BRCA-associated protein 1 (BAP1) and miR-31 combination predicts outcomes in epithelioid malignant pleural mesothelioma

Our plain-English summary of BRCA-associated protein 1 (BAP1) and miR-31 combination predicts outcomes in epithelioid malignant pleural mesothelioma, by A. Murrone, L. Cantini, F. Pecci, et al (Journal of Thoracic Disease, 2021).

The study

• Authors: A. Murrone, L. Cantini, F. Pecci, V. Cognigni, C. Copparoni, S. Rinaldi, I. Fiordoliva, F. Monaco, C. Rubini, F. Barbisan, A. Cimadamore, R. Giampieri, F. Bianchi, M. Tomasetti, M. Amati, L. Santarelli, R. Berardi
• Journal: Journal of Thoracic Disease
• Published: 2021;13(10):5741-5751
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive disease, with few available treatment options. Identification of novel prognostic and predictive biomarkers is a priority. In MPM patients, BRCA-associated protein 1 (BAP1) alterations are detected in about 60% of cases and miR-31 seems to be involved in BAP1 regulation at post-transcriptional level. The aim of this study was to evaluate the interaction between BAP1 and miR-31 in MPM and their prognostic role in MPM.

Methods: The expression of BAP1 and miR-31 was analyzed in tissues of 55 MPM patients treated with first-line chemotherapy. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier method and Log-rank test was used to investigate differences among subgroups. Multivariate Cox regression analysis was used to evaluate independent predictors of survival.

Results: In the whole cohort, loss of BAP1 was associated with a significant improvement in OS, but not in PFS. Lower miR-31 levels were detected in epithelioid MPM (e-MPM) compared to the non-epithelioid subtypes and resulted associated with BAP1 loss. By looking at the e-MPM subgroup, loss of BAP1 was not able to predict clinical outcome. Conversely, miR-31 levels were significantly associated with PFS (P=0.028), but not with OS (P=0.059). By combining the two biomarkers, e-MPM patients with BAP1 loss/low miR-31 levels showed a better prognosis compared to the ones with BAP1 retained/high miR-31 levels (median OS 22.6 vs. 17.0 months, P=0.017 and median PFS 8.7 vs. 5.1 months, P=0.020). The BAP1 and miR-31 combination was confirmed at multivariate analysis as an independent prognostic factor for e-MPM patients.

Conclusions: In this preliminary study, we found that the prognostic stratification of e-MPM patients may be improved by simultaneously assessing of BAP1 status and miR-31 levels. The two-biomarker score is useful to identify a subgroup of e-MPM tumors characterized by BAP1 retained and high miR-31 levels with worse clinical outcome.

2021 Journal of Thoracic Disease. All rights reserved.

In plain English

This retrospective study from Ancona, Italy, examined tumors from 55 consecutive malignant pleural mesothelioma patients seen from 2005 to 2017. All received first-line pemetrexed, with or without platinum. The authors measured two tumor markers: BAP1 protein and a small RNA, miR-31. Asbestos exposure was documented in 47% of patients; BAP1 loss was found in 60%. In the whole group, before adjustment, median overall survival was longer with BAP1 loss than with BAP1 retained (14.9 versus 11.3 months; 95% CIs 7.7 to 22.1 and 4.9 to 17.6). Multivariate analysis did not confirm this; only tumor type and asbestos exposure were independent factors for survival. Among epithelioid patients, BAP1 alone did not predict outcome. Epithelioid patients with BAP1 loss/low miR-31 had longer median overall survival (22.6 versus 17.0 months; 95% CIs 12.0 to 33.2 and 11.5 to 22.5) and progression-free survival (8.7 versus 5.1 months; 95% CIs 3.3 to 14.1 and 2.5 to 7.6) than those with BAP1 retained/high miR-31. The authors concluded the combination may help identify epithelioid tumors with worse outcomes. They noted the small sample and preliminary, retrospective design.

