Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma

Our plain-English summary of Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma, by M. Meerang, K. Bérard, M. Friess, et al (Molecular Oncology, 2016).

The study

• Authors: M. Meerang, K. Bérard, M. Friess, B.K. Bitanihirwe, A. Soltermann, B. Vrugt, E. Felley-Bosco, R. Bueno, W.G. Richards, B. Seifert, R. Stahel, W. Weder, I. Opitz
• Journal: Molecular Oncology
• Published: 2016;10(8):1255-65
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: 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.

Material And Methods: 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).

Results: 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].

Conclusions: 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.

Copyright © 2016 Federation of European Biochemical Societies. All rights reserved.

In plain English

This retrospective study examined tumor tissue from two groups of patients with malignant pleural mesothelioma. The first was 145 Zürich patients (1999 to 2009) meant to receive chemotherapy followed by surgery. The second was 59 Boston patients who had extrapleural pneumonectomy (2002 to 2006). Researchers measured four tumor proteins (Merlin, YAP1, Survivin, CTGF) and compared them with survival and recurrence. Asbestos exposure was not studied. In the Zürich group, the 55 patients with low cytoplasmic Merlin before chemotherapy had median survival of 11 months (95% CI 8 to 14), versus 23 months (95% CI 20 to 26) for the 49 with high levels. In the Boston group, a similar Merlin trend was not statistically significant. A high share of Survivin-positive nuclei was linked to earlier recurrence in both groups and to shorter survival in the Boston group. YAP1 activation showed no link with outcomes. CTGF alone, tested only in the Zürich group, showed no link, but patients with both high CTGF and high Survivin had the worst recurrence outcome. The authors concluded Merlin and Survivin indicated poor prognosis, pending prospective confirmation.

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: Retrospective cohort study of archived tumor tissue (immunohistochemistry on tissue microarrays) linked to clinical outcomes
• Who was studied: Two cohorts of malignant pleural mesothelioma patients. Cohort 1: 145 patients at the University Hospital of Zürich, samples collected 1999 to 2009, intended for induction chemotherapy followed by surgery (133, or 92%, male). Cohort 2: 59 patients treated with extrapleural pneumonectomy at Brigham and Women's Hospital, Boston, samples collected 2002 to 2006 (48, or 81%, male). Epithelioid was the most frequent subtype in both cohorts.
• Exposure: Asbestos exposure was not examined. The factors studied were tumor protein markers: Merlin (the NF2 gene product), YAP1, Survivin and CTGF, measured in cell nuclei and cytoplasm.
• Main results:
  • Cohort 1, before chemotherapy: patients with low cytoplasmic Merlin had a median overall survival of 11 months (95% CI 8 to 14; n = 55), compared with 23 months (95% CI 20 to 26; n = 49) for patients with high levels. Median freedom from recurrence was 11 months versus 15 months.
  • Cohort 1, multivariate analysis: high versus low cytoplasmic Merlin before chemotherapy (above 0.5 vs 0.5 or below) had a hazard ratio of 0.5 (95% CI 0.3 to 0.9, p = 0.01) for overall survival and 0.5 (95% CI 0.3 to 1.0, p = 0.04) for freedom from recurrence (Table 2). In this cohort, female gender, epithelioid histotype and low pT stage were also independent prognosticators for prolonged overall survival.
  • Cohort 2: low cytoplasmic Merlin showed a similar trend toward shorter outcomes that was not statistically significant. Median freedom from recurrence was 11 versus 19 months, and median overall survival was 15 versus 19 months (low vs high).
  • Cohort 1, after chemotherapy: low nuclear Merlin was associated with shorter outcomes. Median overall survival was 15 months (95% CI 11 to 19; n = 69) for low levels versus 22 months (95% CI 20 to 24; n = 60) for high levels. Median freedom from recurrence was 11 versus 14 months.
  • Cohort 1: a high nuclear Survivin labeling index was associated with shorter freedom from recurrence, both before and after chemotherapy. Before chemotherapy, median freedom from recurrence was 17 months (low, n = 52) versus 10 months (high, n = 46). In multivariate analysis, a labeling index above 14% versus 14% or below had a hazard ratio of 3.4 (95% CI 1.7 to 6.8, p = 0.001).
  • Cohort 2: a high nuclear Survivin labeling index was associated with both freedom from recurrence and overall survival. Median freedom from recurrence was 19 months (low, n = 23) versus 12 months (high, n = 26). Median overall survival was 27 months (low, n = 23) versus 14 months (high, n = 26). In multivariate analysis for overall survival, an index above 10 versus 10 or below had a hazard ratio of 2.35 (95% CI 1.27 to 4.33, p = 0.006). Age above 61 years had a hazard ratio of 2.40 (95% CI 1.28 to 4.50, p = 0.006).
  • Constitutive YAP1 activation was found in 59% of cohort 1 and 24% of cohort 2 patients. It was not associated with clinical outcomes in either cohort.
  • CTGF levels alone were not associated with overall survival or freedom from recurrence in cohort 1, so this analysis was not done in cohort 2. However, cohort 1 patients with both high Survivin and high CTGF had the worst freedom from recurrence (multivariate hazard ratio 4.00, 95% CI 1.84 to 8.74, p less than 0.001).
• The authors' conclusion: The authors concluded that Merlin expression and the Survivin labeling index were prognosticators for poor clinical outcome in two independent mesothelioma cohorts. They suggested that, if confirmed, these markers might help identify patients who could benefit from additional treatment.
• Limitations the authors state:
  • Very few cases of the rare sarcomatoid subtype were included, which may limit comparisons between subtypes.
  • The two cohorts received different first-line and second-line treatments, which could affect the prognostic impact of the markers.
  • Because the cohorts were retrospective, the authors state that confirmation in a prospective validation cohort is required.
  • The lack of significance for Merlin in cohort 2 could reflect that cohort's smaller size and its different treatment regimens.
  • The lack of association between YAP1 activation and outcomes may stem from the small size of the cohorts.

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: Merlin, Prognosis, Pleural Mesothelioma, Chemotherapy, Extrapleural Pneumonectomy (EPP), Cisplatin, Overall Survival, Multivariate Analysis.

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• Serum Survivin Levels and Outcome of Chemotherapy in Patients with Malignant Mesothelioma — K. Goričar, V. Kovač, et al. (2015)
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