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?

Question

Accepted Answer

B. Next-generation sequencing (NGS) of tumor tissue. ## 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.

Answer

A. Fluorescence in situ hybridization (FISH)

Answer

C. Southern blot analysis

Answer

D. Immunohistochemistry (IHC) for p53

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

Why NGS is Optimal

Comparison of Investigative Methods

Practice similar questions

Join our NEET PG community

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