*Molecular Basis of Breast Cancer Flashcards
What proportion of all cancers do breast cancers make up ?
10%
What proportion of breast cancers are familial ?
5-10%
Name the main genetic defects associated with breast cancer.
BRCA1 and BRCA2
Identify the main features of genetic inheritance of BRCA1 mutations.
- Autosomal Dominant
- Increases lifetime risk to 50-80%, which means it’s not full penetrant (some are just carriers, i.e. this mutation is just a predisposition to breast cancer)
Identify any other cancers BRCA1 is associated with.
Also increases ovarian risk to 40-50%
How may we test for BRCA1 gene defect ?
• Sequencing
Where in the BRCA1 gene may defects occur ? What is the result of these defects ?
- Mutations occur throughout gene
- Over 650 different mutations identified
- Most result in truncated protein (which may result in truncation of part of protein which normally binds to RAD51 (which assists in DNA repair) and/or part of the protein which is responsible for transcriptional activation)
Why do inherited defects in BRCA1 predispose to cancer?
♦ Why BRCA1 defects are problematic:
- Tumor Supressor Gene
- Overall, caretaker gene. Upon DNA damage, BRCA1 relocalises to sites of damage. Recognises that there is a DNA DS break, and brings with it some proteins that are able to digest away some of the bases to leave an exposed single strand (then BRCA2 takes over)
♦ Why inheriting a defect is problematic:
Two hit hypothesis: Both copies of tumour suppressor gene disrupted in tumour. May arise in both copies of the gene in the same cell by chance (rare and sporadic) or because 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.
Where in the BRCA2 gene may defects occur ? What is the result of these defects ?
- More than 400 mutations reported
- Large gene- likely to have ‘Variants of unknown significance’- missense, intronic and small in frame deletions or insertions
- Most result in truncated protein (which may result in truncation of part of protein which normally binds to RAD51 (which assists in DNA repair))
Identify any other cancers BRCA2 is associated with.
Increases rick of prostate cancer in males (as well as breast cancer in males)
Define Founder Effect, and explain how it links to genes for breast cancer.
An unusually high frequency of a gene in a particular population derived from a small set of unrepresentative ancestors.
BRCA2 has high frequency in Ashkenazi Jewish community (due to inbreeding)
Why do inherited defects in BRCA2 predispose to cancer?
♦ Why BRCA2 defects are problematic:
- BRCA2 disruption associated with spontaneous chromosomal instability, including aberrations such as chromatid breaks, triradial chromosomes and quadriradial chromosomes
- Overall, (after BRCA1 fulfills its role) BRCA2 binds to RAD51, and recruits it to sites of DNA damage. This then stimulates the start of homology directed repair.
♦ Why inheriting a defect is problematic:
Two hit hypothesis: Both copies of tumour suppressor gene disrupted in tumour. May arise in both copies of the gene in the same cell by chance (rare and sporadic) or because 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.
Describe the process of homology directed repair of DNA double strand breaks by BRCA2.
“Template-directed repair. It works during the most critical point of cell replication—after DNA is copied but before it divides. With the two chromatids still held together by a cohesion complex, HRR takes advantage of having a full copy of DNA present and proximally accessible. This enables HRR to find a large area of homology (usually on a sister chromatid) and use it as a template to reconstruct the damaged DNA strand”
To what extent do BRCA1 and 2 participate in the same pathway ?
They do.
Why is the breast specifically affected by mutations in BRCA1/2 ?
1) Tissue specific effects that promote tumourigenesis.
2) Tissue specific expression of BRCA genes.
3) Responsiveness to hormones, especially oestrogen. Metabolism of oestrogen may result in free radicals to increase DNA damage (can set cells off on path to cancer)
4) Bi-allelic loss of BRCA usually detrimental to DNA repair (chromosome instability). Must be compensating mutations that allows BRCA-/- cells to grow out and evolve into full blown tumours.
