METex14 Splicing Alterations and MET Co-Amplification Associated With Synergistic MET Expression in NSCLC

The largest cohort study of MET Exon 14 (METex14) expression using whole transcriptome sequencing pinpointed splice sites associated increased MET stability and oncogenesis in non-small cell lung cancer (NSCLC).

“Diverse genomic alterations associated with METex14 have been characterized through DNA profiling, but these assays remain an imperfect tool for identifying skipped variants as false-negative results may occur," explained So Yeon Kim, MD, MPH, Albert Einstein Cancer Center, Bronx, New York, and colleagues.

A total of 21,582 NSCLC tumor samples were analyzed via next-generation sequencing of DNA and RNA for complete genomic profiling. For DNA, NextSeq’s 592 Gene Panel and NovaSeq’s whole exome sequencing was used. For RNA, NovaSeq’s whole transcriptome sequencing was used. Information collected included PD-L1 and tumor mutational burden, RNA expression for mutation subtypes and MET amplification, immunogenic signatures, and potential pathways of invasion.

Of all the samples, 2.47% (533) exhibited METex14 expression. In those, point mutations at donor splice sites appeared most often (49.5%). Dr Kim et al reported that alterations "often translated to increased MET expression, with MET co-amplification resulting in a synergistic increase in expression (q < .05).” Amplifications of MDM2, HMGA2, and CK4 were the most common coalterations (19.0% versus 1.8% wild-type [WT], 13.2% versus 0.98% WT, and 10.0% versus 1.5% WT, respectively; q < 0.05).

High PDL1 > 50% (52.5% versus 27.3% WT, q < 0.0001), low tumor mutational burden (>10 mutations per megabase, 8.3% versus 36.7% WT, P < .0001), angiogenesis and apical junction pathways (q < 0.05) were also associated with METex14.

“A novel observation of differential MET expression on the basis of mutation subtype was reported in our study, with at least three-fold increase in expression in nearly all mutation subtypes, except for point mutations in splice acceptor site,” wrote Dr Kim et al, concluding that their findings, “provide insight into potential actionable targets for combination strategies in METex14 NSCLC.”

Source:

Kim SY, Yin J, Bohlman S, et al. Characterization of MET Exon 14 skipping alterations (in NSCLC) and identification of potential therapeutic targets using whole transcriptome sequencing. JTO Clin Res Rep. 2022;3(9):100381. doi:10.1016/j.jtocrr.2022.100381