Oncology Flashcards
Describe epigenetics
- Heritable modifications of DNA that do not alter the primary sequence
- Result: altered gene expression
Describe DNA methylation
- Covalent modification of a methyl group to cytosine at position C5 to make 5-methylcytosine
- Most genes have GC rich areas of DNA in their promoter regions - CpG islands
- Methylation of the C residues within the CpG islands leads to gene silencing
- Little or no detectable DNA methylation in yeast and Drosophila
What are characteristics of Prader-Willi syndrome?
- Mental retardation
- Obesity
What are characteristics of Angelman syndrome?
- Mental retardation
- ‘Happy puppet’ syndrome
- Jerky movements + inappropriate laughter
What causes AS and PWS?
Defects in imprinted genes of chromosome 15 of the mother (AS) or the father (PWS)
Describe heterochromatin
- Highly condensed in interphase
- Transcriptionally inactive (contains few genes)
- Replicates late in S phase
Describe euchromatin
- Organised in 30nm fibre during interphase
- Transcriptionally active
- Replicates early in S phase
What is the position effect?
Spreading of heterochromatin into euchromatic regions causes cell to cell variability in gene expression
Explain X-chromosome inactivation
- Discrepancy of 1 X-chromosome in males (XY) but 2 X-chromosomes in females (XX)
- Solution: females need to silence one X-chromosome - X-chromosome inactivation
- Mechanism of silencing is initiated by Xist - X-inactive-specific-transcript ‘marks’ inactive X: only expressed from inactive X-chromosome and codes for an RNA. No protein product and RNA remain in the nucleus. Followed by DNA methylation
Describe genomic printing
- ~200 imprinted genes on autosomes
- Imprinted genes only expressed from one allele
- Dependent on parental origin
- Imprinting resets on passage through germline
What are autosomes?
The chromosomes that are not involved in sex determination ie not X or Y
What are the four stages in the mechanism of chemical carcinogenesis?
- Initiation
- Promotion (reversible)
- Progression (irreversible)
- Malignancy
Describe initiation of carcinogenesis
Initiation event involves cellular genome mutations in tumour suppressor genes and oncogenes
Describe promotion of carcinogenesis
Promotion stimulates proliferation and causes both mutated and normal cells to proliferate
Describe progression of carcinogenesis
Irreversible enhancement/repression of gene expression. Selection of neoplastic cells for optimal growth genotype/phenotype in response to the cellular environment
What happens if there is a high dose of carcinogen?
Tumours develop (carcinogen acts as both initiator and promotor/accelerator)
What happens if there is a low dose of carcinogen?
No tumours develop (no initiator)
What happens if there are multiple doses of promoter?
No tumours develop (requires initiator)
What happens if there is a low dose of carcinogen + promotor?
Tumours develop
What happens to 2-naphthylamine in the liver?
- Converts 2NTA to carcinogenic metabolite 2-amino-naphthol
- This is then detoxified to glucuronide (not carcinogenic)
What happens to glucuronide in the bladder?
- Human urothelial cells express beta-glucuronidase
- Converts glucuronide to a carcinogen
What is asbestosis?
Formation of scar tissue in the lung as a result of exposure to asbestos
What does asbestosis more commonly predispose?
Bronchogenic carcinomas
What does exposure to blue asbestos fibres carry a risk of?
Mesothelioma
What is the latent period of mesothelioma?
25-45 years
What is another factor that increases chance of asbestos related cancer?
Smoking
Describe asbestos fibres
- Asbestos is a fibrous silicate substance
- When inhaled, the needle-like fibres become coated in proteins (asbestos bodies) and their presence excites a macrophage and giant cell response, rather like silicosis
What two genes are most frequently mutated in smoking-related lung cancers?
- K-Ras
- p53
What is the active carcinogen in tobacco smoke?
- 3,4-benzpyrene
- It is a polycyclic aromatic hydrocarbon
Describe the process that causes cancer due to the chemical in tobacco
3,4-benzpyrene is converted by aryl hydrocarbon hydoxylase into benzpyrene diol epoxide that binds to DNA forming damaging adducts
Describe glutathione S transferase (GSTM1)
- Detoxifies carcinogens
- Some individuals have null genotype so no GSTM1 protein is detectable
- GSTM1 is polymorphic in the population, being null in about 30-50% of individuals depending on the ethnic group from which they come
- Homozygous null individuals have an increased risk of lung cancer and smoking-induced bladder cancer
Will all heavy smokers develop lung cancer?
