# MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression

Source: https://onco.cc/key-papers/paper-awad-met-exon-14-mutations-lung-jco-2016/  
OnCo record `paper-awad-met-exon-14-mutations-lung-jco-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Mutations that make lung cancer cells skip a single piece of the MET gene define a group of patients who are much older than the rest of lung oncology, mostly women, and often never smokers.

## Summary

Next-generation sequencing results from 6,376 cancers were interrogated for MET exon 14 mutations, and the clinical, pathological and genomic characteristics of the positive cases were compared with those of KRAS- and EGFR-mutant lung cancers. MET exon 14 mutations were identified in 28 of 933 non-squamous lung cancers, 3.0%, and in no other cancer type in the series. Patients were significantly older, median 72.5 years, than patients with EGFR-mutant (61 years) or KRAS-mutant (65 years) disease; 68% were women and 36% never smokers. Stage IV MET exon 14 tumours were significantly more likely to carry concurrent MET amplification (mean MET to chromosome 7 ratio 4.3 against 1.4) and strong c-Met immunohistochemical expression (mean H score 253 against 155) than earlier-stage cases. A patient whose tumour carried both an exon 14 mutation and amplification of the mutated allele had a major partial response to crizotinib.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Journal of Clinical Oncology
- Year: 2016
- DOI: 10.1200/JCO.2015.63.4600
- Authors: Awad MM, Oxnard GR, Jackman DM, et al.
- Findings: MET exon 14 mutations in 28 of 933 non-squamous lung cancers, 3.0%.; Median age 72.5 years, 68% women, 36% never smokers.; Stage IV cases carry concurrent MET amplification and strong c-Met staining far more often than early-stage cases.; Deep response to crizotinib where the mutated allele was also amplified.
- What it means: It made MET exon 14 a clinical entity rather than a sequencing curiosity, and identified the patients most likely to be missed: older people whose age would otherwise argue against broad sequencing.
- Caveats: Retrospective, from one institution's sequencing stream.; Twenty-eight positive cases.; Treatment evidence is a single response rather than a trial.

## Sources

- Awad et al., J Clin Oncol 2016: MET exon 14 mutations across 6,376 cancers, with age, amplification and c-Met overexpression: https://doi.org/10.1200/JCO.2015.63.4600
- PubMed: https://pubmed.ncbi.nlm.nih.gov/26729443/

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [MET](https://onco.cc/targets/met/)
- drugs: [Capmatinib](https://onco.cc/drugs/capmatinib/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Tepotinib](https://onco.cc/drugs/tepotinib/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- pathways: [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/), [MET exon 14 skipping mutation](https://onco.cc/terms/met-exon-14-skipping/)
- people: [Pasi A. Jänne](https://onco.cc/people/pasi-janne/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)
- biomarkers: [c-Met protein overexpression (IHC 3+ in >= 50% of tumour cells)](https://onco.cc/biomarkers/met-overexpression/), [MET amplification (gene copy number)](https://onco.cc/biomarkers/met-amplification-readout/), [MET exon 14 skipping mutation](https://onco.cc/biomarkers/met-ex14/)

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