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Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malig...

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Autores principales: Santoni-Rugiu, Eric, Lü, Maya Jeje Schuang, Jakobsen, Jan Nyrop, Melchior, Linea Cecilie, Ravn, Jesper, Sørensen, Jens Benn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657838/
https://www.ncbi.nlm.nih.gov/pubmed/34884673
http://dx.doi.org/10.3390/ijms222312868
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author Santoni-Rugiu, Eric
Lü, Maya Jeje Schuang
Jakobsen, Jan Nyrop
Melchior, Linea Cecilie
Ravn, Jesper
Sørensen, Jens Benn
author_facet Santoni-Rugiu, Eric
Lü, Maya Jeje Schuang
Jakobsen, Jan Nyrop
Melchior, Linea Cecilie
Ravn, Jesper
Sørensen, Jens Benn
author_sort Santoni-Rugiu, Eric
collection PubMed
description Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.
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spelling pubmed-86578382021-12-10 Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma Santoni-Rugiu, Eric Lü, Maya Jeje Schuang Jakobsen, Jan Nyrop Melchior, Linea Cecilie Ravn, Jesper Sørensen, Jens Benn Int J Mol Sci Article Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated. MDPI 2021-11-28 /pmc/articles/PMC8657838/ /pubmed/34884673 http://dx.doi.org/10.3390/ijms222312868 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Santoni-Rugiu, Eric
Lü, Maya Jeje Schuang
Jakobsen, Jan Nyrop
Melchior, Linea Cecilie
Ravn, Jesper
Sørensen, Jens Benn
Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma
title Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma
title_full Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma
title_fullStr Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma
title_full_unstemmed Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma
title_short Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma
title_sort correlation of met-receptor overexpression with met gene amplification and patient outcome in malignant mesothelioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657838/
https://www.ncbi.nlm.nih.gov/pubmed/34884673
http://dx.doi.org/10.3390/ijms222312868
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