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

Our plain-English summary of MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial, by E. Maille, S. Brosseau, V. Hanoux, et al (British Journal of Cancer, 2019).

The study

• Authors: E. Maille, S. Brosseau, V. Hanoux, C. Creveuil, C. Danel, E. Bergot, A. Scherpereel, J. Mazières, J. Margery, L. Greillier, C. Audigier-Valette, D. Moro-Sibilot, O. Molinier, R. Corre, I. Monnet, V. Gounant, A. Langlais, F. Morin, G. Levallet, G. Zalcman
• Journal: British Journal of Cancer
• Published: 2019;120(4):387-397
• Type of article: Randomized trial
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study used tumour samples from patients with malignant pleural mesothelioma in the MAPS phase 3 trial, which compared pemetrexed plus cisplatin chemotherapy with or without bevacizumab. It did not study asbestos exposure. The authors tested whether promoter methylation, a chemical change that can switch off a gene, of the MST1 (also called STK4) gene was linked to survival. MST1 methylation was found in 19 of 223 patients tested (8.5%). Their median overall survival was 13.0 months, against 19.3 months for patients without it (hazard ratio 2.40, 95% CI 1.48 to 3.90). After adjusting for other factors the hazard ratio was 1.78 (95% CI 1.09 to 2.93). The link with progression-free survival was not statistically significant. Methylation of several related genes did not influence survival in univariate analysis. In laboratory mesothelioma cell lines, switching off MST1 increased invasion, growth and proliferation and reduced basal cell death. It also caused the protein YAP to build up in the cell nucleus. The authors concluded that MST1 methylation is associated with worse survival and that YAP may be a possible treatment target.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pre-planned, exploratory biomarker study (Bio-MAPS) within a randomised phase 3 trial, with survival analysis using Cox models plus laboratory cell-line experiments
• Who was studied: Patients with malignant pleural mesothelioma in the MAPS trial: 448 patients randomised between 13 February 2008 and 5 January 2014 (trial approved by an ethics committee in France). MST1 methylation status was available for 223 of them. Laboratory work used human mesothelioma cell lines (MSTO-211H, H2452, H28, H2052).
• Exposure: Not an asbestos exposure study. The factor studied was promoter methylation of MST1 (STK4) and other Hippo pathway or RASSF genes in tumour tissue. Asbestos is mentioned only in the background as the main cause of the disease.
• Main results:
  • MST1 promoter was methylated in 19 of 223 tumour samples (8.5%)
  • In univariate analysis, median overall survival was 13.0 months in patients with methylated MST1 versus 19.3 months in patients with unmethylated MST1 (HR 2.40, 95% CI 1.48 to 3.90, p less than 0.001)
  • In multivariate analysis of both treatment arms together, MST1 methylation was associated with worse overall survival (adjusted HR 1.78, 95% CI 1.09 to 2.93, p = 0.022)
  • In bootstrap validation, MST1 methylation was significantly associated with worse overall survival in 59% of 1000 resampled data sets, with an optimism-corrected c-index of 0.67
  • When each treatment arm was analysed separately in multivariate analysis, the survival effect stayed significant only in the bevacizumab arm (HR 2.37, 95% CI 1.16 to 4.83, p = 0.017). An adjusted interaction test did not support a difference by treatment (adjusted HR 1.44, 95% CI 0.71 to 2.93, p = 0.38).
  • MST1 methylation did not significantly predict progression-free survival (univariate HR 1.53, 95% CI 0.95 to 2.46, p = 0.082)
  • RASSF1A, RASSF2A, RASSF6 and RASSF10 were methylated in 11.1%, 14.5%, 21.5% and 4.4% of samples respectively. No sample showed RASSF5, MST2, LATS1 or LATS2 methylation. None of these methylations influenced survival in univariate analysis.
  • In mesothelioma cell lines, switching off MST1 increased invasion through Matrigel and colony formation in soft agar
  • In the same cell lines, switching off MST1 reduced basal apoptosis and increased proliferation
  • Switching off MST1 led to YAP building up in the cell nucleus and to less TAZ in the nucleus
  • Silencing YAP in MST1-depleted MSTO-211H or H2452 cells decreased their invasion through Matrigel
• The authors' conclusion: The authors concluded that MST1 promoter methylation is associated with significantly worse overall survival in malignant pleural mesothelioma. They also concluded that their findings support YAP inhibition as a possible treatment approach.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Cisplatin, Pemetrexed (Alimta), Bevacizumab, Chemotherapy, Overall Survival, Disease-Free Survival.

Related studies

• A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial — E. Maille, J. Levallet, et al. (2022)
• MiR-193b-3p and miR-132-3p as prognostic biomarkers of survival in pleural mesothelioma patients treated with first-line bevacizumab plus pemetrexed-platinum chemotherapy in the IFCT-0701 MAPS phase 3 trial — G. Levallet, C. Creveuil, et al. (2025)
• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort — S. Brosseau, C. Danel, et al. (2019)
• Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma — B.C. Christensen, J.J. Godleski, et al. (2008)

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