Liquid biopsy from a patient with colorectal cancer detects a KRAS G12C mutation in circulating tumour DNA (ctDNA). Which of the following correctly describes the biochemical basis of why KRAS G12C mutations confer oncogenic activity?
- A Glycine-to-cysteine substitution impairs GTPase activity, trapping KRAS in the GTP-bound active state ✓
- B Glycine-to-cysteine substitution enhances GEF-mediated nucleotide exchange, accelerating RAS cycling
- C Glycine-to-cysteine substitution prevents KRAS farnesylation and membrane anchoring
- D Glycine-to-cysteine substitution activates intrinsic phospholipase activity of KRAS
Explanation
KRAS codon 12 mutations substitute glycine (which is uniquely small enough to permit GAP-mediated GTP hydrolysis) with larger amino acids including cysteine. The bulkier cysteine residue sterically occludes the GAP-arginine finger from accessing the catalytic site, severely impairing intrinsic and GAP-stimulated GTPase activity. KRAS remains bound to GTP in the constitutively active state, providing continuous proliferative signalling via RAF-MEK-ERK and PI3K-AKT pathways. GEF activity is not the rate-limiting step affected, and farnesylation and phospholipase activity are not directly impacted by this substitution.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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