Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing
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 g...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | JTO Clinical and Research Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364322001059 |
| _version_ | 1828143418430193664 |
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| author | 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 |
| author_facet | 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 |
| author_sort | So Yeon Kim, MD |
| collection | DOAJ |
| description | 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 < 0.05). Common coalterations were amplifications of MDM2 (19.0% versus 1.8% wild-type [WT]), HMGA2 (13.2% versus 0.98% WT), and CDK4 (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>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. |
| first_indexed | 2024-04-11T19:56:54Z |
| format | Article |
| id | doaj.art-57c16c1c6a93496da63baca1c937d2d4 |
| institution | Directory Open Access Journal |
| issn | 2666-3643 |
| language | English |
| last_indexed | 2024-04-11T19:56:54Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JTO Clinical and Research Reports |
| spelling | doaj.art-57c16c1c6a93496da63baca1c937d2d42022-12-22T04:05:58ZengElsevierJTO Clinical and Research Reports2666-36432022-09-0139100381Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome SequencingSo Yeon Kim, MD0Jun Yin, MD1Stephen Bohlman, MD, PhD2Phillip Walker, PhD3Sanja Dacic, MD, PhD4Chul Kim, MD5Hina Khan, MD6Stephen V. Liu, MD7Patrick C. Ma, MD8Misako Nagasaka, MD, PhD9Karen L. Reckamp, MD10Jim Abraham, PhD11Dipesh Uprety, MD12Feng Wang, PhD13Joanne Xiu, PhD14Jian Zhang, PhD15Haiying Cheng, MD, PhD16Balazs Halmos, MD17Department of Medical Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York; Yale School of Medicine, New Haven, ConnecticutCaris Life Sciences, Phoenix, ArizonaDepartment of Medical Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New YorkCaris Life Sciences, Phoenix, ArizonaYale School of Medicine, New Haven, ConnecticutGeorgetown Lombardi Comprehensive Cancer Center, Washington, District of ColumbiaWarren Alpert Medical School of Brown University, Providence, Rhode IslandGeorgetown Lombardi Comprehensive Cancer Center, Washington, District of ColumbiaPenn State Cancer Institute, Hershey, PennsylvaniaUCI School of Medicine, Orange, CaliforniaCedars-Sinai Medical Center, Los Angeles, CaliforniaCaris Life Sciences, Phoenix, ArizonaKarmanos Cancer Center, Detroit, MichiganDepartment of Medical Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New YorkCaris Life Sciences, Phoenix, ArizonaCaris Life Sciences, Phoenix, ArizonaDepartment of Medical Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New YorkDepartment of Medical Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York; Corresponding author. Address for correspondence: Balazs Halmos, MD, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York.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 < 0.05). Common coalterations were amplifications of MDM2 (19.0% versus 1.8% wild-type [WT]), HMGA2 (13.2% versus 0.98% WT), and CDK4 (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>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.http://www.sciencedirect.com/science/article/pii/S2666364322001059METex14Non–small cell lung cancerWhole transcriptome sequencingRNA expressionMDM2Immune signatures |
| spellingShingle | 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 Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing JTO Clinical and Research Reports METex14 Non–small cell lung cancer Whole transcriptome sequencing RNA expression MDM2 Immune signatures |
| title | Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing |
| title_full | Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing |
| title_fullStr | Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing |
| title_full_unstemmed | Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing |
| title_short | Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing |
| title_sort | characterization of met exon 14 skipping alterations in nsclc and identification of potential therapeutic targets using whole transcriptome sequencing |
| topic | METex14 Non–small cell lung cancer Whole transcriptome sequencing RNA expression MDM2 Immune signatures |
| url | http://www.sciencedirect.com/science/article/pii/S2666364322001059 |
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