3016 - Preferential expression of the affected MET allele in lung carcinomas with heterozygous MET exon 14 skipping mutations: implications for clinical testing

Background

Lung carcinomas (LCs) carrying MET exon 14 skipping (exon 14Δ) mutations are responsive to a number of tyrosine kinase inhibitors. There is a need to incorporate MET analysis in the diagnostic pipeline for LC patients.

Methods

Nucleic acids were extracted from formalin-fixed paraffin-embedded archival LC samples and subjected to cDNA synthesis. This pool of genomic DNA and cDNA was sequentially tested for EGFR, ALK and MET mutations by PCR-based assays.

Results

Allele-specific PCR detected MET exon 14 skipping in 35/1415 (2.5%) EGFR mutation–negative LCs. There was a highly pronounced association with the elderly age of the patients (median age 69 years as compared to 62 years in EGFR/ALK/MET mutation-negative cases; p = 1.821e-06). 34/35 (97%) LCs with MET exon 14 skipping mutations showed preferential expression of the affected MET allele, while the wild-type transcript was almost undetectable in these tumors. In addition, we identified a subset of MET wild-type LCs, which produced normal MET transcript but also expressed residual amounts of MET exon 14Δ RNA message, probably due to alternative splicing.

Conclusions

The mere detection of MET exon 14Δ signal by allele-specific PCR does not warrant the presence of corresponding clonal MET mutation. Comparison of expression of MET exon 14Δ and wild-type alleles is essential for reliable identification of tumors carrying drug-sensitizing MET lesions.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Russian Science Foundation (grant 17-75-30027).

Disclosure

All authors have declared no conflicts of interest.