The two-hit hypothesis of tumor suppressor gene inactivation requires that the second hit in hereditary retinoblastoma most commonly involves which mechanism?

• A Point mutation in the remaining allele
• B Promoter hypermethylation of the inherited allele
• C Amplification of the RB1 wild-type allele
• D Loss of heterozygosity (LOH) at the RB1 locus ✓

Explanation

In hereditary retinoblastoma the first hit is a germline RB1 mutation; the second hit most commonly occurs via loss of heterozygosity — deletion or mitotic recombination at chromosome 13q14 — eliminating the remaining wild-type allele. Point mutations and methylation can also serve as second hits but are less frequent than LOH. Amplification of the wild-type allele would be protective, not tumorigenic.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.