title: Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma.
abstract: Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein-1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes.
  
  
  
  Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre- and post-CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H-score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR).
  
  
  
  Kaplan-Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre-induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post-CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre- and post-CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3-0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3-1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7-6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27-4.33, p = 0.006].
  
  
  
  Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Mayura
authors.initials: M
authors.lastname: Meerang
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Karima
authors.initials: K
authors.lastname: Bérard
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Friess
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Byron K Y
authors.initials: BK
authors.lastname: Bitanihirwe
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Bart
authors.initials: B
authors.lastname: Vrugt
authors.affiliation: Laboratory of Molecular Oncology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Felley-Bosco
authors.affiliation: Thoracic Surgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Thoracic Surgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Department of Biostatistics, Epidemiology, Biostatistics, and Prevention Institute (EBPI), University of Zürich, Zürich 8001, Switzerland.
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.affiliation: Laboratory of Molecular Oncology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stahel
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland. Electronic address: isabelle.schmitt-opitz@usz.ch.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Opitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D015999:Multivariate Analysis; D025581:Neurofibromin 2 / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011379:Prognosis; D000077022:Survivin; D046888:Tissue Array Analysis; D014157:Transcription Factors; D016896:Treatment Outcome; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D000077022:Survivin; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor
keywords: Hippo pathway; Malignant pleural mesothelioma; Merlin; Multimodality treatment; Survivin