Inactivation of BAP1 and the Hippo Pathway Characterizes the Genomic Alterations of Peritoneal Mesothelioma

Our plain-English summary of Inactivation of BAP1 and the Hippo Pathway Characterizes the Genomic Alterations of Peritoneal Mesothelioma, by M. Samuels, M. Williams, A. Hasan, et al (Life, 2026).

The study

• Authors: M. Samuels, M. Williams, A. Hasan, S. Rafie, G.S. Saglimbeni, B. Hsia, S. Nair, S. Aeilias, A. Tauseef
• Journal: Life
• Published: 2026;16(3)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background/objectives: Peritoneal mesothelioma is a rare malignancy characterized by limited therapeutic options and a poor prognosis. Genomic characterization can enhance the understanding of the molecular mechanisms that lead to this disease and can contribute to improved survival outcomes through therapeutic targets.

Methods: Analysis was performed using a dataset from the AACR GENIE database (v17.0-public) comprising 204 samples from 192 patients. Data were analyzed to identify patterns in genomic alterations and clinical demographics. Within the GENIE cohort, histologic subtype information was incomplete and inconsistently reported across contributing institutions. Hence, histological subtype genomic analysis was not viable.

Results: The most common somatic mutation was found in the BAP1 gene (25.98%). Other common mutations were found in the NF2 (15.19%), TP53 (9.3%) and SETD2 (8.3%) genes. Several pathways were found as potential treatment targets including the chromatin remodeling, Hippo, and p53 signaling pathways. Given the size of our dataset, we were unable to draw significant conclusions about certain demographics.

Conclusions: This study presents data that can help draw conclusions on common mutations, mutual exclusivity patterns, and demographics at risk for peritoneal mesothelioma. Genomic analysis of peritoneal mesothelioma may inform possible intervention targets for therapeutic treatment.

In plain English

This study analyzed existing genetic data on peritoneal mesothelioma, a cancer of the abdominal lining. The data, from the public AACR GENIE database (version 17.0), covered 204 samples from 192 patients. This cohort had no survival or treatment-history data, and no patient asbestos-exposure data were reported. The most commonly mutated gene was BAP1 (53 samples; 25.98%), followed by NF2 (15.19%), TP53 (9.3%) and SETD2 (17 samples; 8.3%). Mutations in BAP1 and TRAF7 did not occur together (p less than 0.001). The article reported more SETD2 mutations in women than men (20 versus 4; p = 0.0036), counts that do not match its overall total of 17. CDC42 mutations were found only in women (6 cases); the authors called these sex differences exploratory. No statistically significant race differences in mutation enrichment were found; non-White groups were too small for firm conclusions. CHEK2, SRSF2 and CARM1 mutations appeared only in metastatic samples (25, versus 146 primary), possibly reflecting sampling noise, the authors said. The authors concluded the chromatin remodeling, Hippo signaling and p53 pathways hold potential treatment targets, which they called hypotheses, not validated treatments.

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 descriptive genomic analysis of a public, multi-institution cancer sequencing database (AACR Project GENIE v17.0-public), with no laboratory validation
• Who was studied: 192 patients with a pathologic diagnosis of peritoneal mesothelioma, contributing 204 tumor samples, from the AACR GENIE database, which pools data from 19 international cancer centers. Of the samples, 146 were primary tumors and 25 were metastatic. No collection dates are given.
• Exposure: No asbestos or other exposure was studied in this cohort. The analysis covered somatic mutations, copy number alterations and demographics (sex, race, ethnicity). The introduction mentions asbestos as a known risk factor, citing other studies.
• Main results:
  • BAP1 was the most commonly mutated gene, in 53 samples (25.98%).
  • Other common mutations: NF2 in 31 samples (15.19%), TP53 in 19 (9.3%), SETD2 in 17 (8.3%).
  • Loss-of-heterozygosity events were found in BAP1 (n = 20, 9.8%), CDKN2A (n = 18, 8.8%) and CDKN2B (n = 17, 8.3%).
  • SETD2 mutations were reported as more frequent in women than in men: 20 women (19.42%) versus 4 men (4.76%), p = 0.0036 (nominal, exploratory). These sex-group counts do not match the article's overall count of 17 SETD2-mutated samples.
  • CDC42 mutations occurred only in women (n = 6; p = 0.032). The authors described this as exploratory.
  • There were no statistically significant differences in mutation enrichment by race in this cohort.
  • Co-occurrence was reported for BAP1 and PBRM1 (n = 19; p < 0.001) and for LATS1 and LATS2 (n = 5; p < 0.001).
  • BAP1 and TRAF7 mutations were mutually exclusive (n = 0, p < 0.001).
  • Some mutations were found only in metastatic tumor samples: CHEK2 (n = 2; p = 0.0187), SRSF2 (n = 2; p = 0.0188) and CARM1.
  • The cohort was 41.7% male (n = 80) and 54.2% female (n = 104).
• The authors' conclusion: The authors concluded that recurrent alterations occur in BAP1, NF2, TP53 and SETD2, and that the chromatin remodeling, Hippo signaling and p53 pathways contain potential therapeutic targets. They stated that these targets are biologically plausible hypotheses rather than clinically validated interventions.
• Limitations the authors state:
  • There were no clinical outcome or treatment data, so the effect of the mutations on prognosis could not be analyzed.
  • Data came from different institutions using different sequencing panels with varying gene coverage, which may affect the reported mutation frequencies.
  • The sample was too small for robust analyses by race or histological subtype.
  • Because few non-White patients were included, a larger, more representative cohort is needed for conclusions about race-specific differences.
  • Histologic subtypes were grouped together, so subtype-specific alterations could not be analyzed.
  • The authors stated that mutation frequencies for genes such as BAP1 are slightly inflated by unfiltered inherited (germline) variants in tumor-only sequenced samples.
  • Chi-squared tests were used in small subgroups without adjustment for multiple testing, so the p-values are nominal, exploratory and hypothesis-generating.
  • There were far fewer metastatic samples (25) than primary samples (146), which makes that comparison vulnerable to sampling noise.
  • The authors stated that 'potential therapeutic targets' are hypotheses, not validated treatments.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Peritoneal Mesothelioma, Prognosis, Histological Subtype, Somatic Mutation.

Related studies

• Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations — T. Sato, K. Akao, et al. (2023)
• Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large-Scale Data to Inform Therapeutic Directions — D.L. Jardim, S.Z. Millis, et al. (2021)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array — P. Chirac, D. Maillet, et al. (2016)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways — A. Baldys, P. Pande, et al. (2007)

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