A 35-year-old woman from Mumbai presents with bilateral breast cancer diagnosed at age 28 and 32 years. Her mother died of ovarian cancer at age 45. Genetic testing reveals a germline mutation in a tumor suppressor gene. Which gene is most commonly mutated in this hereditary cancer syndrome?

Explanation

## BRCA1 in Hereditary Breast and Ovarian Cancer Syndrome ### Clinical Presentation — HBOC Syndrome **Key Point:** The combination of **early-onset bilateral breast cancer** + **family history of ovarian cancer** is pathognomonic for BRCA1/BRCA2 mutations. BRCA1 accounts for ~50% of hereditary breast-ovarian cancer (HBOC) cases. **High-Yield:** BRCA1 mutation carriers have: - Breast cancer risk: 70–80% by age 70 - Ovarian cancer risk: 40–50% by age 70 - Younger age of onset (typically <50 years) - Higher risk of triple-negative breast cancer ### BRCA1 vs. BRCA2 — Clinical Distinction | Feature | BRCA1 | BRCA2 | | --- | --- | --- | | **Chromosome** | 17q21 | 13q13 | | **Breast cancer risk** | 70–80% | 60–70% | | **Ovarian cancer risk** | 40–50% | 10–20% | | **Age of onset** | Younger (30s–40s) | Slightly older (40s–50s) | | **Triple-negative BC** | Yes (higher) | No | | **Male breast cancer** | Rare (~5%) | More common (~7%) | | **Pancreatic cancer** | Moderate | Higher | | **Prostate cancer** | Moderate | Higher | **Clinical Pearl:** The strong family history of ovarian cancer (mother at age 45) and early bilateral breast cancer in the proband (age 28 and 32) strongly suggests **BRCA1** rather than BRCA2, as BRCA1 confers higher ovarian cancer risk. ### BRCA1 Function **Mnemonic:** **"BRCA1 = Breast Cancer susceptibility 1, Repair Agent"** — encodes a protein critical for homologous recombination DNA repair. 1. DNA double-strand break recognition 2. RAD51 recruitment 3. Homologous recombination repair 4. Cell cycle checkpoint control **Warning:** Do not confuse BRCA1/BRCA2 with TP53 (Li-Fraumeni syndrome). While both predispose to breast cancer, TP53 also causes sarcomas, brain tumors, and adrenocortical carcinoma; the family history here is specific to breast and ovarian cancer. ### Management of BRCA1 Mutation Carriers ```mermaid flowchart TD A[BRCA1 mutation confirmed]:::outcome --> B{Risk reduction strategy?}:::decision B -->|Surveillance| C[Mammography + MRI screening]:::action B -->|Prevention| D[Risk-reducing mastectomy/oophorectomy]:::action B -->|Therapy| E[PARP inhibitors for BC/OC]:::action C --> F[Early detection, improved outcomes]:::outcome D --> G[Significantly reduced cancer risk]:::outcome E --> H[Enhanced treatment response]:::outcome ``` **High-Yield:** PARP inhibitors (olaparib, rucaparib) are FDA-approved for BRCA1/BRCA2-mutant breast and ovarian cancers because these tumors are deficient in homologous recombination repair.