Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Jan Hendrik Rueschoff; Martina Haberecker; ETOP Mesoscape Consortium; Zoi Tsourti; Kristiaan Nackaerts; Marc de Perrot; Luka Brcic; Ernest Nadal; Sotirios Tsimpoukis; Steven G. Gray; Luca Ampollini; Joachim G. Aerts; Emanuela Felley-Bosco; Michaela B. Kirschner; Kim Monkhorst; Birgit Weynand; Fatemeh Bavaghar-Zaeimi; Miroslav Samarzija; Roger Llatjos; Stephen P. Finn; Enrico Silini; Jan von der Thusen; Nesa Marti; Karerina Vervita; Roswitha Kammler; Solange Peters; Rolf A. Stahel; Paul Baas; Isabelle Opitz

doi:10.1038/s41379-022-01145-0

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

Jan Hendrik Rueschoff, Martina Haberecker, ETOP Mesoscape Consortium, Zoi Tsourti, Kristiaan Nackaerts, Marc de Perrot, Luka Brcic, Ernest Nadal, Sotirios Tsimpoukis, Steven G. Gray, Luca Ampollini, Joachim G. Aerts, Emanuela Felley-Bosco, Michaela B. Kirschner, Kim Monkhorst, Birgit Weynand, Fatemeh Bavaghar-Zaeimi, Miroslav Samarzija, Roger Llatjos, Stephen P. FinnEnrico Silini, Jan von der Thusen, Nesa Marti, Karerina Vervita, Roswitha Kammler, Solange Peters, Rolf A. Stahel, Paul Baas, Isabelle Opitz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

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Abstract

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

Original language	English
Pages (from-to)	1888-1899
Number of pages	12
Journal	Modern Pathology
Volume	35
Issue number	12
Early online date	17 Sept 2022
DOIs	https://doi.org/10.1038/s41379-022-01145-0
Publication status	Published - 1 Dec 2022

Bibliographical note

Funding Information:
This work was supported by ETOP, Oncosuisse [KFS-3626-02-2015], Bristol-Myers Squibb, and Merck, who supplied support for sample handling and assays. Bristol-Myers Squibb and Merck did not have a role in the reporting or interpretation of the study. Open access funding provided by University of Zurich.

Funding Information:
The European Thoracic Oncology Platform (ETOP) coordinated Mesoscape and is responsible for the collection and management of data, data analysis, reporting, and for study design together with the University Hospital of Zurich (USZ). We thank Susanne Dettwiler, Fabiola Prutek and Christiane Mittmann for tissue processing and immunohistochemical staining’s. We thank Bart Vrugt, Alex Soltermann for their contribution to the Mesoscape development and for tumour identification. We acknowledge the Biobanks of the participating centres, and particularly the Department of Pathology and Molecular Pathology at the University Hospital of Zurich, in their role as central Mesoscape laboratory. We thank Martina Friess and Alessandra Matter for their support.

Publisher Copyright:
© 2022, The Author(s).

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Rueschoff, J. H., Haberecker, M., ETOP Mesoscape Consortium, Tsourti, Z., Nackaerts, K., de Perrot, M., Brcic, L., Nadal, E., Tsimpoukis, S., Gray, S. G., Ampollini, L., Aerts, J. G., Felley-Bosco, E., Kirschner, M. B., Monkhorst, K., Weynand, B., Bavaghar-Zaeimi, F., Samarzija, M., Llatjos, R., ... Opitz, I. (2022). Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project. Modern Pathology, 35(12), 1888-1899. https://doi.org/10.1038/s41379-022-01145-0

@article{0d4585fbab1340a1a308bca063e390ed,

title = "Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project",

abstract = "Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-na{\"i}ve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.",

author = "Rueschoff, {Jan Hendrik} and Martina Haberecker and {ETOP Mesoscape Consortium} and Zoi Tsourti and Kristiaan Nackaerts and {de Perrot}, Marc and Luka Brcic and Ernest Nadal and Sotirios Tsimpoukis and Gray, {Steven G.} and Luca Ampollini and Aerts, {Joachim G.} and Emanuela Felley-Bosco and Kirschner, {Michaela B.} and Kim Monkhorst and Birgit Weynand and Fatemeh Bavaghar-Zaeimi and Miroslav Samarzija and Roger Llatjos and Finn, {Stephen P.} and Enrico Silini and {von der Thusen}, Jan and Nesa Marti and Karerina Vervita and Roswitha Kammler and Solange Peters and Stahel, {Rolf A.} and Paul Baas and Isabelle Opitz",

