A 58-year-old woman with ovarian cancer undergoes testing to guide PARP inhibitor eligibility. The tumor shows homologous recombination deficiency (HRD). Which molecular alteration is MOST directly responsible for this phenotype when inherited in the germline?

• A MSH2 mutation causing defective mismatch repair
• B APC mutation disrupting Wnt/β-catenin signaling
• C BRCA1 or BRCA2 mutation causing impaired template-directed DNA repair ✓
• D PTEN loss causing hyperactivated PI3K-AKT pathway

Explanation

BRCA1/2 proteins are essential components of homologous recombination (HR); germline mutations create HRD, which is the biomarker predicting sensitivity to PARP inhibitors because PARP inhibition in HR-deficient cells leads to synthetic lethality. MSH2 mutations cause microsatellite instability (Lynch syndrome) rather than HRD. APC and PTEN mutations do not affect the HR pathway.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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