A 38-year-old Indian woman presents with a palpable mass in her right breast discovered during self-examination. She reports no pain or discharge. On examination, the mass is firm, irregular, and fixed to the chest wall. Mammography reveals a 2.5 cm lesion with microcalcifications. Her mother died of breast cancer at age 42, and her maternal aunt had ovarian cancer at age 50. Genetic testing reveals a pathogenic mutation in the BRCA1 gene. Which of the following best explains the increased cancer susceptibility in this family?

Explanation

## BRCA1 as a Tumor Suppressor Gene ### Mechanism of BRCA1 Loss **Key Point:** BRCA1 is a classic tumor suppressor gene that follows the **two-hit hypothesis** (Knudson model). Individuals with a germline BRCA1 mutation inherit one defective copy; cancer develops when the second allele is somatically lost in a cell. **High-Yield:** Loss of BOTH alleles of BRCA1 eliminates homologous recombination (HR) repair capacity, leading to: - Accumulation of double-strand breaks (DSBs) - Genomic instability - Increased mutation rate and malignant transformation - Predisposition to breast, ovarian, and pancreatic cancers ### Two-Hit Hypothesis in This Case 1. **First hit (germline):** Inherited BRCA1 mutation from mother 2. **Second hit (somatic):** Loss of the wild-type allele in breast epithelial cells → complete loss of HR repair → uncontrolled proliferation and cancer ### Why BRCA1 Matters | Feature | BRCA1 Function | |---------|----------------| | Normal role | DNA double-strand break repair (homologous recombination) | | Loss of both alleles | Defective DSB repair → genomic instability | | Inheritance pattern | Autosomal dominant with incomplete penetrance | | Cancer types | Breast (early onset), ovarian, pancreatic, prostate | **Clinical Pearl:** Heterozygous carriers (one mutant allele) have ~70% lifetime risk of breast cancer by age 80, reflecting the high probability that the second allele will be lost somatically in at least one cell lineage. **Mnemonic: BRCA = **B**reast cancer **R**epair **C**apacity **A**bnormality** — loss of both copies abolishes DNA repair.