MoD Neoplasia 3 Flashcards
What causes neoplasia?
Intrinsic host factors (age, sex, hereditary) and extrinsic factors (environmental and behavioural)
What are the 5 leading behavioural risks for neoplasia?
- high BMI
- low fruit + veg intake
- lack of physical activity
- smoking
- alcohol
What are some examples of environmental risks for neoplasia?
- Chemicals eg 2-napthylamine is used in the dye industry and causes bladder cancer. Some chemicals are pro-carcinogens and need to be activated in liver by p450 enzymes.
- Radiation eg ionising, nuclear, electromagnetic
- Infections
Why is the sequence of carcinogen exposure important?
Some carcinogens are initiators and some are promoters. Ames test shows initiators are mutagens and promoters cause prolonged proliferation
(carcinogens that are both initiators and promoters are called complete carcinogens)
What are the ways in which radiation can damage DNA?
Direct DNA damage - altered bases, single/double strand DNA breaks
Indirect damage - free radicals
What are the ways in which infections can be carcinogenic?
Directly- affect genes that control cell growth
Indirectly- cause chronic tissue injury where the regeneration acts as a promoter or causes new mutations from DNA replication errors.
Give some examples of how certain infections cause neoplasia
HPV (strongly linked to cervical cancer) expresses E6 and E7 proteins which inhibit p53 and pRB function, both of which are important for cell proliferation.
HIV lowers immunity allowing other carcinogenic infections to occur
Hep B and C cause chronic liver cell injury and regeneration (with mutations)
What is the 2 hit hypothesis?
Both alleles have to be mutated (explains why retinoblastomas reported in families at a young age, 1st hit is in the germline so only needs a 2nd hit via somatic mutation)
How does the 2 hit hypothesis vary for tumour suppressor genes and proto-oncogenes?
Tumour suppressor genes prevent tumour growth so there needs to be 2 hits to cause neoplasia - 1 for each allele
Oncogenes are an abnormally activated version of proto-oncogenes and favour neoplastic growth. Only one allele needs to be activated
What is the mechanism of action of the RAS proto-oncogene?
Encodes a small g protein that signals into the cell to push the cell past its cell cycle restriction point.
RAS-GTP causes cyclin D to be converted to CDK which phosphorylates the Rb protein allowing entry into the cell cycle.
The RAS oncogene is always active producing a constant signal to pass through the cell cycles restriction point.
How is the restriction point deregulated? (general)
Combination of an activated oncogene and an inactivated tumour suppressor gene
What doe proto-oncogenes encode?
- growth factors eg PDGF
- growth factor receptors eg HER2
- signal transducers eg RAS
- IC kinases eg BRAF
- transcription factors eg MYC
- cell cycle regulators eg CYCLIN D1
- apoptosis regulators eg BCL2
What do tumour supressor genes encode?
Proteins in the same pathways as those encoded by proto-oncogenes but with anti growth effects eg TP53
What is xeroderma pigmentosum?
A rare syndrome (autosomal recessive) due to mutations in DNA repair genes.
There is an inherited mutation of a gene that affects DNA nucleotide excision repair, so causes nucleotide instability
Patients very sensitive to UV and develop skin cancer young
Mutation also found in sporadic malignant neoplasms
What is hereditary non-polyposis colon cancer syndrome (HNPCC)?
Autosomal dominant germline mutation that affects a DNA mismatch repair gene, so causes microsatellite instability
Associated with colon carcinoma
Mutation also found in sporadic malignant neoplasms
