Abstract
BackgroundAppropriate 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.MethodsPatients 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.Results524 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.ConclusionThe 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.
Highlights
Lung cancer is a leading cause of cancer death in both men and women in the United States and throughout the world
The Lung Cancer Mutation Consortium sponsored by NCI is interested in patients with adenocarcinoma [23]
Our study provides the first clear picture of how driver genes in an non-small cell lung cancer (NSCLC) population can vary with tumor histology and smoking status and finds subgroups of patients in whom alterations in these candidate genes are most enriched; these genes may be targeted for individualized therapies
Summary
Lung cancer is a leading cause of cancer death in both men and women in the United States and throughout the world. Several molecular alterations are known to occur in genes that encode signaling proteins critical for cellular proliferation and survival. These genes have been defined as ‘‘driver genes’’. In lung adenocarcinoma, such driver genes include epidermal growth factor receptor (EGFR), KRAS, BRAF, PIK3CA, and EML4ALK. Mutations in these genes are responsible for both the initiation and maintenance of malignancy [2,3]. By understanding the functions of these driver genes, it may be possible to develop specific therapies for malignancies with known driver gene mutations. We aimed to define subgroups of patients with candidate driver genes in patients with nonsmall cell lung cancer
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