis is the process whereby malignant tumour cells spread from • their site of origin – (known as the PRIMARY SITE or PRIMARY TUMOUR) • to some other distant site in the body – (known as the SECONDARY SITE or SECONDARY TUMOUR or SECONDARY DEPOSIT or METASTASIS or METASTATIC DEPOSIT)
  45. 45. 45 INVASION and METASTASIS • The two properties that accounts for most of the serious (and lethal) consequences of neoplasia. • Associated with – increased cellular motility, – the production of enzymes with proteolytic activity and – alterations in cell adhesion
  46. 46. 46 ROUTES OF METASTASIS 1. BLOOD [ HAEMATOGENOUS] SPREAD 2. LYMPHATIC SPREAD 3. TRANSCOELOMIC SPREAD 4. PERINEURAL SPREAD 5. IMPLANTATION
  47. 47. 47 SPREAD OF TUMOURS
  48. 48. 48 The process of metastasis . . . . • Local growth • Angiogenesis • Further local growth • Alteration in cell-cell and cell-matrix adhesion and altered cell motility • Remodelling and alteration of extra-cellular matrix • Leading to invasion and detachment • Entry into lymphatic and/or blood vessels • Survival in the lymph and/or blood • Arrest at some distant site • Survival at the distant site . . . then repeat the whole sequence • THE SPREAD OF TUMOURS IS NOT RANDOM • DEPENDS ON FACTORS RELATING TO BOTH • SEED (THE TUMOUR CELLS) AND • SOIL (THE SITE OF SPREAD)
  49. 49. 49 STAGE Stage refers to the extent of spread of a tumour. TNM System • T How big the primary tumour is • N Whether nodes are involved • M Whether distant sites are involved (eg. Liver or bone marrow)
  50. 50. 50 WHY IS STAGE SO IMPORTANT? • Key determinant of prognosis • Key factor in determining type of treatment options available – Surgery – Radiotherapy – Chemotherapy
  51. 51. 51
  52. 52. 52
  53. 53. OVERVIEW OF CARCINOGENESIS
  54. 54. 54 The hallmarks of cancer Hanahan & Weinberg Cell 2000; 100: 57-70
  55. 55. 55 Properties of tumour cells 1. Self-sufficiency in growth signals 2. Insensitivity to anti-growth signals 3. Evasion of apoptosis 4. Unrestricted replicative potential 5. Sustained angiogenesis 6. Tissue invasion and metastasis 7. Genetic instability
  56. 56. 56 Self-sufficiency in growth signals • Normal cells depend on exogenous growth factors to stimulate growth and cell proliferation. • Tumour cells grow and divide without these signals. • Why? – because of mutations in genes that encode components of the signalling pathways that normally regulate these processes. – Such mutations lead to constitutively active signalling
  57. 57. 57 Insensitivity to anti-growth signals • Usually the growth and proliferation of cells is controlled by a balance of growth promoting signals and growth inhibitory (or anti-growth) signals. • The loss of growth inhibitory signals or the loss of the ability to respond to these signals is typical of tumour cells.
  58. 58. 58 Evasion of apoptosis • A critical component of normal cell number control is apoptosis (programmed cell death). • Apoptosis is also a mechanisms for the removal of unwanted cells, for example those with significant damage, including genetic damage. • Tumour cells have often developed mutations in key genes whose products are involved in apoptosis such that cell death is blocked.
  59. 59. 59 Unrestricted replicative potential • Normal cells can only divide a finite number of times. • This was first shown by Hayflick in the 1960s – normal human fibroblasts will divide about 70 times if taken from a neonate, – but 40 times from a middle aged person, – and barely divide at all from an elderly person. • Normal cells thus have a restricted replicative potential as a consequence of a number of mechanisms. • Tumour cells have an unrestricted replicative potential and just carry on dividing! • The role of telomerase
  60. 60. 60
  61. 61. 61 Sustained angiogenesis • Tumours will stop growing when they outgrow their blood supply - without this they will have insufficient nutrients and oxygen to sustain themselves – and undergo ischaemia and infarction. • Tumours overcome this problem by the production of various factors that stimulate the formation of new blood vessels.
  62. 62. 62 Tissue invasion & metastasis • Normal cells remain where they are supposed to be and normal tissue boundaries are maintained. • Tumours are characterised by invasion into nearby tissues and structures (ie. normal boundaries are not maintained) and may spread to distant sites (metastasis). • These properties are the main reason why tumours are such a significant clinical problem.
