A 38-year-old woman presents with a diagnosis of hormone receptor-positive invasive ductal carcinoma of the breast. Her father had pancreatic adenocarcinoma at age 55, and her paternal uncle had breast cancer at age 48. Genetic testing reveals a heterozygous loss-of-function mutation in the locus marked **A** in the diagram. Which of the following best explains the pathogenesis of her cancer phenotype in the context of this germline mutation?

Question

Accepted Answer

D. Knudson two-hit model: somatic loss of the wild-type allele in tumor tissue results in homologous recombination repair deficiency and reliance on error-prone alternative pathways. ## Why option 1 is right

The locus marked **A** (13q12.3) encodes BRCA2, a tumor suppressor essential for homologous recombination repair of DNA double-strand breaks via RAD51 interaction. Germline heterozygous mutations cause hereditary breast and ovarian cancer (HBOC) syndrome. The pathogenesis follows Knudson's two-hit model: the patient inherits one mutant allele (first hit), and somatic loss of the wild-type allele in tumor tissue (second hit) eliminates HR capacity, forcing reliance on error-prone alternative repair pathways (NHEJ, base excision repair) that accumulate mutations and drive malignant transformation. This explains both the autosomal dominant inheritance pattern and the tissue-specific cancer predisposition. The ER-positive phenotype is characteristic of BRCA2-associated breast cancers (in contrast to BRCA1-associated triple-negative tumors), and the family history of pancreatic cancer and male breast cancer are hallmark features of BRCA2 mutations.

## Why each distractor is wrong

- **Option 2 (Haploinsufficiency)**: While one functional allele remains, BRCA2 haploinsufficiency is not the primary mechanism of HBOC pathogenesis. The critical event is somatic loss of the remaining wild-type allele, not insufficient dosage of the single copy. Haploinsufficiency is more typical of dosage-sensitive genes (e.g., TP53 in Li-Fraumeni); BRCA2 acts via the two-hit model.

- **Option 3 (Dominant-negative effect)**: BRCA2 mutations typically result in loss-of-function (truncations, frameshift, splice site mutations), not gain-of-function or dominant-negative effects. The mutant protein is usually non-functional or absent, not actively inhibitory of RAD51 complexes.

- **Option 4 (Mismatch repair deficiency)**: BRCA2 is not a component of the mismatch repair (MMR) system (MLH1, MSH2, MSH6, PMS2). MMR deficiency causes Lynch syndrome and microsatellite instability, not HBOC. BRCA2 deficiency causes homologous recombination deficiency (HRD), not MMR deficiency.

**High-Yield:** BRCA2 mutations → two-hit model → HR deficiency → ER+ breast cancer, pancreatic cancer, male breast cancer. PARP inhibitors exploit synthetic lethality in BRCA-mutated tumors.

[cite: NCCN Genetic/Familial High-Risk Assessment Breast/Ovarian/Pancreatic 2024; Knudson WT. Mutation and cancer: statistical study of retinoblastoma. PNAS 1971.]

Answer

A. Dominant-negative effect: the mutant BRCA2 protein actively interferes with RAD51-mediated DNA repair complex formation

Answer

B. Haploinsufficiency: the single functional allele is insufficient to maintain normal DNA repair capacity throughout the cell cycle

Answer

C. Mismatch repair deficiency: germline BRCA2 mutations impair MLH1-MSH2 heterodimer function, leading to microsatellite instability

Explanation

Why option 1 is right

Why each distractor is wrong

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