note = "Funding Information: This work was supported by ETOP, Oncosuisse [KFS-3626-02-2015], Bristol-Myers Squibb, and Merck, who supplied support for sample handling and assays. Bristol-Myers Squibb and Merck did not have a role in the reporting or interpretation of the study. Open access funding provided by University of Zurich. Funding Information: The European Thoracic Oncology Platform (ETOP) coordinated Mesoscape and is responsible for the collection and management of data, data analysis, reporting, and for study design together with the University Hospital of Zurich (USZ). We thank Susanne Dettwiler, Fabiola Prutek and Christiane Mittmann for tissue processing and immunohistochemical staining{\textquoteright}s. We thank Bart Vrugt, Alex Soltermann for their contribution to the Mesoscape development and for tumour identification. We acknowledge the Biobanks of the participating centres, and particularly the Department of Pathology and Molecular Pathology at the University Hospital of Zurich, in their role as central Mesoscape laboratory. We thank Martina Friess and Alessandra Matter for their support. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "1",

doi = "10.1038/s41379-022-01145-0",

language = "English",

volume = "35",

pages = "1888--1899",

journal = "Modern Pathology",

issn = "0893-3952",

publisher = "Elsevier",

number = "12",

}

Rueschoff, JH, Haberecker, M, ETOP Mesoscape Consortium, Tsourti, Z, Nackaerts, K, de Perrot, M, Brcic, L, Nadal, E, Tsimpoukis, S, Gray, SG, Ampollini, L, Aerts, JG, Felley-Bosco, E, Kirschner, MB, Monkhorst, K, Weynand, B, Bavaghar-Zaeimi, F, Samarzija, M, Llatjos, R, Finn, SP, Silini, E, von der Thusen, J, Marti, N, Vervita, K, Kammler, R, Peters, S, Stahel, RA, Baas, P & Opitz, I 2022, 'Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project', Modern Pathology, vol. 35, no. 12, pp. 1888-1899. https://doi.org/10.1038/s41379-022-01145-0

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project. / Rueschoff, Jan Hendrik; Haberecker, Martina; ETOP Mesoscape Consortium et al.
In: Modern Pathology, Vol. 35, No. 12, 01.12.2022, p. 1888-1899.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome

T2 - results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

AU - Rueschoff, Jan Hendrik

AU - Haberecker, Martina

AU - ETOP Mesoscape Consortium

AU - Tsourti, Zoi

AU - Nackaerts, Kristiaan

AU - de Perrot, Marc

AU - Brcic, Luka

AU - Nadal, Ernest

AU - Tsimpoukis, Sotirios

AU - Gray, Steven G.

AU - Ampollini, Luca

AU - Aerts, Joachim G.

AU - Felley-Bosco, Emanuela

AU - Kirschner, Michaela B.

AU - Monkhorst, Kim

AU - Weynand, Birgit

AU - Bavaghar-Zaeimi, Fatemeh

AU - Samarzija, Miroslav

AU - Llatjos, Roger

AU - Finn, Stephen P.

AU - Silini, Enrico

AU - von der Thusen, Jan

AU - Marti, Nesa

AU - Vervita, Karerina

AU - Kammler, Roswitha

AU - Peters, Solange

AU - Stahel, Rolf A.

AU - Baas, Paul

AU - Opitz, Isabelle

N1 - Funding Information: This work was supported by ETOP, Oncosuisse [KFS-3626-02-2015], Bristol-Myers Squibb, and Merck, who supplied support for sample handling and assays. Bristol-Myers Squibb and Merck did not have a role in the reporting or interpretation of the study. Open access funding provided by University of Zurich. Funding Information: The European Thoracic Oncology Platform (ETOP) coordinated Mesoscape and is responsible for the collection and management of data, data analysis, reporting, and for study design together with the University Hospital of Zurich (USZ). We thank Susanne Dettwiler, Fabiola Prutek and Christiane Mittmann for tissue processing and immunohistochemical staining’s. We thank Bart Vrugt, Alex Soltermann for their contribution to the Mesoscape development and for tumour identification. We acknowledge the Biobanks of the participating centres, and particularly the Department of Pathology and Molecular Pathology at the University Hospital of Zurich, in their role as central Mesoscape laboratory. We thank Martina Friess and Alessandra Matter for their support. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

AB - Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

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U2 - 10.1038/s41379-022-01145-0

DO - 10.1038/s41379-022-01145-0

M3 - Article

C2 - 36115922

SN - 0893-3952

VL - 35

SP - 1888

EP - 1899

JO - Modern Pathology

JF - Modern Pathology

IS - 12

ER -

Rueschoff JH, Haberecker M, ETOP Mesoscape Consortium, Tsourti Z, Nackaerts K, de Perrot M et al. Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project. Modern Pathology. 2022 Dec 1;35(12):1888-1899. Epub 2022 Sept 17. doi: 10.1038/s41379-022-01145-0

Expression of phosphorylated ribosomal protein S6 in mesothelioma patients-correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project

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