  63. 63. 63 Genetic instability • Normal cells maintain the integrity of their genomes • Mutation is a key feature of neoplasia • Genetic instability is common in neoplasms. • A characteristic feature of tumours, particularly aggressive tumours, is the unstable nature of their genomes. – They often develop aneuploidy (abnormal DNA content) with abnormal chromosomes and mutation is also common – Hyperchromasia (densely staining) – Pleomorphism (variable size & shape)
  64. 64. 64 Evidence that neoplasia is a genetic disease 1 Nuclear abnormalities are common in tumours – Hyperchromasia – pleomorphism 2 Often see abnormal mitoses 3 Abnormal DNA content is common in tumours 4 Chromosomal abnormalities are common in tumours – Some are specific to particular tumour types – Some are non-specific
  65. 65. 65 5 Nearly all carcinogens are mutagens 6 Specific mutations in growth control genes are common in tumours 7 Genetic instability is a characteristic feature of tumours 8 Tumour cells breed true Evidence that neoplasia is a genetic disease M FISH – GMP lecture 10
  66. 66. 66 9 SOME CANCERS RUN IN FAMILIES There are a number of familial forms of neoplasia. That is genetic abnormalities in genes that predispose to neoplasia that can be inherited. Provide insights into the molecular events in neoplasia Evidence that neoplasia is a genetic disease
  67. 67. 67 TUMOUR PROGRESSION • Clinical and experimental phenomenon • With time tumours grow and successive populations become increasingly abnormal, accumulating more genetic abnormalities (mutations) • Associated with increasingly abnormal appearance and behaviour • Increasingly insensitive to growth inhibitory signals, more resistant to apoptosis, increasingly unstable etc.
  68. 68. 68 Tumours: Multiple genetic events are needed Evidence: clinical examples eg. colorectal cancer
  69. 69. 69 Tumours: Multiple genetic events are needed Evidence: clinical examples eg. tumour progression
  70. 70. 70 Tumours: Multiple genetic events are needed Evidence: Experimental skin tumours in mice
  71. 71. 71 Molecular events in neoplasia Exactly what genes are involved in neoplasia? several hundred genes mutated in tumours have been identified usually encode proteins involved in the kinds of process as being typical of tumours. • Self-sufficiency in growth signals • Insensitivity to anti-growth signals • Evasion of apoptosis • Unrestricted replicative potential • Sustained angiogenesis • Tissue invasion and metastasis We can call such genes 'CANCER CRITICAL GENES' : meaning all genes whose mutation contributes to the causation and progression of cancer.
  72. 72. 72
  73. 73. 73 Cancer critical genes There are two broad categories of cancer critical gene • Oncogenes • Tumour suppressor genes ONCOGENES + Cell number [or other key cellular control] - TUMOUR SUPPRESSOR GENES
  74. 74. 74 Cancer critical genes Cancer critical genes generally are involved in cell cycle or cell death processes [Some are involved in DNA repair] ONCOGENES Stimulate cell division OR inhibit cell death + Cell number [or other Key cellular control] - Inhibit cell division or stimulate cell death TUMOUR SUPPRESSOR GENES
  75. 75. 75 Oncogenes Involved in cancer by an increased activity of the (proto)oncogene stimulating an increase in cell number Genetically dominant Function like an accelerator The gain of function of an oncogene product as a consequence • of more of the gene product being expressed, • or a mutation in the gene such that the resultant protein has increased function, • or expression occurring in the wrong cell type, • or at the wrong time leads to the stimulation of a critical cell process (such as the cell cycle). Examples include is the ras oncogene, myc oncogene, bcr-abl oncogene
  76. 76. 76 Tumour suppressor genes Involved in cancer by a decreased activity of the tumour suppressor gene leading to an increase in cell number Genetically recessive Functions like a brake The loss of function of a tumour suppressor gene product as a consequence • of less of the gene product being expressed, • or a mutation in the gene such that the resultant protein has reduced or loss of function, • It is a genetically recessive event and requires the loss of both copies of the tumour suppressor gene (as first proposed by Knudson in his 'two hit hypothesis'). • Examples include the p53 gene, the APC gene and the Rb gene
  77. 77. 77 Understanding cancer critical genes: an analogy One Accelerator Two brakes A foot on the accelerator can make you go faster! Oncogenes encode potential accelerators of growth. A single event is enough - it is genetically dominant – and involves GAIN OF FUNCTION You have two brakes If one stops working you can use the other. If both stop working you cannot stop and will accelerate. Tumour suppressor genes usually encode the brakes on cell growth – loss of their function can lead to accelerated growth - but it requires 2 events - loss of both brakes. You need LOSS OF FUNCTION of both alleles of a tumour suppressor gene (genetically recessive)!
