Which tumor suppressor gene, when inactivated, is most commonly associated with hereditary retinoblastoma and follows the two-hit hypothesis?

Explanation

## RB1 Gene and Retinoblastoma **Key Point:** RB1 (retinoblastoma gene) is the classic tumor suppressor gene that demonstrates Knudson's two-hit hypothesis. Inactivation of both alleles is required for tumor development. **High-Yield:** RB1 mutations account for ~90% of hereditary retinoblastoma cases and ~40% of sporadic cases. Bilateral retinoblastoma is pathognomonic for germline RB1 mutation. ### Mechanism of RB1 Inactivation 1. **First hit:** Germline or somatic mutation in one RB1 allele 2. **Second hit:** Loss of the remaining wild-type allele in retinal cells 3. **Result:** Loss of RB protein → uncontrolled cell cycle progression → tumor formation ### RB Protein Function | Function | Effect | | --- | --- | | Binds E2F transcription factors | Prevents S-phase entry | | Phosphorylation by CDK4/6 | Releases E2F → G1/S transition | | Loss of RB protein | Constitutive E2F activity → uncontrolled proliferation | **Clinical Pearl:** Patients with germline RB1 mutations have increased risk of secondary malignancies (osteosarcoma, melanoma, lung cancer) due to inherited predisposition and radiation exposure from retinoblastoma treatment. **Mnemonic:** **RB = Retino Blastoma** — RB1 is the founding tumor suppressor gene for hereditary retinoblastoma.