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

Question

Accepted Answer

A. RB1. ## 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.

Answer

B. TP53

Answer

C. BRCA1

Answer

D. APC

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

Explanation

RB1 Gene and Retinoblastoma

Mechanism of RB1 Inactivation

RB Protein Function

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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