  78. 78. Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008) Oncogene Pathways
  79. 79. 79 Activating oncogenes 12 3
  80. 80. 80 erbB2 in breast and ovarian cancer (Neoplasia 6) 1. GENE AMPLIFICATION Positive growth signal Receptor amplification HSR=homogeneously staining region
  81. 81. 81 2. POINT MUTATIONS IN CODING SEQUENCE Positive growth signal Receptor mutation Mutations in oncogenes are termed ‘gain of function or activating mutations’ inappropriate expression of the pathway eg. ras signalling
  82. 82. Many signalling proteins are molecular switches
  83. 83. Mutant ras is always switched on
  84. 84. 84 Altered regulation: myc gene over-expressed in lymphoma New gene formed: bcr-abl with altered/new properties 3. CHROMOSOMAL REARRANGEMENTS
  85. 85. 85 Tumour suppressor genes The Knudson Hypothesis Knudson studies children with an eye tumour called retinoblastoma 2 groups of patients:- • those with a family history • and those without (the majority) Familial form • present earlier in childhood • often had bilateral disease • within an eye could be multi-focal. Sporadic • presented later • only had a single eye involved.
  86. 86. 86 Tumour suppressor genes The Knudson Hypothesis For a tumour to develop Knudson proposed that:- • a gene was involved • mutations were needed in this gene (called the retinoblastoma gene) • normal people have two copies of this gene • one inherited from the father and one from the mother • Needed to have loss of function mutations in BOTH maternal and paternal copies of the retinoblastoma gene
  87. 87. 87 Knudson’s Two-Hit Hypothesis Hereditary Sporadic Multiple tumours, Single tumours, bilateral, early onset. unilateral, late onset
  88. 88. 88 Tumour suppressor genes The Knudson Hypothesis Sporadic form • a mutation has to occur in both copies of the retinoblastoma gene. • If a single mutation could occur in one in a 106 cells in a given period of time then the probability of a mutation occurring in both copies would be one in 1012. • ie. very rare. • the longer the period of time that elapses the more likely this is, but it is unlikely to occur more than in one cells. hence tumours occur late and are unilateral. Familial form • the child inherits from one mutant copy of the retinoblastoma gene. • Since it still requires mutations in both copies for a tumour to develop then the probability of this is one in a 106. • This is a million times more likely than in the sporadic form. • the disease occurs earlier and also there is a high probability of it occurring in more than one cell, and thus tumours may be multi-focal and bilateral.
  89. 89. 89 Familial Sporadic 1 in 106 1 in 106 1 in 106 Overall 1 in 106 Overall 1 in 1012
  90. 90. PEDIGREE OF THE FAMILIAL FORM OF RETINOBLASTOMA • Disease status of 24 children & grandchildren descended from a single male with retinoblastoma in childhood • ~ 50% of his descendants developed disease (red) • Proband did not develop disease but passed the susceptibility to 2 of his children • Proband is one of the small fraction (10%) with incomplete penetrance 90
  91. 91. 91
  92. 92. 92 Ways of inactivating a TSG 92
  93. 93. 93 p53 TSG • Altered in more than 50% of human cancers • Involved in a pathway that responds to DNA damage and allows repair or apoptotic cell death: – if it is not working damage accumulates and tumours can arise. • Is a transcription factor: regulates other genes
  94. 94. 94
  95. 95. PREVALENCE OF P53 MUTATIONS IN HUMAN CANCERS 95
  96. 96. PEDIGREE OF A FAMILY WITH LI-FRAUMENI SYNDROME 96
  97. 97. The component cancers of Li-Fraumeni syndrome tend to show up at different stages of life: Age of Onset 1. Infancy 2. Under 5 years of age 3. Childhood and young adulthood 4. Adolescence 5. Twenties to thirties Type of Cancer 1. Development of adrenocortical carcinoma 2. Development of soft- tissue sarcomas 3. Acute leukaemias and brain tumors 4. Osteosarcomas 5. Premenopausal breast cancer is common Those who survive the first cancer are at higher risk for a second cancer. These second cancers often occur in areas of the body previously treated with radiation. 97
