Prognostic impact of somatic mutations among patients with pleural and peritoneal mesothelioma

Our plain-English summary of Prognostic impact of somatic mutations among patients with pleural and peritoneal mesothelioma, by J.M. Bader, A. Dhiman, N. Aguirre, et al (NPJ Precision Oncology, 2026).

The study

• Authors: J.M. Bader, A. Dhiman, N. Aguirre, K.A. Ofori, P. Gupta, H. Qin, A. Sharma, O. Mitchell, M.Y. Tjota, A.N. Husain, M. Drazer, J. Churpek, H. Kindler, K. Turaga
• Journal: NPJ Precision Oncology
• Published: 2026;10(1)
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a rare cancer with poor prognosis. Somatic mutations show prognostic value in smaller studies; however, detailed survival analysis of mutations, specific variants, and co-mutations are unknown. This study gathered one of the largest mesothelioma cohorts in North America to determine prognostic impact of treatments, tumor characteristics, and somatic mutations. Among 195 patients, 70% (n = 137) had pleural and 30% (n = 58) had peritoneal mesothelioma. NF2, TERT, and CDKN2A had worse OS in pleural mesothelioma. NF2 mutations with truncated NF2 protein (non-sense and frameshift with premature stop codon) had worse OS in pleural mesothelioma (log-rank-p < 0.001). Conversely, NF2 pathogenic mutations with loss-of-function/structural variants were not associated with OS, revealing that NF2 truncating mutations may drive NF2's prognostic impact. This is emphasized by higher mortality at 1-year (44% vs 7.7%, p = 0.044) and 18-months (69% vs 17%, p = 0.006) compared to non-truncating NF2 mutations. Overall, this study found that pleural and peritoneal mesothelioma have unique mutations with prognostic significance. Furthermore, as trials demonstrate varied results in NF2-targeted treatments, this study supports biomarker-informed strategies to guide trial enrollment and development of targeted-therapies.

© 2026. The Author(s).

In plain English

This retrospective study covered 199 adults diagnosed with mesothelioma in 2010–2022 at the University of Chicago whose tumors underwent somatic mutation testing: 137 pleural, 58 peritoneal and 4 with both. Asbestos exposure was recorded for 93 patients (47%); fiber types were not reported. Estimated five-year survival was 25.7% for pleural and 41.8% for peritoneal mesothelioma, but overall survival did not differ significantly between groups. After adjustment, NF2 (hazard ratio 1.95, 95% CI 1.14–3.34) and TERT (2.51, 95% CI 1.16–5.44) mutations were linked to worse survival in pleural mesothelioma. CDKN2A mutations were linked to worse survival before adjustment but not after; no mutation showed an independent association in peritoneal mesothelioma. The authors then compared pleural patients with harmful NF2 mutations who had died or were followed over a year. The 16 whose mutation produced a shortened ('truncated') NF2 protein had higher mortality than the 13 with other harmful NF2 mutations: 44% vs 7.7% at 1 year and 69% vs 17% at 18 months. The authors concluded mutation testing could help predict outcomes, especially in pleural mesothelioma, and that findings need validation in larger prospective cohorts.

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 single-institution cohort study linking tumor somatic mutation profiles to overall survival
• Who was studied: 199 consecutive adults (18 or older) with somatic mutation profiling and confirmed pleural or peritoneal mesothelioma diagnosed 2010 to 2022 at the University of Chicago Mesothelioma Clinic: 137 pleural-only, 58 peritoneal-only, 4 bicavitary; 62% female, 97% white
• Exposure: The main factor studied was somatic tumor mutations found by next-generation sequencing (for example BAP1, CDKN2A, NF2, TP53, TERT). Asbestos exposure was recorded as a patient characteristic for 93 of 199 patients (47%). Fiber types and doses were not reported, and survival was not analyzed by asbestos exposure.
• Main results:
  • Estimated overall survival for peritoneal mesothelioma was 92.6% at 1 year, 74.1% at 2 years and 41.8% at 5 years.
  • Estimated overall survival for pleural mesothelioma was 86.4% at 1 year, 60.4% at 2 years and 25.7% at 5 years. Overall survival did not differ significantly between pleural and peritoneal mesothelioma (log-rank p = 0.079).
  • In unadjusted (Kaplan-Meier) analysis, CDKN2A mutations were associated with worse overall survival in both pleural (p less than 0.001) and peritoneal (p = 0.036) mesothelioma. This was not significant on multivariate analysis.
  • Among all patients, after adjustment, NF2 mutations (HR 1.74, 95% CI 1.08–2.81, p = 0.024) and TERT mutations (HR 2.28, 95% CI 1.16–4.50, p = 0.017) were independently associated with worse overall survival.
  • Among pleural mesothelioma patients, after adjustment, NF2 mutations (HR 1.95, 95% CI 1.14–3.34, p = 0.015) and TERT mutations (HR 2.51, 95% CI 1.16–5.44, p = 0.020) were independently associated with worse overall survival.
  • Among peritoneal mesothelioma patients, no mutation showed a significant independent association with survival.
  • This comparison covered pleural mesothelioma patients with a pathogenic NF2 mutation who either died or had more than 1 year of follow-up. Of these, 16 had truncating variants and 13 had other pathogenic variants.
  • In that comparison, patients with truncating variants had higher mortality than those with other pathogenic variants: 44% vs 7.7% at 1 year (p = 0.044) and 69% vs 17% at 18 months (p = 0.006).
  • Among pleural mesothelioma patients, after adjustment, NF2 truncating mutations were independently associated with worse overall survival (HR 3.32, 95% CI 1.71–6.43, p less than 0.001).
  • Among pleural mesothelioma patients, non-truncating pathogenic NF2 mutations showed no significant effect on survival (HR 0.91, 95% CI 0.35–2.35, p = 0.84).
  • TERT mutations were more likely to occur together with CDKN2A mutations (odds ratio 3.3, 95% CI 1.08–10.0, p = 0.02).
  • BAP1 mutations did not show significant survival differences. The authors noted this may have been limited by sample size.
• The authors' conclusion: The authors concluded that pleural and peritoneal mesothelioma have distinct somatic mutation profiles. They found that TERT and NF2 truncating mutations were independently associated with worse survival in pleural mesothelioma. They stated that their findings support using somatic mutation testing to predict outcomes, particularly in pleural mesothelioma, and that these findings need validation in prospective multicenter studies.
• Limitations the authors state:
  • The study was retrospective and conducted within a single health system, which may introduce selection bias and limit generalizability.
  • Patients who did not receive next-generation sequencing were excluded.
  • Sample sizes within specific mutation subgroups were modest, which may limit statistical power.
  • Operator bias in how laboratory protocols were carried out may have affected mutation detection in some cases.
  • Protein-level (immunohistochemical) validation and germline (inherited) genetic testing were not available.
  • Residual confounding may remain despite multivariable adjustment.

Topics

Medical terms in this study, explained in our Lexicon: Somatic Mutation, Peritoneal Mesothelioma, Mesothelioma, Prognosis, CDKN2A, Pleural Mesothelioma, Biomarker.

Related studies

• BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma — H. Alakus, S.E. Yost, et al. (2015)
• Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases — D.B. Chapel, J.J. Schulte, et al. (2021)
• Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations — M.G. Zauderer, M. Bott, et al. (2013)
• Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene — A. Ghafoor, I. Mian, et al. (2021)
• How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations — H. Rehrauer, L. Wu, et al. (2018)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)

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