Brief Report: Critical Role for DNA-Based Sequencing in Discriminating Distinct Primary Lung Cancers With Different MET Exon 14 Skipping Mutations

Introduction: MET exon 14 (METex14) skipping mutations are found in 3% to 4% of NSCLC and can be detected through DNA- or RNA-based sequencing assays. Although RNA sequencing simply reports skipping of exon 14, DNA sequencing assays indicate the precise DNA nucleotide changes that result in METex14 skipping. Here, we reveal the importance of DNA-based sequencing assays for identifying patients with multiple, distinct, METex14-mutant lung cancers. Methods: NSCLC cases with available targeted exome next-generation sequencing through OncoPanel or Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assays were evaluated. Patients with METex14 mutations in ≥2 NSCLC tumor samples at any stage were reviewed to assess tumor relatedness based on clinicopathologic and genomic criteria. Results: Among 589 patients with METex14-mutant NSCLC and available in-house next-generation sequencing, 112 had ≥2 NSCLC tumor samples sequenced with METex14 mutations; among these, seven patients had two distinct METex14-mutant primary lung cancers, and one patient had three primary METex14-mutant lung cancers. Four cases were synchronous primary cancers, occurring within 12 months of the initial diagnosis, whereas the other four were metachronous, occurring after 12 months. Comprehensive DNA genomic analysis confirmed the distinct clonality of the tumors, with each case showing different METex14 alterations and other distinct genomic events, supporting the diagnosis of independent primary lung cancers. Conclusions: DNA-based sequencing of the MET gene improves staging accuracy to guide appropriate management for patients with multiple primary METex14-mutant NSCLCs.