88 Molecular basis of breast cancer Flashcards
What % of all cancer is breast cancer?
~ 10%
What proportion of breast cancers is familial?
5-10%
Which 2 main genes defects predispose to breast cancer?
BRCA1 and BRCA2
BRCA1 gene defect, predisposes to which cancers?
Breast and ovarian cancer
What is the BRCA1 gene defect?
- Autosomal dominant
- Increases lifetime risk of breast cancer to 50-80%
- Not completely penetrant
- Increases ovarian risk to 40-50%
- 1863 amino acids
How to test for BRCA1 gene defect?
Sequencing
• Mutations occur throughout gene
• >650 different mutations identified
• Most result in truncated protein
Why do defects in BRCA1 predispose to cancer?
Two-hit hypothesis:
Both copies of tumour suppressor gene disrupted in tumour. Either:
1. May arise in both copies of the gene in the same cell by chance (rare and sporadic)
OR
2. Patient has inherited one defective copy of the gene already. In this situation only need one further mutation to occur by chance and tumour will arise.
Inheritance of the mutation therefore predisposes to disease
What is the role of BRCA1?
In the DNA damage response. Relocalises to the site of damage, therefore acting as a caretaker instead of a gatekeeper
BRCA2 gene defects?
- Increase risk of prostate cancer in males and breast cancer in females
- Is a larger gene so more likely to have variants of unknown significance such as: Missense, intronic and small in frame deletions/insertions
- > 400 mutations reported
- Most result in truncated protein
- Founder effect
What does BRCA2 do?
i dont know
BRCA2 deficient cells are sensitive to…
DNA damaging agents:
• Cells from Tr/Tr mice are more sensitive to DNA damaging agents where damage has to be repaired via DNA DS repair pathway.
What is the process of DNA double strand breaks?
Homology directed repair of DNA double strand breaks:
- Structure unwound to reveal SS section
- Then there is a cofrmation of D-loop structure
- Where damaged DNA becomes intercalated with undamaged DNA of replicated chromosome (during S phase, i.e. doubling)
- Intercalated produces repair template which restores wild type helix
Role of BRCA2 and DNA damage response?
- BRCA2 recruits Rad51 to sites of DNA damage
- BRCA2 promotes nucleation of the Rad51 filament
- BRCA2 stimulates Rad51-mediated strand exchange with D-loop formation
D-loop formation is the initial stage when the damage strand and template are brought together. Key in DNA DS break repairs
What does breast cancer evolve from BRCA1/2 gene defects instead of other sites?
- Tissue specific effects that promote tumourigenesis
- Tissue specific expression of BRCA genes
- Responsiveness to hormones, especially oestrogen
- Bi-allelic loss of BRCA usually detrimental (chromosome instability)
- Must be compensating mutations that allows BRCA-/- cells to grow out and evolve into full blown tumours
Other gene defects linked to breast cancer?
BRCA1 BRCA2 TP53 PTEN ATM CHEK2 BRIP1 PALB2 79 common SNPs
