A 48-year-old woman has a serum CA-125 of 890 U/mL and a pelvic mass. Pathology shows papillary clusters with psammoma bodies and serous differentiation. The BRCA1 promoter is found methylated on somatic testing. Which statement best describes the molecular consequence of this finding?

• A Gain-of-function mutation activating the PI3K/AKT pathway
• B Loss of MSH2/MLH1 mismatch repair resulting in microsatellite instability
• C Transcriptional silencing of BRCA1 leading to homologous recombination deficiency ✓
• D TP53 missense mutation stabilizing p53 protein in cell nuclei

Explanation

BRCA1 promoter hypermethylation causes epigenetic silencing, eliminating BRCA1 protein and impairing homologous recombination (HR) — the high-fidelity DNA double-strand break repair pathway. This creates 'BRCAness,' rendering tumors sensitive to PARP inhibitors. The consequence is functionally equivalent to germline BRCA1 mutation. MSH2/MLH1 methylation causes microsatellite instability; TP53 missense mutations trap p53 in nuclei; PI3K activation does not result from BRCA1 silencing.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.