Prospective Analysis of Mesotheliomas in Subjects With BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease

Our plain-English summary of Prospective Analysis of Mesotheliomas in Subjects With BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease, by X. Wu, F.V. Hernandez, H. Wang, et al (Journal of Thoracic Oncology, 2025).

The study

• Authors: X. