Original Study| Volume 20, ISSUE 1, e123-e132, January 2019

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Molecular Diagnostic Assays and Clinicopathologic Implications of MET Exon 14 Skipping Mutation in Non–small-cell Lung Cancer

Published:October 10, 2018DOI:



      Recent studies revealed MET exon 14 skipping (METex14) as a biomarker that predicts the response to MET inhibitors in non–small-cell lung cancer (NSCLC). However, METex14 genomic alterations exhibit a highly diverse sequence composition, posing a challenge for clinical diagnostic testing. This study aimed to find a reasonable diagnostic assay for METex14 and identify its clinicopathologic implications.

      Materials and Methods

      We performed a comprehensive analysis of METex14 in 414 EGFR/KRAS/ALK/ROS1-negative (quadruple negative) surgically resected NSCLCs. We used real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Sanger sequencing for the first assay, followed by next-generation sequencing (NGS; hybrid-capture targeted DNA/RNA sequencing). Clinicopathologic implications of the METex14 group were analyzed in a total of 880 NSCLCs.


      METex14 was confirmed in 13 (3.1%) patients by DNA- and RNA-NGS. After comparison of assay results, qRT-PCR and NGS demonstrated the highest concordance rate. The mean variant allele frequency was 10.5% and 49% in DNA- and RNA-NGS, respectively. DNA-NGS revealed various lengths of indel and substitutions around and in exon 14. Moreover, METex14 was associated with adenocarcinoma (4.8%; 11/230) or sarcomatoid carcinoma (9.5%; 2/21), old age, never-smokers, and early stage of disease.


      METex14 occurs in about 3% of NSCLCs and has characteristic clinicopathologic features. NGS should be the first assay of choice as a multiplex testing. Sanger sequencing can detect METex14, but sensitivity can be hampered by large deletions or low allele frequency. qRT-PCR, an mRNA-based method, is sensitive and specific and can be appropriate for screening METex14 as a single gene testing.


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      Linked Article

      • MET Immunohistochemistry Should Be Avoided in Selecting Non–small-cell Lung Cancers Requiring MET Exon 14 Skipping Mutation Analysis
        Clinical Lung CancerVol. 20Issue 3
        • Preview
          Because MET exon 14 skipping mutations have been reported as biomarkers predicting response to tyrosine kinase inhibitors, searching for MET mutations has become mandatory for treatment choices in patients with non–small-cell lung cancer (NSCLC).1 MET exon 14 skipping mutations occur typically in tumors lacking other molecular alterations in EGFR, KRAS, BRAFV600, ALK, and ROS1 genes.2 Beyond multiplex testing, using next generation sequencing methods analyzing MET with other oncogenes, a multistep diagnostic strategy combining individual gene testing may be chosen by some laboratories, notably for turnaround times and cost-related reasons.
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