Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Abstract

Background: Non-small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer-related death. Over the past few decades, genomic alterations of cancer driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next-generation sequencing (NGS) assay.

Materials and methods: A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26-89), and 83% cases were adenocarcinoma. NGS-based genomic profiling of major lung cancer-related genes was performed on formalin-fixed paraffin-embedded tumor samples and matched blood.

Results: Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor (EGFR), ALK, ERBB2, MET, BRAF, RET, and ROS1. Twenty-seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty-six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR-mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. In patients <40 years of age, the ALK-positive percentage was up to 28.2%. Moreover, 3.2% of ALK-positive patients harbored multi ALK rearrangements, and seven new partner genes were identified.

Conclusion: More unique features of cancer driver genes in Chinese NSCLC were identified by next-generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC.

Implications for practice: Molecular targeted therapy is now the standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next-generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR-mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK-positive patients harbored multi ALK rearrangement, and seven new partner genes were identified.

Keywords: Molecular genomic profile; Next‐generation sequencing; Non‐small cell lung cancer.

Figure 1.

Distribution of EGFR mutations in Chinese cohort. Profiling of overlapping EGFR alteration types (A) and mutation spectra among Chinese patients with EGFR‐mutant non‐small cell lung carcinoma (B). Co‐occurring of EGFR common and uncommon mutations with other genomic alterations were analyzed (C). *Indicates p < .05; **Indicates p < .01. Abbreviations: EGFR, epidermal growth factor receptor; KDD, kinase domain duplication.

Figure 2.

The incidence of ALK fusion and EGFR mutations in Chinese NSCLC according to different age groups. Red curve represents the frequency of patients with ALK fusion in each age group. Black curve represents the frequency of patients with EGFR mutations in each age group.

Figure 3.

The frequency and distribution of EML4‐ALK fusion subtypes identified in Chinese NSCLC cohort.

Figure 4.

Genomic alterations in 1,200 cases of Chinese non‐small cell lung carcinoma. 37 lung cancer‐related genes and their composition of alteration types, including clinically relevant genomic alterations of the driver genes, are shown by cohort as a whole (NSCLC) as well as by adenocarcinoma cases (LUAD) and squamous carcinoma cases (LUSC). For comparison, corresponding The Cancer Genome Atlas figures are juxtaposed on the right. Abbreviations: LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NSCLC, non‐small cell lung cancer.

Figure 5.

Germline mutations of cancer susceptibility genes identified with a multigene panel among 1,200 Chinese individuals with non‐small cell lung carcinoma. Abbreviations: EGFR, epidermal growth factor receptor; MMR, mismatch repair; NSCLC, non‐small cell lung cancer.