A 48-year-old Indian woman is found to have a BRCA1 mutation on genetic testing after presenting with invasive ductal carcinoma of the breast. Immunohistochemistry shows loss of BRCA1 protein expression in the tumour cells. Which of the following best explains why loss of BRCA1 function predisposes to malignant transformation?

Explanation

## BRCA1 Loss and Breast Cancer Predisposition ### BRCA1 Function and Classification **Key Point:** BRCA1 is a **tumour suppressor gene**, not an oncogene. Its primary role is in homologous recombination (HR) DNA repair, particularly in response to double-strand breaks (DSBs). ### Molecular Role of BRCA1 1. **DNA Repair Protein** - Part of the BRCA1-PALB2-BRCA2 complex - Facilitates homologous recombination repair of DSBs - Essential for maintaining genomic stability 2. **Cell Cycle Checkpoint Control** - Interacts with p53 and CHK2 - Activates G1/S and G2/M checkpoints in response to DNA damage - Triggers apoptosis if damage cannot be repaired 3. **Transcriptional Regulation** - Modulates expression of genes involved in DNA repair and apoptosis ### Consequences of BRCA1 Loss ```mermaid flowchart TD A[BRCA1 Mutation/Loss]:::outcome --> B[Defective Homologous Recombination]:::outcome B --> C[Accumulation of Unrepaired DSBs]:::outcome C --> D[Genomic Instability]:::outcome D --> E[Mutations in p53, PTEN, other TSGs]:::outcome E --> F[Malignant Transformation]:::urgent A --> G[Loss of Checkpoint Control]:::outcome G --> F ``` ### High-Yield Features of BRCA1-Associated Breast Cancer | Feature | Characteristic | |---------|----------------| | Age of onset | Earlier (often <50 years) | | Tumour type | Often triple-negative (ER−, PR−, HER2−) | | Histology | Invasive ductal carcinoma, high grade | | Genomic signature | High mutational burden, HRD (homologous recombination deficiency) | | Contralateral risk | ~50% lifetime risk of second breast cancer | | Ovarian cancer risk | ~40% lifetime risk | **High-Yield:** BRCA1-mutant tumours show **homologous recombination deficiency (HRD)**, making them sensitive to: - PARP inhibitors (olaparib, rucaparib) - Platinum-based chemotherapy ### Why Loss Leads to Cancer 1. **Two-hit model:** BRCA1 mutations are inherited; somatic loss of the wild-type allele in breast epithelium creates a null state 2. **Mutator phenotype:** Without functional HR, cells accumulate mutations at a high rate 3. **Secondary hits:** These mutations often inactivate p53, activate KRAS, or dysregulate other oncogenes 4. **Checkpoint failure:** Loss of BRCA1-mediated G1/S and G2/M arrest allows cells with DNA damage to progress through the cell cycle **Clinical Pearl:** BRCA1-associated cancers are often diagnosed at a younger age and with higher grade because the genomic instability accelerates accumulation of oncogenic mutations. [cite:Robbins 10e Ch 7]