Use of Oncogene Overlap by Tissue-Based Next-Generation Sequencing to Explore the Mutational Landscape and Survival Impact of HER2, KRAS and MET Copy-Number Gain in Nonsmall Cell Lung Cancer

Background: Gene copy number gain (CNG) is a continuous variable. The relevant cutpoint for HER2, KRAS and MET CNG in non-mall cell lung cancer remains uncertain. As de novo driver oncogenes are largely mutually exclusive, oncogene overlap analysis can be used to explore CNG thresholds. Patient and Methods: We retrospectively analysed NGS of DNA/RNA in 13,702 NSCLC adenocarcinoma samples. Alternate and same-gene driver oncogene co-occurrence with HER2, KRAS and MET CNG was examined. Overall survival (OS) from time of biopsy collection was correlated with CNG and pathogenic mutations in driver oncogenes (Driver+). Results: The frequency of Driver+ tumors decreased with increasing CNG. Setting CNG thresholds by oncogene overlap and dataset size (CNA ≥ 6 for HER2, KRAS and ≥ 4 for MET), tumors considered relevantly amplified (Amp) for MET, HER2 and KRAS were significantly less likely to be Driver+ (P < .001). When Driver+ did overlap with Amp status, same-gene alterations (mutation and CNG) were significantly enriched for all 3 genes (HER2, KRAS and MET), while BRAF and EGFR mutations were more common in MET-Amp than in HER2- or KRAS-Amp tumors. A negative OS association with Amp status was independent of Driver+ status for HER2 and MET, however not KRAS. Conclusion: Tissue NGS-based HER2, KRAS and MET CNG thresholds set by oncogene overlap identified potentially clinically relevant “Amp” subgroups with altered genetic profiles and decreased survival. Prospective research into targeted therapy benefit in these groups is encouraged.