Carcinogens: Cause of Cancer Flashcards
What are the categories of human carcinogens?
- Chemicals (PAHs, Nitroamines)
- Infectious agents (HPV, Helicobacter Pylori)
- Radiation (UV light)
- Minerals ( asbestos, heavy metals)
- Physiological (Oestrogen, androgens)
- Chronic inflammation ( free radicals, growth factors)
Give the target tissue of the following agents:
- Alcohol
- Aflatoxin
- Asbestos
- X-rays
- UV-light
- Oestrogen
- Tobacco smoke
- HBV (Hep B virus)
- HPV (Human Papilloma Virus)`
- Pharynx/;arynx/liver.oesophagus
- Liver
- Lung pleura
- Bone marrow (leukaemia)
- Skin
- Breast
- Mouth/lung/Oesophagus, pancreas, kidney, bladder
- Liver
- Cervix
What is a carcinogen?
Any agent that significantly increases the risk of developing cancer- often genotoxic
-Complete carcinogens can initiate and promote
What are initiators?
Can chemically modify/damage DNA
What are promoters?
Often non-genotoxic - induce proliferation and DNA replication
What is initiation also known as? What does it require?
-Mutation induction
Requires:
-Chemical modification of DNA
-Replication of modified DNA and mis-incorporation by DNA polymerase
How do good promoters contribute to carcinogenesis?
- Stimulate the two rounds of DNA replication required for mutation fixation
- Stimulate clonal expansion of mutated cells enabling accumulation of further mutations
What are the common type of genetic abnormalities?
- Base pair substitution (smallest giving rise to change in gene function. Can result in aa substitution/missense introducing a ‘stop’ codon
- Frameshift
- Deletion
- Gene amplification (Cell having 100+ copies of a gene normally only 2)
- Chromosomal translocation (Genes being moved to a more transcriptionally active region or recombined into new gene fusions 300/500 cancers)
- Chromosomal inversion (chromosomes present in inappropriate numbers or show evidence of exchange of material)
- Aneuploidy (Departure from normal structure/number of chromosomes)
What does aberrant methylation of gene promoters lead to?
Epigenetic inactivation of TSGs
What happens in inactivation of TSGs?
- Gene promoters can become aberrantly methylated in tumours
- Most common = inactivation event
- Promotor methylation seems to be important in inactivation of tumour suppressor genes
- More than 1/2 TSGs involved in familial cancer syndromes are due to gremlin mutations
What are the consequences of mutations to gene/DNA?
- Mutations in oncogenes lead to a gain in function= base pair substitutions, amplification, inversions, translocations
- Mutations found in TSGs lead to a loss in function = base pair substitutions, frameshift, deletions, insertions, chromosomal rearrangement, chromosome loss, promoter methylation
What is metabolic activation?
- Process required for a pro carcinogen to become a full carcinogen
- Procarcinogens require enzymatic/metabolic activation before they react with DNA= aromatic amines
- Direct acting: Interact directly with DNA (O2 radicals, UV light, ionising radiation)
How can Benzopyrene be generated/
- Combustion of most organic materials = meat, fuel, tobacco
- Benzopyrene is a procarcinogen
- Hotspots of DNA damage formed by reaction of BPDE with TP53 gene
What is Benzopyrene broken down into and what is its final product?
1) Benzopyrene
2) Benzopyrene 7,8 epoxide
3) Benzopyrene 7,8 dihydrodiol
4) Benzopyrene 7,8 diol, 9,10 epoxide= ultimate carcinogen
How does carcinogen exposure lead to cancer? (mechanism)
1) Carcinogen exposure
2) Metabolic activation (e.g cytochrome p450)
3) DNA damage (DNA repair) or Detoxification excretion (glutathione S-transferase)
4) DNA replication
5) Mutation (Proto-oncogen or TSG)
6) Progression
7) Cancer
