MET amplifications present a potential therapeutic target in NSCLC and while FISH is conventionally used to asses it, there is no clinically defined cutoff. NGS is becoming routine in molecular diagnostics, and provides a means to assess MET amplification in the context of comprehensive genomic profiling. Here, we assess MET amplifications in NSCLC, in addition to TMB and concomitant driver mutations.
222 NSCLC cases were screened, and 26 samples were selected based on increased MET gene copy number (GCN) detected by FISH (Cappuzzo score, MET GCN >5). Cases were reclassified to determine amplification versus high polysomy by University of Colorado Cancer Center (UCCC) FISH-criteria. Archival tissue samples were evaluated by PGDx elio™ tissue complete (assay under development; Personal Genome Diagnostics), a 500+ gene NGS panel.
Eight patients were amplified by UCCC FISH-criteria (1 patient high-amplified (MET/CEP7 >5) and 7 patients intermediate-amplified (>2.2 to < 5)). Five of these 8 patients (4 intermediate-amplified; 1 high-amplified) were also found to have MET amplification by NGS (>3 fold cutoff) and were male smokers, with a median age of 57 years, with no concurrent driver alterations. One MET-amplified sample also had a concomitant exon 14 skipping mutation. The 3 discordant cases were highly heterogeneous by FISH with focal MET amplifications. Eighteen patients exhibited high copy number gain by FISH but were negative for MET amplifications according to UCCC FISH-criteria and NGS. Five of these cases had driver mutations (2 = KRAS exon 2 mutations and 3 = EGFR sensitizing mutations). TMB scores in NGS MET-positive were lower than NGS MET-negative cases: 5.9 vs. 12.5 mut/Mb exome equivalent.
NGS and FISH produced similar MET amplification status. The wide range of MET classifications via FISH, together with tumor heterogeneity and lack of clinically relevant thresholds, could contribute to discordance. In most cases negative for MET amplification by NGS, alternative driver mutations and/or higher TMB were identified. These results suggest that, while these technologies provide complementary value, further clinical data is needed to define clinically meaningful MET alterations.
The authors.
Has not received any funding.
E. Weingartner: Full / Part-time employment: Personal Genome Diagnostics. G. Cerqueira: Full / Part-time employment: Personal Genome Diagnostics. D. Nichol: Full / Part-time employment: Personal Genome Diagnostics. J. Simmons: Full / Part-time employment: Personal Genome Diagnostics. All other authors have declared no conflicts of interest.