A 32-year-old woman presents to the oncology clinic with a history of bilateral breast cancer diagnosed at ages 28 and 31 years. Her mother had ovarian cancer at age 45, and her maternal grandmother had breast cancer at age 50. Genetic testing reveals a pathogenic mutation in the BRCA1 gene. Which of the following best explains the inheritance pattern and the molecular mechanism of tumor development in this family?

## BRCA1 as a Tumor Suppressor Gene ### Inheritance Pattern **Key Point:** BRCA1 mutations follow **autosomal dominant inheritance** with high penetrance (~70% lifetime risk of breast cancer by age 80). Affected individuals inherit one mutant allele from a heterozygous parent. ### Molecular Mechanism: Two-Hit Hypothesis **High-Yield:** BRCA1 is a classic **gatekeeper tumor suppressor**. Carcinogenesis requires: 1. **First hit (germline):** Inherited mutant BRCA1 allele present in all cells 2. **Second hit (somatic):** Loss of the wild-type allele in a breast/ovarian epithelial cell (loss of heterozygosity, LOH) Once both alleles are inactivated, the cell loses critical DNA repair and checkpoint control, leading to malignancy. ### BRCA1 Function **Clinical Pearl:** BRCA1 is a **DNA repair gene** (homologous recombination repair pathway) and encodes a nuclear protein that: - Detects and repairs double-strand breaks - Regulates G1/S and G2/M cell cycle checkpoints (via p53 interaction) - Maintains chromosomal stability **Mnemonic:** **BRCA = Break Repair & Cell-cycle Arrest** — loss leads to genomic instability and uncontrolled proliferation. ### Clinical Features Consistent with BRCA1 - Early-onset bilateral breast cancer (as in this case) - Ovarian cancer (especially in the same family) - Triple-negative breast cancers (BRCA1-mutant tumors often lack ER, PR, HER2) - Autosomal dominant pedigree with affected males and females [cite:Robbins 10e Ch 7]