The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors
Published version of a preprint
Abstract
Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting. Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors. Cancer Discov; 5(8); 850–9. ©2015 AACR. See related commentary by Ma, p. 802. See related article by Paik et al., p. 842. This article is highlighted in the In This Issue feature, p. 783
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In the citing paper
“Importantly, large-scale profiling studies utilizing either whole exome sequencing or broad targeted sequencing panels in NSCLC tumors have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation15, 34, 58–62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“Landmark large scale sequencing studies have established a census of major KRAS co-mutations in both early-stage and advanced LUAD15, 34, 59, 62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“Although EGFR –mutant tumors represent the prototypical oncogene-addicted LUAD subgroup that spearheaded adoption of the single-driver model, the overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when the analysis is limited to pre-defined sets of cancer-relevant genes within established panels (FoundationOne, Guardant360, MSK-IMPACT)15, 59, 72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“NKX2–1 amplification is significantly enriched in EGFR-mutant LUAD”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“earlier studies that identified a central role for WNT signaling in LUAD metastasis”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“like CTNNB1 mutations, are encountered preferentially in advanced-stage tumors15, 34, 72, 73”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“but are less likely to harbor TP53 alterations (23.8%−26.5%) compared with other driver subgroups15, 128.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“experimental data demonstrating increased invasive potential of EGFR and CTNNB1 co-mutated NSCLC cells in vitro15, 34, 72, 73, 120, 121”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“PIK3CA mutations, including classical kinase (H1074R and H1074L) and helical (E545K and E542K) domain mutations are observed in 9%−12.4% of advanced stage EGFR-mutant LUAD”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“Activating mutations in CTNNB1 represent one of the most consistently co-selected alterations in EGFR-mutant LUAD across different studies.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“advanced-stage ALK-rearrangement -positive LUAD are enriched in somatic alterations in CDKN2A (32.5%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“and CDKN2B (26.5%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“their prevalence increases in late-stage tumors (5.3% - 9.6%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“these tumors are characterized by highly significant enrichment of MDM2 and CDK4 amplification (41.6%) compared with other driver oncogenes”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“both RET and ROS1 fusion-positive LUAD are characterized by high rates of concurrent CDKN2A loss (29.8% and 30.4% for RET and ROS1-rearranged tumors respectively)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“CDKN2B loss (25% and 17.7% respectively)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“The spectrum of co-occurring alterations in BRAF-mutant NSCLC mirrors the background frequency of alterations in TP53 (53.3%), LKB1 (16.2%), ATM (5.8%), NF1 (6.9%), PIK3CA (6.6%), KEAP1 (6.6%), MYC (10.8%), NKX2–1 (7.3%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“as well as frequent mutations in RB1 (8.9%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“whereas loss of CDKN2A (24.1%) and CDKN2B (17.5%) occur with similar frequencies to that in the overall population of patients with NSCLC15.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“both RET and ROS1 fusion-positive LUAD are characterized by high rates of concurrent CDKN2A loss (29.8% and 30.4% for RET and ROS1-rearranged tumors respectively)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“although the frequency of TP53 mutations appears to be somewhat higher compared to ALK-rearranged tumors (34.6%−45.5% for RET-and 45.6% for ROS1- rearranged tumors)15, 131.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“patients with ERBB2-mutant NSCLC exhibit preferential amplification of NKX2–1 (19.4%) and ERBB2 itself (14.4%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“as well as amplification of MET itself15.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“CDKN2B loss (25% and 17.7% respectively)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“relative paucity of TP53 mutations”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“but the frequencies of co-mutations in TP53 (51.7%), CDKN2A (27.2%), CDKN2B (17.2%), PIK3CA (5%), CTNNB1 (4.4%) and MDM2 amplification (7.2%) are similar to that observed in the overall population of patients with NSCLC15.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“In contrast, mutations in TP53 (33.57%) are under-represented”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
In the citing paper
“although alterations in RB1, MDM2, CDKN2A (16.6%) and CDKN2B (11.2%) are less frequent within this molecular subgroup15.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [15]
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Metadata
- Authors
- Frampton, G. M., Ali, S. M., Rosenzweig, M., Chmielecki, J., Lu, X., Bauer, T. M., Akimov, M., Bufill, J. A., Lee, C., Jentz, D., Hoover, R., Ou, S.-H. I., Salgia, R., Brennan, T., Chalmers, Z. R., Jaeger, S., Huang, A., Elvin, J. A., Erlich, R., Fichtenholtz, A., Gowen, K. A., Greenbowe, J., Johnson, A., Khaira, D., McMahon, C., Sanford, E. M., Roels, S., White, J., Greshock, J., Schlegel, R., Lipson, D., Yelensky, R., Morosini, D., Ross, J. S., Collisson, E., Peters, M., Stephens, P. J., & Miller, V. A.
- Affiliations
- Foundation Medicine (United States) (US)
- University of California, San Francisco (US)
- Tennessee Oncology (US)
- Novartis (Switzerland) (CH)
- 5Michiana Hematology-Oncology, PC, Mishawaka, Indiana.
- University of North Carolina at Chapel Hill (US)
- South Bend Medical Foundation (US)
- University of California, Irvine (US)
- University of Chicago (US)
- 1Foundation Medicine Inc., Cambridge, Massachusetts.
- Corresponding author
- Frampton, Garrett M.
- ORCID
- Frampton, Garrett M.
- Ali, Siraj M.
- Rosenzweig, Mark
- Chmielecki, Juliann
- Lu, Xinyuan
- Bauer, Todd M.
- Akimov, Mikhail
- Lee, Carrie
- Ou, Sai-Hong Ignatius
- Salgia, Ravi
- Chalmers, Zachary R.
- Huang, Alan
- Elvin, Julia A.
- Johnson, Adrienne
- Sanford, Eric M.
- Roels, Steven
- Greshock, Joel
- Lipson, Doron
- Yelensky, Roman
- Ross, Jeffrey S.
- Collisson, Eric
- Miller, Vincent A.
- Venue
- Cancer Discovery
- Published
- 2015-08-01
- Volume
- 5
- Issue
- 8
- Pages
- 850-859
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2160212814
- Cited by
- 796
- References
- 41
- Citations by year
- 2026: 26 · 2025: 47 · 2024: 69 · 2023: 83 · 2022: 73 · 2021: 97 · 2020: 91 · 2019: 71 · 2018: 71 · 2017: 86 · 2016: 65 · 2015: 13
- FWCI
- 62.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA016086)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- MET activation, MET inhibitors, exon skipping, lung adenocarcinoma, glioma, histiocytic sarcoma, targeted therapy sensitivity, oncogenic transformation, comprehensive genomic profiling, tumor genomic profiles
- MeSH terms
- Aged, Aged, 80 and over, Antineoplastic Agents, Exons, Female, Humans, Immunohistochemistry, Male, Mutation, Neoplasm Staging, Neoplasms, Tomography, X-Ray Computed, Cluster Analysis, Alternative Splicing, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Gene Expression Profiling, Genomics, Protein Kinase Inhibitors
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