Question 1

What does BRCA1 do in DNA repair?

Accepted Answer

BRCA1 is essential for homologous recombination (HR), the high-fidelity pathway for repairing DNA double-strand breaks. It nucleates a repair complex including PALB2, BRCA2, and RAD51 at damage sites, using the intact sister chromatid as a template for accurate reconstruction of the broken sequence.

Question 2

Does a BRCA1 mutation mean you will get cancer?

Accepted Answer

A BRCA1 mutation significantly raises cancer risk but does not guarantee it. Carriers face approximately 50–70% lifetime breast cancer risk and 40–45% ovarian cancer risk, compared to 12% and 1.2% respectively in the general population — a meaningful difference but not a certainty.

Question 3

How do PARP inhibitors exploit BRCA1 mutations?

Accepted Answer

PARP inhibitors (olaparib, niraparib) exploit synthetic lethality: BRCA1-deficient cells are already unable to perform homologous recombination, and PARP inhibition blocks the backup single-strand break repair pathway. Tumour cells accumulate lethal DNA damage they cannot repair, while normal cells with intact HR survive.

Question 4

What is the difference between BRCA1 and BRCA2?

Accepted Answer

Both proteins function in homologous recombination, but BRCA1 primarily coordinates damage signalling and early repair steps, while BRCA2 directly loads the RAD51 recombinase onto single-stranded DNA at the break site. Clinically, BRCA1 mutations carry higher ovarian cancer risk than BRCA2.

Question 5

What is homologous recombination deficiency (HRD) and how is it used clinically?

Accepted Answer

HRD describes the inability of tumour cells to repair DNA double-strand breaks by homologous recombination. While BRCA1/2 mutations are the best-known cause, HRD also arises from mutations in PALB2, RAD51C, RAD51D, BRIP1, and other HR genes. Genomic HRD assays (Myriad myChoice CDx, FoundationOne CDx) measure three genomic scar signatures: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). These scars accumulate because HRD-deficient cells cannot repair DSBs faithfully. HRD-positive status — defined as a composite genomic instability score above a threshold — predicts PARP inhibitor benefit even in patients without detectable BRCA1/2 mutations, expanding eligibility for olaparib and niraparib in ovarian cancer.

Question 6

What is BRCA1 Signature 3 and why does it matter?

Accepted Answer

Mutational Signature 3 (COSMIC classification) is characterised by a specific pattern of substitutions and indels — predominantly C>T transitions and a high proportion of large deletions — that accumulates in cells deficient in homologous recombination. It is generated when HR-deficient cells resort to error-prone repair pathways (NHEJ, MMEJ) for DSBs. Signature 3 is detectable in tumours with BRCA1 or BRCA2 mutations, but also in HRD tumours caused by other HR gene alterations, and can be present even when the causative BRCA mutation is undetected by sequencing (e.g., due to epigenetic silencing of BRCA1). Clinically, Signature 3 status is increasingly used as a surrogate biomarker for platinum and PARP inhibitor sensitivity.

Question 7

How does PARP inhibitor resistance develop in BRCA1-mutant cancer, and what are the options afterwards?

Accepted Answer

PARP inhibitor resistance in BRCA1-mutant tumours primarily arises through HR restoration: BRCA1 reversion mutations (~25–30% of cases) create intragenic deletions or substitutions that restore the BRCA1 reading frame and partial HR function; loss of 53BP1 or Shieldin complex components shifts DSB repair back toward HR-like pathways without restoring BRCA1; PARP1 mutations reduce PARP trapping. After PARP inhibitor failure, options include: platinum-based chemotherapy (exploits the same HRD but through a different mechanism, showing activity in ~40% of BRCA1-mutant PARP inhibitor-resistant cases), CDK12 inhibitors (being investigated), and clinical trials targeting specific resistance mechanisms detected in liquid biopsy.

BRCA1 Gene Function

Overview

More Tumor Suppressor Genes