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MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial

Elodie Maille 1, 2 Solenn Brosseau 3 Vincent Hanoux 4 Christian Creveuil 5 Claire Danel 6 Emmanuel Bergot 7, 2 Arnaud Scherpereel 8 Julien Mazières 9 Jacques Margery 10 Laurent Greillier 11, 12 Clarisse Audigier-Valette 13 Denis Moro-Sibilot 14, 15 Olivier Molinier 16 Romain Corre 17 Isabelle Monnet 18 Valérie Gounant 19 Alexandra Langlais 20 Franck Morin 20 Guénaëlle Levallet 7, 2 Gérard Zalcman 21, 22 
Abstract : Background: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.Methods: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.Results: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09–2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.Conclusions: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
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Elodie Maille, Solenn Brosseau, Vincent Hanoux, Christian Creveuil, Claire Danel, et al.. MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial. British Journal of Cancer, Cancer Research UK, 2019, 120 (4), pp.387-397. ⟨10.1038/s41416-019-0379-8⟩. ⟨hal-02103278⟩

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