MET Exon 14 Skipping: A Splicing Change That Activates MET

The Underlying Mechanism

Exon 14 of MET encodes a juxtamembrane region containing a binding site for the CBL ubiquitin ligase, which normally tags activated MET for degradation. When exon 14 is skipped during splicing, that site is lost.

The result is a MET receptor that is not properly turned off, so MET signalling persists and drives proliferation and survival.

Many DNA Changes, One Consequence

Exon 14 skipping can be caused by point mutations, insertions or deletions affecting the splice donor or acceptor sites, or the branch point, at either end of the exon. Hundreds of distinct variants have been reported.

Because the causal change can sit in intronic sequence, assays need to cover the splice-site regions, and RNA-based sequencing can confirm that skipping actually occurs.

Not the Same as MET Amplification

MET amplification increases the number of MET gene copies and is a separate event. It occurs de novo in a small fraction of lung cancers and, more commonly, as an acquired resistance mechanism to EGFR inhibitors.

A tumour can have exon 14 skipping, amplification, both or neither, and the two are tested and interpreted differently.

Frequency and Treatment

MET exon 14 skipping is found in roughly 3 to 4 percent of non-small-cell lung cancers, with a higher rate in the rare pulmonary sarcomatoid carcinoma subtype and in older patients.

Selective MET inhibitors capmatinib and tepotinib are approved for this indication, with meaningful response rates. Peripheral oedema is a common on-target effect, and acquired resistance can develop through secondary MET mutations or bypass signalling.

Interpretation Notes

A report should make clear whether it is describing exon 14 skipping or MET amplification, and ideally confirm skipping at the RNA level when the DNA change is unusual.

MET exon 14 skipping is usually mutually exclusive with other lung-cancer drivers.

Key Takeaways

• ·Loss of exon 14 removes the CBL site, so MET is not degraded normally and signalling persists.
• ·Many different splice-site DNA changes cause it; assays must cover those regions.
• ·It is distinct from MET amplification and interpreted separately.
• ·Capmatinib and tepotinib are approved; peripheral oedema is a common effect.