  98. 98. Tumours: Multiple genetic events are needed Evidence: clinical examples eg. colorectal cancer 98
  99. 99. NORMAL COLON INNER SURFACE OF THE COLON OF A PATIENT WITH FAMILIAL ADENOMATOUS POLYPOSIS 99
  100. 100. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 CHRPE rare CHRPE frequent EXON AAPC LESS PROFUSE POLYPOSIS PROFUSE POLYOSIS EARLY ONSET THE APC GENE- genotype/phenotype correlations MUTATION CLUSTER REGION FAP GARDNER’S SYNDROME AAPC MULTIPLE ADENOMAS AS FOR FAP VARIABLE NOS OF ADENOMAS DUODENAL POLYPOSIS, GASTRIC ADENOMAS, CHRPE AS FOR FAP + EPIDERMOID CYSTS, DESMOID TUMOURS GASTRIC POLYPS OF FUNDAL GLANDS 100
  101. 101. FOUR GENERATION FAMILY PEDIGREE WITH AN INHERITED PREDISPOSITION TO BREAST & OVARIAN CANCER 101
  102. 102. BRCA1 Tumour Suppressor Gene Isolated by positional cloning as one of the genes predisposing to early onset breast and ovarian cancer Germline mutations of BRCA1 found in 50% inherited breast cancers 81% inherited breast-ovarian cancer) Penetrance varies based on age and population 56-85% by age 70 for inherited breast cancer 16-60% by age 70 for inherited ovarian cancer Sporadic disease - BRCA1 mutations detected in 10% of sporadic ovarian cancer - Reduced protein expression observed in the majority of sporadic breast cancers 102
  103. 103. 22 (1) Regulation of transcription (2) DNA damage (3) Cell cycle BRCA1 Function 103
  104. 104. XERODERMA PIGMENTOSUM 2 mutant copies of the same gene inherited – one from each parent Very rare condition Susceptibility to skin cancer Inherited defect in DNA repair (excision repair) Skin cancer rates 2000-fold > normal Average age 8yrs cf 60yrs general population 20-fold > brain, lung, stomach, breast & leukaemias Also a cancer critical gene!! 104
  105. 105. XERODERMA PIGMENTOSUM PEDIGREE Both parents are ‘carriers’ with no disease symptoms Child has 50% chance of inheriting mutant allele from each parent Overall probability of developing XP is 50%x50%=25% 1st generation 2/8 children developed the disease All of their children inherit a mutant allele so are carriers Some in the 1st generation may be carriers but not evident from the pedigree 105
  106. 106. FOUR GENERATION FAMILY PEDIGREE WITH AN INHERITED PREDISPOSITION TO BREAST & OVARIAN CANCER 106
  107. 107. 30 50 70 AGE (YEARS) PROBABILITYOFBREASTOROVARIANCANCER(%) 50 100 With BRCA1 mutation With family history Without BRCA1 mutation WHY BOTHER TO TEST FOR BRCA1 MUTATIONS? 107
  108. 108. RISKS/BENEFITS OF CANCER GENETIC TESTING • Ambiguous results • Results cause anxiety • Lack of prevention strategies • Discrimination • Strain on family relationships • Ends uncertainty • Possible absence of mutation • Improved medical care • Clarifies risk for relatives • Informed reproductive choices RISKS BENEFITS 108
  109. 109. ETHICAL ISSUES • Patient confidentiality - insurance - employment • Commercialism – Myriad Genetics • Prenatal testing Harris, Winship & Spriggs Lancet Oncology 2005; 6: 301-10 ‘Controversies and ethical issues in cancer- genetics clinics’. To be continued PoDT year 2 – clinical genetics 109
  110. 110. A MULTIFACTORIAL DISEASE • Having these mutant genes inherited from a parent is not enough: need other mutations • Also the other genes in the genome contribute to overall risk – The deck of cards! • Modifying loci – Penetrance – The exact mutation 110
  111. 111. The causes of neoplasia Carcinogenesis is the process by which a normal cell is converted into a neoplastic cell A carcinogen is an agent that can cause neoplasia • Most neoplasms occur as a consequence of environmental factors • Epidemiological and experimental studies provide insight into carcinogens • It is rare for a carcinogen to act by itself - it usually requires co-factors • Genetic variability in the population and other host factors contributes to carcinogenesis • Carcinogens are almost invariably mutagens
  112. 112. The causes of neoplasia • Toxins such as smoking • Ionising radiation • Non-ionising radiation • Viruses • Bacteria • Fungi • Parasites • Hormones • Diet • Inherited genes There is a complex interplay between environmental factors and host factors, including genetics susceptibility
