TSG Flashcards
What are the main suppressor genes that play a role in cell growth and death?
p53 and pRB
What happens to a TSG in cancer?
The TSG is inactive allowing uncontrolled proliferation and avoidance of death due to loss of suppression and checkpoints.
If a cancer results from an inherited gene, where in the body will the cancer be present?
In every cell but this is not common as most mutations are somatic
What type of cancer is associated with the loss of RB1?
Retinoblastoma and osteosarcoma
What type of cancer is associated with the loss of p53?
Li-Fraumeni:
Breast, adrenal and most other sarcomas
Where does the cancer develop with the loss of ATM?
T and B cells
Which type of cancer is associated with the loss of BRCA1/2?
Breast, ovarian and prostate
What is a TSG?
Produce proteins to negatively regulate growth and form components of cell cycle checkpoints to ensure genome integrity when under stress.
How many alleles must be lost for a TSG to be inactive?
Both alleles as TSG are recessive in cancer = Knudson’s two hit hypothesis
How are both alleles lost in an inherited manner? How are both alleles lost in a non inherited manner?
Inherited: 1st mutation is germ line + 2nd mutation is somatic = bilateral
Non: Both mutations are somatic and arise in the same cell where the cancer originates = unilateral
What is retinoblastoma?
A cancer of the retina arising due to a mutation in Rb gene. Metastases can develop out of the eye, displace the retina and compress the optic nerve
How does a child present with retinoblastoma?
White light reflection as it reflects off the tumour mass.
Squint
When does a child present with retinoblastoma?
If Bilateral it presents within the first year
If Unilateral it presents later, around 24-30mnths as 2 somatic hits are needed.
What are the characteristics of a retinoblastoma that results from an inhertited mutation?
Multiple bilateral tumours with early onset and the gene progresses through generations. Increases the risk of other cancers over time
What are the characteristics of a retinoblastoma that results from a somatic mutation?
Single, unilateral tumour with late onset.
How can retinoblastoma be treated?
Laser, thermo/chemo/radiotherapy or surgery
What is the familial mutation that contributes to the retinoblastoma?
Large deletion or single base substitution or small length mutations that cause a loss in reading frame.
Most are autosomal dominant = complete penetrance (presents in all with the mutation)
Rare alleles will show incomplete penetrance
What is the cause for the somatic mutation that contributes to retinoblastoma?
Gene deletions, base substitutions, small length mutations.
What happens to the allele at a locus when both are mutated?
Lose heterozygosity of the RB locus as become mutant
What is the function of RB?
Creates a restriction point at G1/S, acting as a transcriptional repressor.
What is G1 phase driven by and what happens in this stage?
Cyclin/Cdk activity drives DNA replication in G1. Once it has passed the G1/s checkpoint the cell is committed to the cell cycle an cannot be moved to G0.
How does pRB repress transcription? What other proteins are involved?
pRB is associated with a complex formed by E2F family of TF, p300 and HDAC to repress transcription
What is p300?
A histone acetylase to prime transcription
What is HDAC?
A histone deacetylase that represses transcription.
What causes pRb to be phosphorylated and what does this result in?
Cyclin D/ccdk4 phosphorylates to activate pRB. It causes dissociation of HDAC from the complex. Whilst pRB is still associated with E2F, only some transcription can occur as E2F is not fully active.