Abstract
Non-small cell lung cancer (NSCLC) is featured with complex genomic alterations. Molecular profiling of large cohort of NSCLC patients is thus a prerequisite for precision medicine. We first validated the detection performance of a next-generation sequencing (NGS) cancer hotspot panel, OncoAim, on formalin-fixed paraffin-embedded (FFPE) samples. We then utilized OncoAim to delineate the genomic aberrations in Chinese NSCLC patients. Overall detection performance was powerful for mutations with allele frequency (MAF) ≥ 5% at >500 × coverage depth, with >99% sensitivity, high specificity (positive predictive value > 99%), 94% accuracy and 96% repeatability. Profiling 422 NSCLC FFPE samples revealed that patient characteristics, including gender, age, lymphatic spread, histologic grade and histologic subtype were significantly associated with the mutation incidence of EGFR and TP53. Moreover, RTK signaling pathway activation was enriched in adenocarcinoma, while PI(3)K pathway activation, oxidative stress pathway activation, and TP53 pathway inhibition were more prevalent in squamous cell carcinoma. Additionally, novel co-existence (e.g., variants in BRAF and PTEN) and mutual-exclusiveness (e.g., alterations in EGFR and NFE2L2) were found. Finally, we revealed distinct mutation spectrum in TP53, as well as a previously undervalued PTEN aberration. Our findings could aid in improving diagnosis, prognosis and personalized therapeutic decisions of Chinese NSCLC patients.
Highlights
Non-small cell lung cancer (NSCLC) is featured with complex genomic alterations
We evaluated the detection performance of OncoAim on single nucleotide variants (SNVs) and short insertions and deletions (INDELs) in formalin-fixed paraffin-embedded (FFPE) specimens using Ion Torrent PGM (Personal Genome Machine) platform
For SNVs detection performance, we used 4 individual reference standards (i.e., HD200, HD300, HD301, and HD802) and 4 mixed reference standards (i.e., HD300-HD706, HD802-HD260, HD301-HD706, and HD200-HD706). These references together possessed 54 known SNVs with mutations with allele frequency (MAF) ranging from 1% to 70.0% (Table S3a)
Summary
Non-small cell lung cancer (NSCLC) is featured with complex genomic alterations. We first validated the detection performance of a next-generation sequencing (NGS) cancer hotspot panel, OncoAim, on formalin-fixed paraffin-embedded (FFPE) samples. We utilized OncoAim to delineate the genomic aberrations in Chinese NSCLC patients. Profiling 422 NSCLC FFPE samples revealed that patient characteristics, including gender, age, lymphatic spread, histologic grade and histologic subtype were significantly associated with the mutation incidence of EGFR and TP53. The advent of next-generation sequencing (NGS) has broadened the landscape of genetic aberrations[5,6,7], making it possible to implement targeted treatment tailored for specific mutations in individual patients[1,8,9]. Lung cancer is characterized with complex genomic aberrations[10]. The mutational frequency of EGFR can vary from 10% in Western populations to 30% in Asians, and KRAS mutation incidence in Western populations is approximately 18-26% versus 3.8-8% in Asians[12], and within
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