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

Authors
 Eun Kyung Kim  ;  Kyung A. Kim  ;  Chang Young Lee  ;  Sangwoo Kim  ;  Sunhee Chang  ;  Byoung Chul Cho  ;  Hyo Sup Shim 
Citation
 CLINICAL LUNG CANCER , Vol.20(1) : e123-e132, 2019 
Journal Title
 CLINICAL LUNG CANCER 
ISSN
 1525-7304 
Issue Date
2019
Keywords
MET proto-oncogene ; Molecular diagnostics ; Next-generation sequencing ; Polymerase chain reaction ; Splice variant
Abstract
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
Full Text
https://www.sciencedirect.com/science/article/pii/S1525730418302651
DOI
10.1016/j.cllc.2018.10.004
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung A.(김경아)
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Lee, Chang Young(이창영)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/169981
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