What are the 5 ways of identifying human carcinogens?
1) Geographical variation in risk - studies in migrant populations
2) Occupational exposure
3) Accidental exposure
4) Big epidemiological surveys
5) Laboratory experiments
What are the categories of carcinogens? 6
1) Chemicals eg. PAHs, nitrosamines
2) Infectious agents eg. HPV, H pylori
3) Radiation eg. UV light, radon
4) Minerals eg. asbestos, heavy metals
5) Physiological eg. oestrogen, androgens
6) Chronic inflammation - free radicals and growth factors
Aflatoxin targets what tissue?
Alcohol targets what 4 tissues?
Pharynx, larynx, oesophagus, liver
Asbestos targets what tissue?
X-rays target what tissue?
Bone marrow (leukaemia)
UV light targets what tissue?
Oestrogen targets what tissue?
Tobacco smoke targets what 6 tissues?
Mouth, lung, oesophagus, pancreas, kidney, bladder etc.
HBV targets what tissue?
HPV targets which tissue?
What is meant by the term carcinogen?
Any agent that significantly increases the risk of developing cancer
What is the difference between initiator, promotor and complete carcinogens?
Initiators are genotoxic i.e. can chemical modify or damage DNA
Promotors are non genetic and induce proliferation and DNA replication
Complete carcinogens can do both
Name a complete carcinogen?
What 2 things does mutation indiction (initiation) require?
Chemical modification of DNA
Replication of modified DNA and mis-incorporation by DNA polymerase - requires 2 rounds of replication for a mutations to be fixed
The presence of what in the DNA exacerbates the tendency of polymerase to make mistakes?
Chemical modifications - miscoding or non-coding adducts or lesions
In which 2 ways do promotor carcinogens contribute to carcinogenesis?
1) They can stimulate the 2 rounds of DNA replication required for mutation fixation
2) Secondly they can stimulate clonal expansion of mutated cells, which enables the accumulation of further mutations
Why is clonal expansion of a cell with 1 mutation so important in carcinogenesis?
To form a malignant cell need 2-8 specific mutations, very hard for a cell to acquire these without significant clonal expansion
Give 2 examples of endogenous mutagens?
1) Oxygen radicals
2) Lipid metabolism byproducts
Describe the process of initiation, promotion and progression using a mouse model skin tumour?
1) Genotoxic initiating agent damages DNA
2) Promoting agent fixes the damage as a mutation and converts normal calls into mutant initiated cell
3) Promoting agent stimulates clonal expansion of initiated cells to produce papillomas
4) Further rounds of mutations and clonal expansion allows papilloma to progress to carcinoma
Give the 7 common genetic abnormalities?
1) Base pair substitution
4) Gene amplification (having up to a hundred copies of a gene it would normally only have 2 copies of)
5) Chromosomal translocation
6) Chromosomal inversion
What is meant by a TSG?
Tumour suppressor gene
What is the most common TSG inactivation event?
Abberant methylation of gene promotor
What is meant by CpG islands and what role do they have in TSG inactivation?
Approximately 70% of genes have CpG islands associated with their promoter sequence, CpG methylation is only effective in shutting down the expression of a gene if it occurs within the promotor sequence of the gene - this is how TSGs are inactivated
Give 4 mutations that occur in oncogenes?
1) Base pair substitutions
3) Translocation eg. proto-oncogene moved to an area where the genes are more frequently expressed thus ends up expressed more frequently to
What do mutations in oncogenes lead to?
A gain of function
What do mutations in TSGs lead to?
Loss of function
Give 7 types of mutation which can occur in TSGs?
1) Base pair substitutions
5) Chromosomal rearrangements
6) Chromosome loss
7) Promoter methylation
What is meant by a direct activating carcinogen? Give 4 examples.
Interact directly with DNA:
1) Oxygen radicals
3) UV light
4) Ionising radiation
What is meant by a procarcinogen?
Carcinogens which require enzymatic (metabolic) activation before they react with DNA, though not yet carcinogenic they are often toxic and its the enzymes that normally function in the detoxification and excretion of toxic chemicals which are normally implicated in their activation
How can the process of metabolic activation of procarcinogens present a genetic influence on the formation of a malignant tumour?
Enzymes involved in activation of procarcinogens are normally those involved in excretion and detoxification. People who have enzymes which activate a particular chemical more efficiently are more likely to get cancer as are those which excrete the activated chemical less efficiently
Name 2 procarcinogens?
1) Aromatic amines
2) Polycyclic aromatic hydrocarbons (PAHs)
Which enzymes are involved in the conversion of Benzopyrene to BDPE and thus the activation of benzopyrene a procarcinogen?
P450 mixed function oxidases and epoxide hydrolase
How does BDPE damage DNA and how is Benzopyrene produced?
Benzopyrene is generated through the combustion of most organic material such as meat, tobacco and fuel
BDPE forms a DNA adduct
Mutational defects in mismatch repair enzymes gives a predisposition to what disease?
Hereditary non polyposis colorectal cancer, also known as Lynch syndrome
Mutational defects in recombinational repair proteins gives a predisposition to what disease?
Mutational defects in nucleotide-excision repair proteins gives a pre-disposition to what disease?
Genetic polymorphisms in genes encoding which 3 types of enzyme involved in the process from carinogen exposure to cancer may confer greater or lesser susceptibility to the effects of carcinogenic exposure?
1) Metabolic activation enzymes
2) Detoxification/ Excretion enzymes
3) DNA repair eznymes
Give 5 of the bodies defences against cancer?
1) Dietary antioxidants
2) Detoxification mechanisms
3) DNA repair enzymes
4) Apoptotic response to unrepaired genetic damage
5) Immune response to infection and abnormal cells
How many carcinogens have been identified in tobacco smoke?
Give 5 carcinogens which have been found in tobacco smoke?
1) Polycyclic aromatic hydrocarbons eg. benzopyrene, require metabolic activation
2) Acrolein - acrid smell, potent direct-actin mutagen
3) Nitrosamines - formed during curing of leaves
4) Radioactive lead and polonium
5) Heavy metals - cadmium, chromium
In combination with promotion by alcohol tobacco smoke leads to what increased risk for head and neck cancer?
100 fold increased risk
Alcohol is linked to what 7 cancers?
Alcohol is converted into what substance which can cause DNA damage?
Alcohol increases the levels of which 2 hormones?
oestrogen and testosterone
How does alcohol affect the cells of the upper GI system?
Increases uptake of carcinogenic chemicals into cells within the upper GI system
How can alcohol affect surface epithelium what does this lead to?
Can kill surface epithelium leading to unscheduled proliferation - increases chance of mutation
Alcohol reduces levels of what chemical needed for accurate DNA replication?
Reduces levels of folate
All of the strongest risk factors for breast cancer are associated with what?
Increased exposure to oestrogen which can both stimulate cell division and induce DNA damage
Give 7 breast cancer risk factors?
2) Oral contraception
3) Alcohol consumption
4) Age of 1st pregnancy >30 years
5) Early menarche
6) Later menopause
7) Post-menopausal obesity
Why does chronic inflammation play an important role in cancer?
The inflammatory response results in a double hit:
1) DNA damage from release of free radicals by immune cells - initiation
2) Growth factor induced cell division to repair tissue damage - promotion
What proportion of cancer deaths are attributable to environmental or behavioural factors ie preventable causes?
What role can diet play in cancer incidence?
In some cases diet leads to exposure to carcinogens eg. red meat, burnt food, heavy metals and in some its the absence of protective factors which can lead to the increased cancer incidence eg. fibre and antioxidants.