A 16-month-old boy presents with leukocoria. Examination reveals bilateral retinal masses, and his father was treated for unilateral retinoblastoma in childhood. Molecular analysis confirms a germline RB1 mutation. Loss of the remaining wild-type allele promotes tumour formation primarily because:

• A Free E2F is sequestered in the cytoplasm and can no longer activate S-phase genes
• B Loss of RB1 kinase activity permits uncontrolled phosphorylation of cyclin D
• C Unbound E2F transcription factors are free to activate genes required for the G1 to S transition ✓
• D The mutant protein gains dominant-negative activity that degrades p21

Explanation

In its hypophosphorylated state the RB protein binds E2F and represses transcription of cyclin E and other S-phase entry genes. Loss of both alleles removes this brake, freeing E2F to drive proliferation. Option B inverts the biology: cyclin D and CDK4/6 phosphorylate RB, not the other way round, so RB has no kinase activity of its own. This case illustrates the two-hit hypothesis, since the child inherited the first hit and the second hit occurs somatically.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.