- No
- In some smokers, AHH may not be expressed therefore DNA-binding epoxides are not generated
Describe carcinogenesis following chemotherapy
- Rare
- Secondary carcinogenesis can occur from the use of alkylating agents in chemotherapy
- Risk of secondary tumours following cancer treatment
- These result from DNA-damage inflicted on surviving normal somatic cells during treatment
- DNA strand breakage and base damage induced
Why are nitrites and nitrates in our diet carcinogenic risks?
- Gut bacteria convert nitrites and nitrates into nitrosamines
- These are carcinogens that can lead to cancers of gastro-intestinal tract and liver
How do nitrites and nitrates get into our diet?
- Food additives
- Fertilisers that enter drinking water
What is aflatoxicosis?
Aflatoxicosis is poisoning, especially of the liver, that results from ingestion of aflatoxins from contaminated food
How can UV radiation be dangerous?
- Non-ionising (causes excitation of atoms)
- Damages DNA
- Form pyrimidine dimers but can also break DNA by indirect mechanisms
- Caucasians susceptible to melanoma and basal cell carcinoma
What does neoplasm translate to?
New growth
Describe a tumour
Usually one cell type with supporting tissue structures
- Neoplastic cells
- Stroma (connective tissue, fibroblasts, blood vessels, immune cells)
Autonomous
-Response to physiological stimuli lost or abnormal allowing unregulated growth
What is the main risk for all adult cancers?
Age
Describe benign tumours
- Well circumscribed
- Slow growth
- No necrosis
- Non-invasive
- No metastasis
Describe malignant tumours
- Poorly circumscribed
- Rapid growth
- Often necrotic
- Invasive
- Metastasis
What are some clinical effects of benign tumours?
- Do not invade or metastasise
- Space occupying effects - obstruction, epilepsy, conduction abnormalities
- Haemorrhage - pulmonary, gastrointestinal
- Hormone production - pituitary, adrenal, endocrine pancreas
What are some ways that tumours spread?
- Directly invade locally
- Via the lymphatics
- Via the bloodstream (haematological)
- Through body cavities (transcoelomic)
What are some microscopic features of benign cells?
- Resemble tissue of origin
- Well circumscribed
- Well differentiated
- Minimal nuclear pleomorphism
- Mitotic figures normal
- No necrosis
What are some microscopic features of malignant cells?
- Variable resemblance
- Poorly circumscribed
- Variable differentiation
- Variable pleomorphism may be anaplastic
- Mitotic figures abnormal
- Necrotic
What are some cytological features of malignancy?
- High nucleo-cytoplasmic ratio
- Nuclear hyperchromasia
- Nuclear pleomorphism
- Abnormal chromatin structure
- Abnormal mitotic figures
What do the letters stand for in TNM staging?
- T - tumour size
- N - degree of lymph node involvement
- M - extent of distant metastases
Explain the nomenclature of tumours
- All end in -oma
- Benign epithelial tumours are either papillomas or adenomas
- Benign connective tissue tumours begin with term denoting cell of origin e.g lipoma
- Malignant epithelial tumours are carcinomas
- Malignant connective tissue tumours are sarcomas
Describe teratomas
- Contains elements of all three embryonic germ cell layers
- Of germ cell origin
- Benign and malignant forms
- Ovarian - almost always benign
- Testicular - more often malignant
What are onocgenes?
-Drivers of neoplastic behaviour
How do oncogenes work?
- Direct stimulation of cell cycle dependent transcription
- Increased/activation of growth factor receptors
- Increased growth factor
- Interference with intracellular signalling
How do oncogenes work?
- Direct stimulation of cell cycle dependent transcription
- Increased/activation of growth factor receptors
- Increased growth factor
- Interference with intracellular signalling
What do gatekeepers do?
- Inhibit proliferation or promote the death of cells, especially those with DNA damage
- Send negative signals to the cell
What do caretakers do?
- Maintain integrity of the genome by promoting DNA repair
- Nucleotide excision repair
- Mismatch repair
- DNA double strand break repair
What is an example of a protein that acts as a gatekeeper and caretaker?
p53
What does p53 do?
- Cell cycle arrest
- DNA repair
- Block of angiogenesis
- Apoptosis
Is BCL-2 pro or anti apoptotic?
Anti-apoptotic
How does a proto-oncogene become an oncogene?
A single mutation
What are the 7 deadly sins relating to metastasis?
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis
- Defects in DNA repair
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasise
What causes cancer?
Mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms
Changes in the DNA caused by covalent modification:
- spontaneous or genetic predisposition
- ionising radiation or UV radiation
- chemical carcinogens
What are the 3 main approaches to dealing with established cancers?