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 study of tumor biomarkers (BAP1 by immunohistochemistry, miR-31 by quantitative RT-PCR) and survival
• Who was studied: 55 consecutive patients with malignant pleural mesothelioma referred to one institution in Ancona, Italy, between 2005 and 2017 (84% male, median age 71). All were treated with first-line pemetrexed-platinum (80%) or pemetrexed alone (20%). Tumor types: 74% epithelioid, 13% sarcomatoid, 13% biphasic.
• Exposure: The study's main focus was tumor markers (BAP1 status and miR-31 levels), not asbestos. Asbestos exposure was recorded at interview: patients who had worked in the asbestos-related industry were counted as exposed, which was 47% of patients. No fiber types were reported.
• Main results:
  • BAP1 loss was found in 60% of the 55 cases and was mainly associated with the epithelioid subtype (P=0.016).
  • In the whole cohort, in unadjusted analysis, BAP1 loss was associated with longer overall survival (median 14.9 months, 95% CI 7.7 to 22.1, for BAP1 loss versus 11.3 months, 95% CI 4.9 to 17.6, for BAP1 retained, P=0.021). It was not associated with longer progression-free survival (P=0.243).
  • In the whole cohort, the link between BAP1 loss and better overall survival was not confirmed in multivariate analysis.
  • In the whole-cohort multivariate analysis, only asbestos exposure and tumor type were independent factors for overall survival. For asbestos exposure, HR 1.953, 95% CI 1.006 to 3.789, P=0.048.
  • Epithelioid tumors had lower miR-31 levels than non-epithelioid tumors (P=0.04).
  • Among epithelioid patients, BAP1 status alone did not significantly predict overall survival (P=0.271) or progression-free survival (P=0.453).
  • Among epithelioid patients, low miR-31 was associated with better progression-free survival (median 7.7 versus 5.9 months for high miR-31, P=0.028). The difference in overall survival was not significant (18.4 versus 17.0 months, P=0.059).
  • Among epithelioid patients, those with BAP1 loss/low miR-31 had longer median overall survival than the BAP1 retained/high miR-31 subgroup: 22.6 months (95% CI 12.0 to 33.2) versus 17.0 months (95% CI 11.5 to 22.5), P=0.017.
  • Among epithelioid patients, the BAP1 loss/low miR-31 group also had longer median progression-free survival: 8.7 months (95% CI 3.3 to 14.1) versus 5.1 months (95% CI 2.5 to 7.6), P=0.020.
  • In multivariate analysis of epithelioid patients, the BAP1 retained/high miR-31 group had HR 2.207 (95% CI 1.062 to 4.587, P=0.034) for overall survival and HR 2.146 (95% CI 1.050 to 4.388, P=0.036) for progression-free survival.
  • In the small non-epithelioid group, the article reports that BAP1 loss/low miR-31 was associated with poor progression-free survival (HR 6.430, 95% CI 1.350 to 30.62, P=0.019).
• The authors' conclusion: The authors postulated that combining BAP1 status with miR-31 levels may help detect, within epithelioid mesothelioma, an aggressive subtype (BAP1 retained and high miR-31) with a worse outcome. They called for prospective studies.
• Limitations the authors state:
  • Small sample size, and the study was preliminary and retrospective.
  • No correction for multiple testing was performed.
  • BAP1 staining was not measured semiquantitatively, so a weak effect of miR-31 on BAP1 protein levels cannot be ruled out.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Epithelioid, Pleural Mesothelioma, Biomarker, Chemotherapy, Overall Survival, Progression-Free Survival, Non-epithelioid.

Related studies

• The "Brescia panel" (Claudin-4 and BRCA-associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas — L. Bernardi, T. Bizzarro, et al. (2021)
• The C-Reactive Protein/Albumin Ratio May Predict the Long-Term Outcome in Patients with Malignant Pleural Mesothelioma — N. Yoshida, H. Baba (2018)
• BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations — M. Cigognetti, S. Lonardi, et al. (2015)
• BRCA1-Associated Protein 1 (BAP1) Immunohistochemical Expression as a Diagnostic Tool in Malignant Pleural Mesothelioma Classification: A Large Retrospective Study — L. Righi, E. Duregon, et al. (2016)
• A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair — R. Parrotta, A. Okonska, et al. (2017)
• Diagnostic accuracy of BRCA1-associated protein 1 in malignant mesothelioma: a meta-analysis — L.M. Wang, Z.W. Shi, et al. (2017)

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