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MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung
Raphaël Saffroy1,2, Vincent Fallet3,4, Nicolas Girard5
1Department of Biochemistry and Oncogenetics, AP-HP Hôpital Paul-Brousse, Hôpitaux Universitaire Paris Sud, Villejuif, France.
Abstract:
MET exon 14 splicing mutations are new targetable oncogenic drivers reported in 3% of non-small cell lung cancer (NSCLC) cases and have been shown to be more common in pulmonary sarcomatoid carcinomas (PSCs). This study sought to screen mutations affecting MET exon 14 splice sites in a large SC cohort of Caucasian patients, with a large adenocarcinoma cohort as internal control.We tested 81 patients with SC and 150 with adenocarcinoma for splice site DNA mutations leading to RNA splicing-based skipping of MET exon 14. To this end, we employed a mass spectrometry-based custom-designed PCR assay for routine analysis of whole MET exon 14 and flanking intronic regions using formalin-fixed paraffin-embedded (FFPE) tumor samples.Our results revealed a 4.9% mutation rate for MET exon 14 mutations in Caucasian SC patients, which is, though highly variable, within the usual range reported in NSCLC. Discrepancies with previous results reported in SC could be accounted for the small number of cases, ethnicity, epithelial component, and percentage of other driver mutations, such as KRAS, in the patient populations studied. Based on our study findings, SC patients should be screened for MET exon 14 mutations in the same manner as adenocarcinoma patients.
Insights
MET exon 14 splicing mutations, a targetable driver in lung cancer, were found in 4.9% of Caucasian sarcomatoid carcinoma patients. Screening these mutations in sarcomatoid carcinoma is recommended, similar to adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MET exon 14 splicing mutations are oncogenic drivers in 3% of non-small cell lung cancer (NSCLC).
- These mutations are more prevalent in pulmonary sarcomatoid carcinomas (PSCs).
Purpose of the Study:
- To screen for MET exon 14 splice site mutations in a large cohort of Caucasian sarcomatoid carcinoma (SC) patients.
- To compare mutation rates with a cohort of adenocarcinoma patients as an internal control.
Main Methods:
- A mass spectrometry-based custom PCR assay was used to analyze MET exon 14 and flanking intronic regions.
- Formalin-fixed paraffin-embedded (FFPE) tumor samples from 81 SC patients and 150 adenocarcinoma patients were tested.
- The assay detected splice site DNA mutations causing MET exon 14 skipping.
Main Results:
- A 4.9% mutation rate for MET exon 14 mutations was identified in Caucasian SC patients.
- This rate falls within the expected range for NSCLC, despite variability.
- Discrepancies with prior SC studies may be due to case numbers, ethnicity, or co-occurring mutations like KRAS.
Conclusions:
- Sarcomatoid carcinoma patients should be screened for MET exon 14 mutations.
- Screening protocols for SC should align with those for adenocarcinoma.
- Identifying these targetable mutations can inform treatment strategies for NSCLC.