In the Knudson 'two-hit hypothesis' for retinoblastoma, which statement correctly differentiates sporadic from hereditary forms in terms of molecular events?

• A Sporadic: first mutation germline, second somatic; Hereditary: both mutations somatic
• B Both forms require three somatic mutations; hereditary form requires only two
• C Sporadic form involves MYCN amplification instead of RB1 mutation
• D Sporadic: both RB1 mutations occur somatically in one retinal cell; Hereditary: first mutation germline, second somatic ✓

Explanation

Knudson's two-hit model: In hereditary (familial) retinoblastoma, the first hit is a germline mutation (present in all cells), and only one additional somatic mutation in any retinal cell is required to lose both functional copies of RB1, explaining bilateral/multifocal presentation. In sporadic retinoblastoma, both hits must occur somatically in the same retinal cell, which is statistically less likely, explaining unilateral/unifocal presentation. A small subset of sporadic unilateral retinoblastoma involves MYCN amplification with wild-type RB1, but this is an exception.

Reference: Khurana Comprehensive Ophthalmology, 7th ed.

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Written and medically reviewed by the StethoPrep medical team.