JTO Clinical and Research Reports (Sep 2022)

Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing

  • So Yeon Kim, MD,
  • Jun Yin, MD,
  • Stephen Bohlman, MD, PhD,
  • Phillip Walker, PhD,
  • Sanja Dacic, MD, PhD,
  • Chul Kim, MD,
  • Hina Khan, MD,
  • Stephen V. Liu, MD,
  • Patrick C. Ma, MD,
  • Misako Nagasaka, MD, PhD,
  • Karen L. Reckamp, MD,
  • Jim Abraham, PhD,
  • Dipesh Uprety, MD,
  • Feng Wang, PhD,
  • Joanne Xiu, PhD,
  • Jian Zhang, PhD,
  • Haiying Cheng, MD, PhD,
  • Balazs Halmos, MD

Journal volume & issue
Vol. 3, no. 9
p. 100381

Abstract

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Introduction: Genomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of MET Exon 14 (METex14) using whole transcriptome sequencing. Methods: A total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing). Clinicopathologic information including programmed death-ligand 1 and tumor mutational burden were collected and RNA expression for mutation subtypes and MET amplification were quantified. Immunogenic signatures and potential pathways of invasion were characterized using single-sample gene set enrichment analysis and mRNA gene signatures. Results: A total of 533tumors (2.47%) with METex14 were identified. The most common alterations were point mutations (49.5%) at donor splice sites. Most alterations translated to increased MET expression, with MET co-amplification resulting in synergistic increase in expression (q 50% (52.5% versus 27.3% WT, q 10 mutations per megabase, 8.3% versus 36.7% WT, p < 0.0001) were associated with METex14, which were also enriched in both immunogenic signatures and immunosuppressive checkpoints. Pathways associated with METex14 included angiogenesis and apical junction pathways (q < 0.05). Conclusions: METex14 splicing alterations and MET co-amplification translated to higher and synergistic MET expression at the transcriptomic level. High frequencies of MDM2 and CDK4 co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in METex14 NSCLC.

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