The Knudson 'two-hit' hypothesis was originally described for retinoblastoma. In the hereditary form, the first hit is:

• A A somatic mutation in one RB1 allele in the retinoblast
• B Promoter hypermethylation of RB1 in retinal stem cells
• C Loss of heterozygosity at 13q14 in a single retinoblast
• D A germline mutation in one RB1 allele present in every cell ✓

Explanation

In hereditary retinoblastoma, the first hit is a germline (constitutional) mutation in one RB1 allele inherited from an affected parent or arising de novo; this mutation is present in every cell of the body. The tumor arises when a second somatic mutation ('second hit') inactivates the remaining wild-type allele in a retinoblast. This explains bilateral, multifocal disease and earlier onset compared to sporadic cases where both hits must occur somatically in the same cell.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.