Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers

Abstract

Purpose: We previously showed that 90% (47 of 52; 95% CI, 0.79 to 0.96) of lung adenocarcinomas from East Asian never-smokers harbored well-known oncogenic mutations in just four genes: EGFR, HER2, ALK, and KRAS. Here, we sought to extend these findings to more samples and identify driver alterations in tumors negative for these mutations.

Experimental design: We have collected and analyzed 202 resected lung adenocarcinomas from never smokers seen at Fudan University Shanghai Cancer Center. Since mutations were mutually exclusive in the first 52 examined, we determined the status of EGFR, KRAS, HER2, ALK, and BRAF in stepwise fashion as previously described. Samples negative for mutations in these 5 genes were subsequently examined for known ROS1 fusions by RT-PCR and direct sequencing.

Results: 152 tumors (75.3%) harbored EGFR mutations, 12 (6%) had HER2 mutations, 10 (5%) had ALK fusions all involving EML4 as the 5' partner, 4 (2%) had KRAS mutations, and 2 (1%) harbored ROS1 fusions. No BRAF mutation were detected.

Conclusion: The vast majority (176 of 202; 87.1%, 95% CI: 0.82 to 0.91) of lung adenocarcinomas from never smokers harbor mutant kinases sensitive to available TKIs. Interestingly, patients with EGFR mutant patients tend to be older than those without EGFR mutations (58.3 Vs 54.3, P = 0.016) and patient without any known oncogenic driver tend to be diagnosed at a younger age (52.3 Vs 57.9, P = 0.013). Collectively, these data indicate that the majority of never smokers with lung adenocarcinoma could benefit from treatment with a specific tyrosine kinase inhibitor.

Figure 1. Spectrum of oncogenic driver mutations in lung adenocarcinomas from never smokers.

From 202 tumors, 75.3% (152/202) harbored EGFR kinase domain mutations, 5.9% (12/202) HER2 mutations, 5.0% (10/202) ALK fusions, and 2% (4/202) KRAS mutations, 1% (2/202) of tumors harbor ROS1 fusion. There are 10.9% (22/202) with unknown oncogenic driver mutations.

Figure 2. Detection of CD74-ROS1 fusions in lung adenocarcinomas from never smokers.

(A) Agarose gel electrophoresis analysis of RT-PCR products for CD74-ROS1 fusions. E32, CD74-ROS1 exon 32 fusion; E34, CD74-ROS1 exon 34 fusion. (B) Sequencing of RT-PCR product from a tumor (No.72) identified a fusion of CD74 exon 6 to ROS1 exon 34. (C) Sequencing of RT-PCR product from a tumor (No.136) identified a fusion of CD74 exon 6 to both ROS1 exon 32 and exon 34.

Figure 3. Detection of ROS1 mRNA levels in lung adenocarcinomas from never smokers either with indicated oncogenic driver mutations or negative for all known oncogenic driver mutations.