Which of the following molecular alterations in cancer represents a gain-of-function mutation that constitutively activates a downstream signaling cascade without receptor engagement?
- A KRAS point mutation at codon 12 locking RAS in GTP-bound form ✓
- B Deletion of PTEN leading to unopposed PI3K signaling
- C Loss of RB1 releasing E2F transcription factors
- D TP53 missense mutation acting as dominant negative
Correct answer: A. KRAS point mutation at codon 12 locking RAS in GTP-bound form
Explanation
KRAS point mutations at codon 12 (or 13) substitute glycine and prevent GTPase activity, locking RAS in the active GTP-bound state and constitutively activating downstream MAPK and PI3K pathways without receptor engagement. PTEN deletion is a loss-of-function. RB1 loss releases E2F but this is a tumor suppressor mechanism. TP53 missense mutations are gain-of-function but act by different mechanisms.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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