MET exon 14 skipping mutation

What is measured: a mutation at the splice sites flanking exon 14 of MET that deletes the juxtamembrane domain containing the Y1003 degradation signal. How: RNA-based next-generation sequencing is preferred because it detects the skipped transcript directly; DNA panels must cover the intronic splice regions and still miss 10 to 20 percent because the breakpoints vary; plasma cell-free DNA can detect it. Related tests: FISH or sequencing copy number for MET amplification (high-level gain, a MET to CEP7 ratio of 5 or more or ten copies or more, is more likely to respond) and c-Met immunohistochemistry for overexpression (3+ in half or more of cells selects telisotuzumab vedotin, not the kinase inhibitors). Frequency: 3 to 4 percent of non-small-cell lung cancers, 20 to 30 percent of pulmonary sarcomatoid carcinomas, and papillary renal cell carcinoma. What a positive result changes: capmatinib (GEOMETRY mono-1, response rate 68 percent first line), tepotinib (VISION) or savolitinib (China; and with osimertinib for MET-amplified resistance in EGFR-mutant disease) replace chemotherapy and immunotherapy, which works poorly here despite high PD-L1; resistance comes through MET D1228 and Y1230 mutations or KRAS and other bypass lesions; telisotuzumab vedotin serves c-Met-overexpressing EGFR wild-type nonsquamous disease. Where it matters: MET-altered NSCLC, NSCLC and papillary RCC.