A child with bilateral retinoblastoma has a germline RB1 mutation inherited from his father, who had unilateral retinoblastoma treated in infancy. Tumor development in the child required loss of the remaining normal RB1 allele in retinal cells. The requirement for loss of both alleles reflects:

• A Recessive behavior of tumor suppressor genes at the cellular level, so both alleles must be inactivated ✓
• B Dominant-negative action of the mutant protein blocking the tetrameric complex
• C Gain-of-function activity of the truncated RB1 protein promoting cell cycle entry
• D Genomic imprinting requiring mutation of the maternally derived allele specifically

Explanation

Tumor suppressor genes act recessively at the cellular level: one functional allele suffices, so tumorigenesis requires inactivation of both alleles, the two-hit hypothesis proposed by Knudson. Germline inheritance of the first hit makes a second somatic hit likely in multiple retinal cells, hence bilateral, multifocal and early-onset tumors. Dominant-negative mechanisms characterize some oncogene-related proteins such as fibrillin interactions, and RB1 shows no parent-of-origin imprinting effect.

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.