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. 2012;7(6):e40109.
doi: 10.1371/journal.pone.0040109. Epub 2012 Jun 29.

Identification of enriched driver gene alterations in subgroups of non-small cell lung cancer patients based on histology and smoking status

She-Juan An  1 , Zhi-Hong Chen, Jian Su, Xu-Chao Zhang, Wen-Zhao Zhong, Jin-Ji Yang, Qing Zhou, Xue-Ning Yang, Ling Huang, Ji-Lin Guan, Qiang Nie, Hong-Hong Yan, Tony S Mok, Yi-Long Wu
Affiliations

Identification of enriched driver gene alterations in subgroups of non-small cell lung cancer patients based on histology and smoking status

She-Juan An et al. PLoS One. 2012.

Abstract

Background: Appropriate patient selection is needed for targeted therapies that are efficacious only in patients with specific genetic alterations. We aimed to define subgroups of patients with candidate driver genes in patients with non-small cell lung cancer.

Methods: Patients with primary lung cancer who underwent clinical genetic tests at Guangdong General Hospital were enrolled. Driver genes were detected by sequencing, high-resolution melt analysis, qPCR, or multiple PCR and RACE methods.

Results: 524 patients were enrolled in this study, and the differences in driver gene alterations among subgroups were analyzed based on histology and smoking status. In a subgroup of non-smokers with adenocarcinoma, EGFR was the most frequently altered gene, with a mutation rate of 49.8%, followed by EML4-ALK (9.3%), PTEN (9.1%), PIK3CA (5.2%), c-Met (4.8%), KRAS (4.5%), STK11 (2.7%), and BRAF (1.9%). The three most frequently altered genes in a subgroup of smokers with adenocarcinoma were EGFR (22.0%), STK11 (19.0%), and KRAS (12.0%). We only found EGFR (8.0%), c-Met (2.8%), and PIK3CA (2.6%) alterations in the non-smoker with squamous cell carcinoma (SCC) subgroup. PTEN (16.1%), STK11 (8.3%), and PIK3CA (7.2%) were the three most frequently enriched genes in smokers with SCC. DDR2 and FGFR2 only presented in smokers with SCC (4.4% and 2.2%, respectively). Among these four subgroups, the differences in EGFR, KRAS, and PTEN mutations were statistically significant.

Conclusion: The distinct features of driver gene alterations in different subgroups based on histology and smoking status were helpful in defining patients for future clinical trials that target these genes. This study also suggests that we may consider patients with infrequent alterations of driver genes as having rare or orphan diseases that should be managed with special molecularly targeted therapies.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Study design and key procedures.
Figure 2
Figure 2. EGFR mutation rate in TK domain (N = 147).
Exon 20+21, mutations of exon 20 and exon 21 concurrently presented in the same patients; Exon19+21, mutations of exon 19 and exon 21 concurrently presented in the same patients.
Figure 3
Figure 3. Rates of driver gene variations and survival analysis in patients with different histologic type and smoking status.
(a), Survival analysis of subgroups, (b) Rates of driver gene variations of subgroups. NS with AC: patients with adenocarcinoma in non-smokers, S with AC: patients with adenocarcinoma in smokers, NS with SCC: patients with squamous cell carcinoma in non-smokers, S with SCC: patients with squamous cell carcinoma in smokers.
Figure 4
Figure 4. Survival analysis of driver genes.
(a), Survival analysis of all of the EGFR detected patients; (b), Survival analysis of the stage I patients. NR: not reached.
See this image and copyright information in PMC

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