  113. 113. How do we find carcinogens? • Epidemiology – Geographical risk – Historical changes – Occupational risk – Behavioural risk • Experimental evidence – Cell culture – Animal models
  114. 114. Genetic damage is the key to neoplasia Chemical carcinogenesis • History – Percival Pott 1776 • Identified skin cancer in chimney sweeps as being due to soot – Aniline dyes and bladder cancer
  115. 115. Genetic damage is the key to neoplasia Chemical carcinogenesis • Diverse compounds – Direct acting – Indirect acting: require metabolic activation • Examples – Alkylating agents (direct) – Polycyclin hyrdocarbons (indirect)
  116. 116. Genetic damage is the key to neoplasia Chemical Carcinogenesis – Ames test • Use bacteria that can only grow on particular media – Treat with compound: do they mutate to grow on other media? – Pre treat compound with metabolic enzymes (liver microsaomes) and repeat – Animal studies • As good as it gets! . . . . but possibly not always relevant to man
  117. 117. Figure 2.24 The Biology of Cancer (© Garland Science 2007) THE AMES TEST
  118. 118. Genetic damage is the key to neoplasia Chemical carcinogenesis – Human studies – Epidemiology – Complex and difficult but lots of good evidence for environmental chemical carcinogens • Asbestos • Aflatoxins • Aniline dyes
  119. 119. Genetic damage is the key to neoplasia Chemical carcinogenesis – Smoking – Huge number of chemicals involved – Clear evidence for carcinogenic role of smoking – “If everyone smoked then lung cancer would be a genetic disease” – Emphasises the point that we are all genetically different • Xenobiotic metabolism • DNA repair • Other
  120. 120. Genetic damage is the key to neoplasia Radiation carcinogenesis • Ionising radiation • Hiroshima, Nagasaki, Chernobyl, Laboratory accidents • Environmental radiation – Aberdeen, Cornwall, – radon exposure • Therapeutic & diagnostic radiation
  121. 121. Genetic damage is the key to neoplasia Radiation carcinogenesis • Non-ionising radiation • UV causes skin cancer – Low risk in Negroes, high risk in Caucasians, high risk in albinos – Families with defective DNA repair (Xeroderma pigmentosa)
  122. 122. Genetic damage is the key to neoplasia SOME EXCEPTIONS • Hormones – Act as promoters, stimulating cell proliferation – Breast, endometrial and ovarian cancer are hormone dependent (used in treatment) • Bacteria, fungi and parasites – Gastritis caused by Helicobacter pylori – Aflatoxins (carcinogen) produced by Aspergillus flavus and liver cancer – Bladder inflammation caused by Schistosomes (Eygpt) - bladder cancer
  123. 123. Genetic damage is the key to neoplasia Viruses and cancer • Good evidence in experimental models • Good evidence that viruses cause human cancer – HPV and cervical cancer – HBV and liver cancer – EBV and lymphoma • Viral genes functioning in human cells
  124. 124. Viral carcinogenesis I • Viral genes can act as dominant transforming oncogenes like ras • Viral genes can encode proteins that can inactivate cellular proteins – HPV encodes 2 proteins called E6 and E7 that bind to and inactivate p53 and Rb thus effectively inactivating these tumour suppressor proteins (genes)
  125. 125. 125 Human papillomavirus and the pathogenesis of cervical carcinomas This histological section of a human papillomavirus (HPV)-infected cervical epithelium reveals, through immunostaining with an anti-HPV antibody stain (brown), clusters of HPV-infected cells in dysplastic areas of the epithelium, termed high-grade squamous intraepithelial lesions (HSILs). The dysplastic cells arise, in large part, from the ability of the HPV E7 oncoprotein to inactivate pRb and thus block entrance into a postmitotic state, and to suppress apoptosis, the latter being achieved through the actions of the viral E6 oncoprotein, which targets the host cell’s p53 protein for destruction. The resulting lesions progress with a low but significant frequency to cervical carcinomas.
