The two-hit hypothesis of tumor suppressor gene inactivation was first proposed based on observations in patients with retinoblastoma. In a child with hereditary retinoblastoma, which statement best describes the genetic events?
- A One RB1 allele is lost somatically in all retinal cells; the second hit occurs constitutionally
- B Both RB1 alleles are simultaneously deleted at fertilization, making all retinal cells pre-malignant
- C A germline mutation inactivates one RB1 allele; somatic loss or mutation of the second allele in a retinal cell triggers tumor ✓
- D Epigenetic silencing of both alleles by methylation occurs without any sequence mutation
Correct answer: C. A germline mutation inactivates one RB1 allele; somatic loss or mutation of the second allele in a retinal cell triggers tumor
Explanation
In hereditary retinoblastoma, every somatic cell carries one constitutionally inactivated RB1 allele (first hit, inherited). A single somatic event inactivating the remaining normal allele in any retinal progenitor cell (second hit) leads to tumor formation; thus tumors are often bilateral and multifocal. Sporadic retinoblastoma requires two independent somatic mutations in the same cell — a much rarer event yielding unilateral, unifocal disease.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.