A 52-year-old woman with a strong family history of breast and ovarian cancer is found to carry a BRCA1 mutation. Regarding BRCA1 and BRCA2 tumor suppressor genes, all of the following are true EXCEPT:

Question

Accepted Answer

A. BRCA1 mutations are associated with increased risk of triple-negative breast cancer, while BRCA2 mutations typically present as hormone receptor-positive tumors. ## BRCA1 and BRCA2: Homologous Recombination Repair Genes

### Core Function

**Key Point:** BRCA1 and BRCA2 are essential components of the homologous recombination (HR) DNA repair pathway. Germline mutations confer high cancer predisposition.

### Correct Statements Analysis

| Statement | Accuracy | Rationale |
| --- | --- | --- |
| HR repair role | ✓ True | Both proteins essential for RAD51-mediated DSB repair |
| Cancer risk | ✓ True | Breast ~70%, ovarian ~40% lifetime penetrance |
| Chemotherapy sensitivity | ✓ True | Defective HR → platinum sensitivity (BRCAness) |
| Tumor phenotype association | ✗ False | **BRCA1 → TNBC; BRCA2 → ER/PR positive** |

### The Critical Error: Tumor Phenotype Reversal

**High-Yield:** The statement reverses the established phenotype-genotype correlation:

- **BRCA1 mutations** → **Triple-negative breast cancer (TNBC)** — ER/PR/HER2 negative
  - Mechanism: BRCA1 involved in estrogen receptor regulation
  - Typically younger age at onset (mean 41–43 years)
  - More aggressive behavior

- **BRCA2 mutations** → **Hormone receptor-positive (ER/PR+) breast cancer**
  - Often indistinguishable from sporadic breast cancer phenotypically
  - Slightly older age at onset than BRCA1

**Clinical Pearl:** This distinction is crucial for:
- Genetic counseling (BRCA1 carriers: aggressive surveillance, consider risk-reducing surgery earlier)
- Treatment planning (TNBC requires chemotherapy; ER+ may benefit from endocrine therapy)
- Prognosis estimation

### Why the Other Options Are Correct

1. **HR repair function:** Both BRCA1 and BRCA2 interact with RAD51 and facilitate homologous recombination repair of DSBs.
2. **Cancer risk penetrance:** Well-established epidemiological data from SEER and international registries.
3. **Chemotherapy sensitivity:** BRCA-mutated tumors exhibit "BRCAness" — platinum and PARP inhibitor sensitivity due to HR deficiency.

Answer

B. Mutations in BRCA1/BRCA2 increase lifetime risk of breast cancer to approximately 70% and ovarian cancer to 40%

Answer

C. BRCA1/BRCA2-mutated tumors are highly sensitive to platinum-based chemotherapy due to impaired DNA repair

Answer

D. BRCA1 and BRCA2 encode proteins involved in homologous recombination repair of double-strand DNA breaks

A 52-year-old woman with a strong family history of breast and ovarian cancer is found to carry a BRCA1 mutation. Regarding BRCA1 and BRCA2 tumor suppressor genes, all of the following are true EXCEPT:

Explanation

BRCA1 and BRCA2: Homologous Recombination Repair Genes

Core Function

Correct Statements Analysis

The Critical Error: Tumor Phenotype Reversal

Why the Other Options Are Correct

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Statement	Accuracy	Rationale
HR repair role	✓ True	Both proteins essential for RAD51-mediated DSB repair
Cancer risk	✓ True	Breast _{70%, ovarian}40% lifetime penetrance
Chemotherapy sensitivity	✓ True	Defective HR → platinum sensitivity (BRCAness)
Tumor phenotype association	✗ False	BRCA1 → TNBC; BRCA2 → ER/PR positive