MET Exon 14 Skipping Mutations in NSCLC

Lyudmila A. Bazhenova, MD: MET is a tyrosine kinase receptor. Usually, hepatocyte growth factor is a ligand for MET. Once MET has been activated, it results in dimerization and signaling through multiple intracellular pathways, resulting in tumor growth and proliferation. What’s interesting is how MET exon 14 skipping mutations affect MET signaling. Usually, a mutation resulting in the skipping of exon 14 happens in the intron region of MET, resulting in alternative splicing, and therefore, deletion of the juxtamembrane domain of the MET receptor. The juxtamembrane domain is very important because that’s where Cbl binds, and Cbl marks the receptor for degradation. So, there is no place for Cbl to bind. The receptor does not get degraded. Therefore, it continues to signal, resulting in tumor growth.

Overall, reports of MET exon 14 skipping mutations range from about 1.5% to 6%, depending on what data you are reading. The largest data set reported was by Garrett Frampton, PhD, which looked at 38,000 patients who received sequencing by the Foundation Medicine, Inc platform. They found the incidence of MET exon 14 skipping mutations to be approximately 3%.

It is also interesting that a very rare subtype of lung cancer called sarcomatoid carcinoma has been reported to have a higher incidence of MET exon 14 skipping mutations. Xue-wen Liu, MD, PhD, reported that 22% of patients with sarcomatoid carcinoma have MET exon 14 skipping mutations.

MET exon 14 skipping mutations can be found in both adenocarcinoma and squamous cell carcinoma. Patients with adenocarcinoma are more likely to harbor MET exon 14 skipping mutations. The majority of those patients are nonsmokers, but smokers have also been described to have MET exon 14 skipping mutations.

Another thing we have not touched upon yet is MET amplification. MET amplifications differ from MET exon 14 skipping mutations, and they happen in approximately 1% of patients. MET is also felt to be an oncogenic driver, because patients with MET exon 14 skipping mutations are less likely to have other concurrent genomic alterations.

Joshua M. Bauml, MD: MET exon 14 skipping alterations tend to occur about 5% of the time in nonsquamous non–small cell lung cancer, though they can occur at higher rates in certain histologies. Most notably, the rates are as high as 20% in sarcomatoid non–small cell lung cancer. So, it’s critical that we get testing done. One of the important things to remember when you’re doing this testing is that the mutation is in the intron of MET. And so, if your next-generation sequencing panel tends to focus on the exons, it will miss this. I know that many of my colleagues who are utilizing DNA-based next-generation sequencing may miss detecting MET exon 14 skipping alterations. In fact, using our next-generation sequencing assay at the University of Pennsylvania, I have found most of our alterations detected are on our RNA-based fusion assay as a 13-to-15 fusion, which is another way of saying exon 14 was skipped.

In terms of the risk factors, as I mentioned, patients with sarcomatoid lung cancer are at the highest risk. However, this is an alteration that can be found in people with a smoking history. They tend to be older than your other molecular driver alteration patient populations. Those are the major risk factors.

Transcript Edited for Clarity