A 52-year-old man with a 30-year smoking history presents with a lung mass on chest X-ray. Bronchoscopy shows a central airway lesion suspicious for squamous cell carcinoma. Which investigation is most appropriate to detect KRAS mutations and guide targeted therapy decisions?

Explanation

## Investigation for Oncogene Mutation Detection **Key Point:** NGS is the gold standard for detecting point mutations, insertions, deletions, and copy number variations in oncogenes like KRAS, enabling comprehensive genomic profiling and treatment selection. ### Why NGS is Optimal NGS offers: - Detection of KRAS point mutations (G12C, G12V, G12D most common in lung cancer) - Simultaneous assessment of multiple genes (EGFR, TP53, ALK, ROS1) - High sensitivity and specificity (>95%) - Quantification of allelic frequency - Cost-effective for multi-gene panels - Actionable data for precision oncology (e.g., sotorasib for KRAS G12C) ### Comparison of Investigative Methods | Investigation | Best For | Limitations | |---|---|---| | **NGS** | Point mutations, indels, CNV, multi-gene profiling | Requires adequate tissue; turnaround 1–2 weeks | | **FISH** | Gene amplifications (HER2, ALK, ROS1) | Cannot detect point mutations; limited to 1–2 genes | | **IHC** | Protein expression, surrogate markers | Indirect; p53 IHC does not identify specific mutations | | **Southern blot** | Large deletions, rearrangements | Obsolete; low sensitivity; labor-intensive | **High-Yield:** KRAS mutations occur in ~30% of lung adenocarcinomas and ~5% of squamous cell carcinomas. NGS is now standard-of-care for all advanced NSCLC to identify actionable mutations (EGFR, ALK, ROS1, KRAS G12C, BRAF, MET, NTRK). **Clinical Pearl:** KRAS G12C mutations are now druggable with sotorasib (Lumakras) or adagrasib, making mutation detection therapeutically critical.