A 68-year-old heavy smoker man is found to have a peripheral lung adenocarcinoma. Molecular profiling shows a KRAS mutation. Which codon is most commonly mutated in KRAS-mutant lung adenocarcinoma, and what is the clinical significance?

• A Codon 61; associated with never-smokers and good prognosis
• B Codon 12; associated with smoking history and resistance to EGFR TKIs ✓
• C Codon 13; associated with ALK rearrangement
• D Codon 146; associated with BRAF V600E co-mutation

Explanation

KRAS mutations in lung adenocarcinoma occur predominantly at codon 12 (most common), followed by codon 13. They are strongly associated with smoking history and are mutually exclusive with EGFR mutations. KRAS-mutant tumors do not respond to EGFR TKIs. Codon 61 and 146 are less common sites. KRAS and ALK rearrangements are generally mutually exclusive oncogenic drivers.

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

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