  126. 126. Viral carcinogenesis II • Viruses can also integrate into the genome of a cells and do one of two things Activate the expression of a cellular gene (proto-oncogene) OR Inactivate a gene by disrupting it (inactivate a TSG)
  127. 127. Viral carcinogenesis III • Viruses can also function in neoplasia by stimulating proliferation (HBV in liver; EBV in lymphocytes) and thus acting as a promoter • Also some viruses can cause immunosuppression (EBV and HIV) and this may be associated with development of tumours
  128. 128. Genetic damage is the key to neoplasia Host factors – Race, – diet, – gender, – inherited factors, etc • Familial cancers
  129. 129. Hereditary cancer • Some tumours run in families • We know the genes involved in some cases – Familial polyposis coli • (APC) – Hereditary non polyposis colon cancer • (DNA repair enzymes) – Breast cancer (+/- ovarian cancer) • BRCA1 and BRCA2 – Li Fraumeni syndrome • p53
  130. 130. Hereditary cancer • Having these mutant genes inherited from a parent is not enough: need other mutations • Also the other genes in the genome contribute to overall risk – The deck of cards! • Modifying loci – Penetrance – The exact mutation
  131. 131. Genetic damage is the key to neoplasia • Abnormalities of DNA repair genes are common in cancer • Can be inherited or be acquired – Mismatch repair – Double strand repair – Nueclotide excsion repair
  132. 132. Genetic damage is the key to neoplasia • Familial cancers are relatively rare • Genes involved in familial forms of cancer are (usually) also involved in the sporadic forms of cancer
  133. 133. Overview of treatment options Accurate clinical diagnosis of patients with neoplastic disease requires a logical and careful application of history taking clinical examination and appropriate special tests & investigations. Ultimately the diagnosis of neoplasia requires histopathological assessment or a tissue diagnosis. This involves cytology (eg. fine needle aspiration) needle or core biopsy incision biopsy or excision biopsy
  134. 134. Multi-disciplinary team approach The diagnosis and treatment of cancer is increasingly complex Requires a multi-disciplinary team (MDT) of professionals including – Surgical oncologists – Radiation oncologists – Medical oncologists – Pathologists – Radiologists – Geneticist – General practitioners – Palliative care specialists – Psychologists – Social workers – Nurses – Chaplains etc . . . . . . . . . .
  135. 135. New information helps diagnosis • Molecular profiles • Expression arrays • Antibodies • More robust and reproducible diagnoses and classification • Identification of subgroups that need specific therapies • Tailored treatments
  136. 136. Identifying prognostic factors Things that predict survival • Tumour type • Stage and Grade • Karnovsky status • Tumour factors – Gene expression – Proliferation
  137. 137. Identifying predictive factors Things that predict response to therapy • Sub types of tumour • Expression of various genes • Expression of p53 • Expression of other genes
  138. 138. Survival curves (Kaplan-Meier) TUMOUR TYPE Mesothelioma Seminoma Time 100% 1 yr 10 yr
  139. 139. Survival curves (Kaplan-Meier) STAGE
  140. 140. Survival curves (Kaplan-Meier) GENE EXPRESSION
  141. 141. Figure 16.4a The Biology of Cancer (© Garland Science 2007) Analysis of expression levels of 70 ‘prognosis genes’ in 295 primary breast cancers Stratification into 2 groups based on common patterns of expression Kaplan-Meier plot following survival of 151 patients over 10 years shows they have a dramatically different clinical course GENE EXPRESSION ARRAYS
  142. 142. Treatment goals The goals of patient management: • Cure • Palliation – with the aim of improving lifespan and quality of life
  143. 143. Treatment principles I Are based upon: • Biological behaviour of the tumour • Extent and bulk of disease • Mortality and morbidity of any therapies • The efficacy of the therapies • The general well being of the patient including co- existent (co-morbid) diseases
  144. 144. • Screening – Early Diagnosis is preferable (eg. Breast cancer) – Diagnosis at a pre-malignant stage (eg. Cervical cytology) • Prevention – Behaviour modification (eg. smoking, sun exposure) – Risk avoidance (eg. occupational risks, dietary factors) Treatment principles II
  145. 145. Cancer cure: difficult but not hopeless! • SURGERY is very effective • For some tumours chemotherapy and radiotherapy are very effective • Over the last decade all sorts of new approaches and new drugs coming into the clinic. • Lots of hope for the future . . . . . . .
