Cancer 3 Flashcards
(31 cards)
What is a tumour suppressor gene (TSG)?
A gene that prevents cells from progressing to a cancerous state by regulating cell division, DNA repair, or apoptosis.
How do tumour suppressor genes become inactivated in cancer?
Through mutation or loss of both gene copies
What is the key genetic difference between oncogenes and TSGs?
Oncogenes need one activating mutation; TSGs require two inactivating events (loss of both alleles).
How does inheriting one defective TSG allele affect cancer risk?
It increases the risk by accelerating the loss of the second allele, raising the chance of cancer development.
What is a somatic point mutation’s effect on TSGs?
It can cause frameshifts or premature stop codons, leading to non-functional or degraded proteins.
How do structural chromosomal variants contribute to TSG loss?
They may delete entire genes or crucial exons, inactivating gene function.
What is loss of heterozygosity (LoH)?
The loss of the remaining functional allele, resulting in homozygosity for the mutant allele.
How does LoH occur most commonly?
mis-segregation during mitotic recombination (crossing over between homologous chromosomes)
- leads to loss of heterozygosity
what are two of the most important genes in cancer?
Retinoblastoma (Rb)
p53
What are the two forms of retinoblastoma?
Familial (hereditary) and sporadic (non-hereditary)
what does retinoblastoma cause?
a tumour of the eye
What is the inheritance pattern of familial retinoblastoma?
Autosomal dominant inheritance; ~50% of children inherit the mutant allele.
How does tumour development differ in familial vs sporadic Rb?
Familial: bilateral tumours (normally tumours are single cell origin), early onset. Sporadic: unilateral, requires two somatic mutations, majority of cases
What is the key role of Rb protein?
controls progression of the cell cycle into the cell-autonomous program from extracellular signals
what does the bilateral effect of retinoblastoma say about familial retinoblastoma?
that the inherited problem:
- Increases likelihood of disease
- accelerates the disease
- Affects ALL cells of the eyes, so no single cell origin
why does sporadic retinoblastoma take longer than familial to develop?
because the eye cells in familial retinoblastoma all already contain a heterozygous copy of the mutation, and less time is required to develop the second because the eye cells are more susceptible to acquiring the second mutation (for an unknown reason)
How do mitogens affect the Rb pathway?
They stimulate cyclin D-CDK4/6 production, which phosphorylates and inactivates Rb, which releases E2Fs trancription factors which transcribe cyclin E and CDK2, which then phosphorylise Rb to completion and E2Fs cause cell cycle to progress
where are E2Fs in a normal cell?
held by Rb proteins to prevent them going free
Why is the restriction point significant?
Once passed, cell division proceeds autonomously, independent of external signals.
What happens if both Rb alleles are lost?
E2F is unregulated, leading to uncontrolled cell proliferation.
what is the most commonly mutated gene in cancer?
p53
What is the function of p53 in normal cells?
It halts the cell cycle to allow DNA repair or triggers apoptosis if damage is irreparable.
describe normal p53 binding to DNA
binds to specific sites of DNA ~450 different sites) and induces transcription of other regulatory proteins which cause sustained cell cycle arrest
How is p53 activated in response to DNA damage?
damaged DNA stimulates ATM to stabilise p53 and prevent its degradation (by phosphorylation)
- then p53 can bind genomic motifs, causing transcription of p21, which inhibits CDK2 and causes and sustained G1 and G2 arrest, which stops cell dividing so DNA can be repaired
