METex14 skipping testing guidance for lung cancer patients: The guidance from the biomarker committee, the Japan lung cancer society

MET, a proto-oncogene located in 7q21-q31, encodes a receptor tyrosine kinase, of which mutations, amplification, fusions and overexpression are reported to be associated with oncogenesis. MET exon 14 (METex14) skipping is one of such MET alterations, and this abnormality is caused by genetic deletions or mutations in the intron/exon boundary sites as splice-site abnormalities, resulting in the generation of a deleted transcript in exon 14. This exon encodes juxtamembrane domain, which contains the binding site of c-Cbl E 3 ubiquitin ligase. Therefore, lack of METex14 suppresses ubiquitination and degradation, which lead to functional MET activation. In 2020, tepotinib and capmatinib were approved for the treatment of advanced recurrent lung cancer with this alteration. To implement the molecular testing to detect METex14 skipping in clinical practice, a practical guidance was released from the Biomarker Committee of the Japan Lung Cancer Society, and the content is introduced in this article.