  146. 146. How do current therapies work? • Exploit properties of tumour cells – Proliferation & loss of cell cycle control – Genetic instability • Most drugs and radiation cause massive DNA damage and induce cell cycle arrest and cell death
  147. 147. Figure 16.7 The Biology of Cancer (© Garland Science 2007) low doses of doxorubicin on hepatoma cells induce ‘mitotic catastrophe’ in tumour cells because they often lack G2/M checkpoint controls and so continue into mitosis without repairing the chromosomal damage. Normal cells with intact checkpoints arrest mitosis until damage is repaired. Increasing aneuploidy, polyploidy and cell death with time
  148. 148. Figure 9.8 The Biology of Cancer (© Garland Science 2007) THE CENTRAL ROLE OF P53 Various cellular stresses can upregulate p53 with a variety of downstream effects IHC of an ovarian carcinoma stained for p53 protein. Intense staining is that of mutant p53.
  149. 149. Cancers can evolve resistance to treatment • Just like bacteria and antibiotics! • Mutation and natural selection for resistant clones • If the apoptotic pathway is not working then drugs will not work. – Therefore, Increased resistance when there is mutant p53 • Increased expression of MDR1 in tumours: an efflux pump that exports exogenous compounds out of cells
  150. 150. Monitoring treatment I • Clinical examination • Radiology • Tumour markers – Measure something produced by the tumour cells as an index of tumour burden • AFP (alpha feto protein in liver cancer) • AFP & HCG (human chorionic ganadotrophin in testicular cancer)
  151. 151. Monitoring treatment II
  152. 152. Monitoring treatment IIIa Time Clinical examination Occult disease
  153. 153. Monitoring treatment IIIb Time Radiological examination Occult disease
  154. 154. Monitoring treatment IIIc Time Biochemical examination Level of marker Occult disease
  155. 155. Monitoring treatment IIIc Time Molecular marker MINIMAL RESIDUAL DISEASE
  156. 156. New treatments are based on new understanding of cancer biology: p53 • Drugs that reactivate mutant p53: restoring sensitivity to current drugs. • Viruses that will only grow in cells with mutant p53 as biological therapy • Side effects of current therapy include cell death in bone marrow due to p53 function in normal cells: use drugs that inactivate p53 in normal cells to reduce side effects of current therapies and increase therapeutic ratio
  157. 157. What about blocking blood vessels? • Angiogenesis is key to tumour growth so is an obvious target • Angiogenesis is induced by various factors such as VEGF: this acts on a receptor VEGF-R to induce new blood vessels to grow. Design drugs that block the receptor so that the tumour derived VEGF does not work?
  158. 158. Small molecules can be designed to target specific oncogenic proteins • The example of HERCEPTIN – An antibody that blocks the erbB2 receptor (also called HER2) now used in breast cancer • The example of GLEEVEC – A small molecule that blocks the active site of the abnormal bcr-abl protein, now used in CML (chronic myeloid leukaemia)
  159. 159. INTRACELLULAR SIGNALLING VIA THE ERBB2 RECEPTOR LIGAND RECEPTOR mRNA NUCLEUS INTRACELLULAR TRANSDUCER ERBB2 RECEPTOR INTRACELLULAR SIGNALLING VIA THE ERBB2 RECEPTOR LIGAND
  160. 160. AMPLIFICATION OF THE ERBB2 PROTO-ONCOGENE LIGAND INTRACELLULAR TRANSDUCER NUCLEUS ERB B2 RECEPTOR
  161. 161. THERAPY VIA RECEPTOR BLOCKING BY ANTIBODY LIGAND INTRACELLULAR TRANSDUCER NUCLEUS RECEPTOR ANTIBODY Herceptin
  162. 162. Understanding cancer biology leads to rationale tailored treatments • Next generation of treatments will be based on our new understanding PLUS • Specific treatments for specific patients based on genetic and molecular knowledge . . . . . . Grounds for optimism

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