Mechanisms of oncogenesis Flashcards
What is the relationship between cancers and age?
- The older you get, the higher the risk of developing cancer
- Prostate cancer mortality early doubles every 5 years after 70
What happens with migrants and cancer risk?
- Incidence of colorecal cancer varies dramatically
- Migrants will start to have the rate of cancer similar to the new population, after just a couple of generations
- Shows that a huge risk factor is our lifestyle/ environment
Give some examples of carcinogens
- Chemical - coal tar, cigarette smoke, aflatoxin (fungi)
- Physical - UV, asbestos (fine particle size)
- Viral - Hep B, EBV
- Heritable - predisposition
How do we activate procarcinogens?
- Require conversion by enzymes present in the ER in cells - may be performed in Ames test
- eg Benzo(a)pyrene in cigarette smoke is converted to a diol epoxide by mixed function oxidases.
What are direct acting carcinogens?
- Reactive electrophiles
- Ready to be carcinogenic
What is the ames test?
- Uses salmonella strain that has a mutation making it unable to synthesise histidine - however need histidine to grow
- if added substance causes lots of growth, then it has mutagenic carcinogen in it, as it has reverted the strain to His+
- If there is no/little growth, then it isnt
What is the role of a tumour promote/ initiator?
- Multiple initiators will lead to development of cancer
- However a single initiator will not - requires promoters after it to stimulate the growth
- Promoters and then initiator will not work however
- Initiators carry out some of the stemps, then promoters increase the numbers of the partially mutated cells
What are phorbol esters?
- Best known examples of tumour promoters - analogues of DAG -> PKC
What sort of radiation gives the highest annual dose?
- Ionising radiation is the highest risk, but Natural background radiation gives largest dose
- Areas with lots of granite have highest level of radiation
What are the mechanisms of Ionising/ UV radiation and DNA damage?
Ionising
- Damages the DNA and causes it to break
- If it fails to repair then it causes translocations and so differential expression
UV
- UV radiation damages the DNA by adding pyrimidine dimers from T or C bases
- These dimers cause mutations
Give some examples of syndromes that predispose to cancer
DNA repair defects
- Ataxia telangiectasia
- Fanconi’s anaemia
- Xeroderma pigmentosum
- Bloom’s syndrome
Chromosomal abnormalities
- Downs
- Klinefelters - males have increased risk of breast cancer
What viruses are associated with cancer in humans?
DNA viruses
- EBV - Burkitt’s lymphoma, nasopharyngeal carcinoma
- HPV - cervical carcinoma, warts
- Hep B - hepatoma
- RNA retroviruses = HTLV-1 - adult T-cell luekaemia lymphoma
What properties are required for a tumourigenic virus?
- Stable association with cells- chromosomal integration or episome formation
- Must not kill the cell - needs to replicate DNA, suppresses lytic cycle and then releases by budding
- Must evade the immune surveillance - immune suppression, viral ags not expressed at cell surface
What is Knudson’s hypothesis for hereditary cancers?
- 2 hits is required for development of sporadic cancer
- In hereditary cancers, the first event is provided in the germline, so only need 1 hit to lose heterozygosity and cause cancer
What are the 6 cytogenetic mechanisms for allelic loss?
- point mutation
- non-disjunction
- nondisjunction and duplication
- mitotic recombination
- Deletion
- Gene conversion
