Correlation of MET-receptor overexpression with MET gene amplification and patient outcome in malignant mesothelioma
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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.
I: International Journal of Molecular Sciences, Bind 22, Nr. 23, 12868, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Correlation of MET-receptor overexpression with MET gene amplification and patient outcome in malignant mesothelioma
AU - Santoni-Rugiu, Eric
AU - Lü, Maya Jeje Schuang
AU - Jakobsen, Jan Nyrop
AU - Melchior, Linea Cecilie
AU - Ravn, Jesper
AU - Sørensen, Jens Benn
N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Fluorescence in situ hybridization
KW - Gene amplification
KW - Immunohistochemistry
KW - Malignant mesothelioma
KW - MET
KW - Overexpression
KW - Patient outcome
U2 - 10.3390/ijms222312868
DO - 10.3390/ijms222312868
M3 - Journal article
C2 - 34884673
AN - SCOPUS:85119898113
VL - 22
JO - International Journal of Molecular Sciences (CD-ROM)
JF - International Journal of Molecular Sciences (CD-ROM)
SN - 1424-6783
IS - 23
M1 - 12868
ER -
ID: 286999182