Genomic Characterization of Concurrent Alterations in Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Mutations

SIMPLE SUMMARY: Genomic driver alterations with potential impact on prognosis and treatment response are increasing in non-small cell lung cancer (NSCLC). However, few comprehensive data are available on tumor heterogeneity in all these specific subgroups. We conducted this research with the aim to describe specific molecular co-mutation patterns occurring across the main actionable gene subgroups of NSCLC. The findings from the current research are proposed as a backbone in the knowledge of molecular heterogeneity as analyzed by comprehensive genomic profiling in NSCLCs with driver gene alterations, at the basis of subsequent evaluations related to clinical outcomes. ABSTRACT: An increasing number of driver genomic alterations with potential targeted treatments have been identified in non-small cell lung cancer (NSCLC). Much less is known about the incidence and different distribution of concurrent alterations, as identified by comprehensive genomic profiling in oncogene-addicted NSCLCs. Genomic data from advanced NSCLC consecutively analyzed using a broad next-generation sequencing panel were retrospectively collected. Tumors harboring at least one main actionable gene alteration were categorized according to the presence/absence of concurrent genomic aberrations, to evaluate different patterns among the main oncogene-addicted NSCLCs. Three-hundred-nine actionable gene alterations were identified in 284 advanced NSCLC patients during the study period. Twenty-five tumor samples (8%) displayed concurrent alterations in actionable genes. Co-occurrences involving any pathogenic variant or copy number variation (CNV) were identified in 82.8% of cases. Overall, statistically significant differences in the number of concurrent alterations, and the distribution of TP53, STK11, cyclines and receptor tyrosin kinase (RTK) aberrations were observed across the eight actionable gene groups. NGS analyses of oncogene-addicted NSCLCs showed a different distribution and pattern of co-alteration profiles. Further investigations are needed to evaluate the prognostic and treatment-related impact of these concurrent alterations, hooked to the main gene aberrations.