A child develops bilateral retinoblastoma by age 18 months. His mother was treated for unilateral retinoblastoma in childhood. Analysis of the child's tumor shows loss of the wild-type allele at 13q14. According to the two-hit hypothesis, the first hit in hereditary retinoblastoma consists of:

• A Somatic deletion of one RB1 allele occurring in every retinal cell
• B Two independent somatic point mutations inactivating both alleles within a single retinal cell
• C Germline mutation of one RB1 allele inherited from an affected parent, followed by somatic loss of the remaining allele in a retinal cell ✓
• D Amplification of MYCN driving uncontrolled proliferation despite intact RB1

Explanation

RB1 is a classic tumor suppressor gene following Knudson's two-hit model. In hereditary retinoblastoma, the first hit is a germline mutation in one RB1 allele present in every cell, inherited from an affected parent; the second hit is usually somatic deletion or mutation of the remaining wild-type allele in a single retinal cell. Because only one additional event is needed, tumors are bilateral and arise early. Two independent somatic hits in the same cell describe the rare sporadic form, which is unilateral and later onset.

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.