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.
Keywords
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Article info
Publication history
Published online: October 10, 2018
Accepted:
October 2,
2018
Received in revised form:
September 27,
2018
Received:
April 25,
2018
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- MET Immunohistochemistry Should Be Avoided in Selecting Non–small-cell Lung Cancers Requiring MET Exon 14 Skipping Mutation AnalysisClinical Lung CancerVol. 20Issue 3
- PreviewBecause 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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