Rb

**Function / Pathophysiology** - RB1 is a tumor suppressor gene located on chromosome 13q14. Its product, pRb, is a nuclear phosphoprotein that acts as the "brake" at the G1/S checkpoint. - Hypophosphorylated (active) pRb binds E2F transcription factors, preventing transcription of S-phase genes and halting the cell cycle in G1. - Growth factor signaling → cyclin D/CDK4/6 → phosphorylation of pRb → release of E2F → progression into S phase. CDK inhibitors p16 (INK4a) and p21 block this phosphorylation, keeping pRb active. - Inactivation of pRb occurs by RB1 mutation or deletion. It also occurs through viral oncoproteins, such as HPV E7 and adenovirus E1A, which bind and inactivate pRb. (HPV E6 degrades p53.) - Cyclin D/CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) are used in HR+/HER2– breast cancer. They keep pRb hypophosphorylated, so they need functional RB1 to work.

**Knudson two-hit hypothesis** - Both alleles must be inactivated for tumor development. - Hereditary (~40%): the patient inherits one defective allele (germline, autosomal dominant with high penetrance, about 90%) and a second somatic hit occurs later. Typically presents early, often bilateral or multifocal, and may involve the pineal gland (trilateral retinoblastoma). - Sporadic (~60%): both hits are somatic. Typically unilateral, unifocal, and presents later. - The disease is inherited as a dominant trait but is recessive at the cellular level (loss of heterozygosity).

**Clinical significance** - Retinoblastoma is the most common primary intraocular malignancy of childhood. It presents with leukocoria (absent red reflex, "white pupil"), strabismus, and decreased vision. Histology shows small round blue cells with Flexner-Wintersteiner rosettes. - Hereditary retinoblastoma carries a markedly increased risk of second primary malignancies, especially osteosarcoma (classically in the femur/long bones), as well as soft-tissue sarcomas, melanoma, and pinealoblastoma. Risk is increased further by radiation therapy. - RB1 is also inactivated in small cell lung cancer (nearly universal, along with p53) and in some bladder and breast cancers.

**High-yield associations / mnemonics** - Tumor suppressor "gatekeepers" at the cell cycle: Rb (G1/S) and p53 (G1/S, "guardian of the genome"). Both are inactivated in HPV-related cancers. - Chromosome 13: RB1 at 13q14, BRCA2 at 13q12. - Other "Rb" meanings: **Rubidium** (element), **Rb** in neuroanatomy/anatomy is rarely used; in labs, "RB" may mean red blood cell or reticulocyte count in some contexts, but on USMLE Rb nearly always means retinoblastoma gene/protein.

**Management (brief)** - Treatment is focused on globe salvage and survival: intra-arterial or systemic chemotherapy, focal therapy (laser, cryotherapy), and enucleation for advanced disease. Genetic counseling and screening of siblings and offspring are essential.