- Surgical excision
- Radiotherapy
- Chemotherapy
What are the four types of agent traditionally used to treat cancer?
- Alkylating agents
- Antimetabolites
- Cytotoxic antibiotics
- Plant derivatives
Describe alkylating agents
- Most commonly employed anticancer drug
- These are compounds which have the property of forming covalent bonds with suitable nucleophilic substances in the cell under physiological conditions
- Causes intrastrand crosslinking of DNA
How do alkylating agents cause DNA crosslinking?
- Normally guanine residues in DNA exist predominantly in the keto tautomer
- This allows them to readily make Watson-Crick base pairs by hydrogen bonding with cytosine
- When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed
- This modified guanine can mispair with thymine residues during DNA synthesis creating a mutation
How do alkylating agents treat cancer?
The mutation that it causes result in DNA damage which triggers cell death by apoptosis
What are the major groups of alkylating agents?
- Nitrogen mustards
- Ethylenimines
- Alkylsulphonates
- Hydrazines and triazines
- Nitrosoureas
- Platinum based compounds
Give an example of a nitrogen mustard
Cyclophosphamide
Give an example of an alkylsulphonate
Busulphan
Give an example of a nitrosoureas
lomustine or carmustine
Give an example of a platinum based compound
Cisplatin
What are the major groups of the antimetabolites?
- Antifolates - e.g methotrexate
- Antipyrimidines - e.g 5-FU, gemcitabine
- Antipurines - e.g mercaptopurine, thioguanine
Describe methotrexate
- Folate analogue
- Usually given orally but can also be given intramuscularly, IV or intrathecally
- Low lipid solubility so does not cross the blood brain barrier easily
- Polyglutamated which means it can be retained within cells for weeks
What does methotrexate inhibit?
DHFR
Describe the antipyrimidines
- Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP)
- It is converted into a fraudulent nucleotide FDUMP. Cannot be converted into DTMP
- Cytarabine is an analogue of cytosine but has arabinose and not ribose attached
- Undergoes phosphorylation to give cytosine arabinoside triphosphate
- This inhibits DNA polymerase
- Gemicitabine is an anologue of cytarabine
Describe the antipurines
- Mercaptopurine, thioguanine, fludarabine
- Mercaptopurine is converted to 6-mercaptopurine-ribose-phosphate called lethal synthesis
- 6-mercaptopurine-ribose-phosphate inhibits a number of enzymes in the de novo synthesis of purines
- Fludarabine in its triphosphate form inhibits DNA polymerase
What are some cytotoxic antibiotics?
- Anthracyclines
- Dactinomycin
- Bleomycin
- Mitomycin
Describe anthracyclines
- The main anticancer anthracycline antibiotic is doxorubicin. Others are daunorubicin, idarubicin, epirubicin, aclarubicin and mitoxantrone
- It binds to DNA and inhibits both DNA and RNA synthesis
- Its main cytotoxic action appears to be mediated through an effect on topoisomerase II the activity of which is markedly increased in proliferating cells
What are some plant derivatives used to treat cancer?
- Spindle poisons - affect microtubule function and prevent mitotic spindle formation
- Vinca alkaloids
- Taxanes
- Camptothecins
- Etoposide
What are some other anticancer drugs?
- Hormones (hormone inhibitors)
- Monoclonal antibodies
- Protein kinase inhibitors
- Miscellaneous agents
What are the main drawbacks of chemotherapy of cancer?
- Target cell proliferation not the more lethal properties of invasiveness and metastasis
- Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
- The development of resistance, particularly multidrug resistance, to anticancer drugs
- Leaves some remaining cells
Describe tumour lysis syndrome
- An acute side-effect of chemotherapy and a metabolic emergency
- Occurs due to rapid cell lysis and large amounts of cell metabolites in blood
- It is characterised by hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia
- If untreated can lead to acute renal failure, cardiac arrest and death
- Risk assess patients prior to chemotherapy
- Monitor and respond to deranged urea and electrolytes/fluid balance: dialysis may be required
Describe the bone marrow side effect of chemotherapy
- Myelosuppression - reduced production of cells which provide immunity, oxygen transport and clotting common with many chemotherapy agents
- Only actively dividing cells in the bone marrow are affected
- Monitor full blood count prior to then daily during treatment cycles
- Occasional use of recombinant human granulocyte-colony stimulating factors recommended to reduce incidence/duration of myelosuppression
- Cells with shorter life span are more affected
What are some gastro-intestinal side effect of chemotherapy?
- Nausea and vomiting
- Loss of appetite
- Constipation
- Diarrhoea
