carcinogenesis Flashcards
what is a carcinogen?
any agent that significantly increases the risk of developing cancer
what is the role of promotion in carcinogenesis?
it stimulates DNA replication for mutation fixation
it also stimulates clonal expansion of mutated cells which enables accumulation of further mutations
what are the common genetic abnormalities that can lead to cancer
base pair substitution chromosomal translocation frameshift deletion/insertion gene amplification chromosomal inversion aneuploidy
what are the categories of human carcinogens
- Chemicals e.g. PAHs, nitrosamines
- Infectious agents e.g. human papilloma virus, Helicobacter pylori
- Radiation e.g. UV light, radon
- Minerals e.g. asbestos, heavy metals
- Physiological e.g. oestrogen, androgens
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
Aflatoxin targets what tissue?
liver
Alcohol targets what 4 tissues?
Pharynx, larynx, oesophagus, liver
asbestos targets which tissue?
lung pleura
xray targets which tissue?
bone marrow
Tobacco smoke targets what 6 tissues?
Mouth, lung, oesophagus, pancreas, kidney, bladder etc.
HBV targets what tissue?
liver
hpv targets which tissue?
the cervix
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?
UV light
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 mutagen
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
What is meant by a TSG?
tumour suppressor gene
