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?

Question

Accepted Answer

B. BRCA1. ## 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.

Answer

A. BRCA2

Answer

C. PTEN

Answer

D. TP53

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

BRCA1 vs. BRCA2 — Clinical Distinction

BRCA1 Function

Management of BRCA1 Mutation Carriers

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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