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Distinct MET Protein Localization Associated With MET Exon 14 Mutation Types in Patients With Non-small-cell Lung

Tian Qiu¹, Weihua Li¹, Tongtong Zhang²

¹Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Clinical Lung Cancer

|January 18, 2018

Abstract

Background:

The MET gene has been recognized as a potential important therapeutic target in non-small-cell lung cancer (NSCLC). We sought to investigate the MET exon 14 mutations in a cohort of Chinese patients with NSCLC.

Methods:

We tested 461 NSCLCs for MET exon 14 mutations by sequencing whole exon 14 and its flanking introns. The protein expression was determined by immunohistochemical analysis.

Results:

In this study, we identified MET exon 14 mutations in 9 (2.0%) of 461 NSCLCs. Of these 9 mutations, 7 (77.8%) were located in the splice sites of MET exon 14, with MET overexpression in 6. One point mutation c.3010C>T (p.Arg1004Ter) was nonsense mutation with no MET expression. One insertion mutation was within exon 14 of MET with MET overexpression. MET protein localization in tumor cells with MET exon 14 mutations was different between mutation types. Three point mutations that disrupted the splice donor site of intron 14 were membranous staining, whereas the other mutations were cytoplasmic staining. Patients with MET exon 14 splice site mutations were significantly older. The incidence of MET exon 14 mutations in sarcomatoid carcinoma was significantly higher than in other histologic types (P = .034).

Conclusion:

Distinct MET protein localization is associated with MET exon 14 mutation types in patients with NSCLC. Different MET exon 14 mutation types were identified in a subset of Chinese patients with NSCLC who could possibly benefit from MET targeted therapy.

Insights

MET exon 14 mutations were found in 2.0% of Chinese non-small-cell lung cancer (NSCLC) patients. Specific mutation types correlate with MET protein localization and may benefit from targeted therapy.

Area of Science:

Oncology
Genetics
Molecular Biology

Background:

The MET gene is a potential therapeutic target in non-small-cell lung cancer (NSCLC).
Investigating MET exon 14 mutations is crucial for understanding NSCLC pathogenesis and treatment.

Purpose of the Study:

To investigate the prevalence and characteristics of MET exon 14 mutations in Chinese NSCLC patients.
To correlate MET exon 14 mutation types with MET protein expression and localization.
To identify potential patient subsets that may benefit from MET-targeted therapies.

Main Methods:

Sequencing of MET exon 14 and flanking introns in 461 NSCLC samples.
Immunohistochemical analysis to determine MET protein expression and localization.
Statistical analysis to evaluate associations between mutation types, patient demographics, and tumor histology.

Main Results:

MET exon 14 mutations were identified in 9 (2.0%) of 461 NSCLCs.
Most mutations (77.8%) occurred at splice sites, often associated with MET overexpression.
Distinct MET protein localization patterns (membranous vs. cytoplasmic) were observed based on mutation type.
MET exon 14 splice site mutations were linked to older patient age and a higher incidence in sarcomatoid carcinoma.

Conclusions:

MET exon 14 mutation types influence MET protein localization in NSCLC.
Identifying specific MET exon 14 mutations in Chinese NSCLC patients can guide the selection for MET-targeted therapy.

Read full analysis

Keywords:

Chinese Immunohistochemistry MET exon 14 skipping Sequencing Targeted therapy

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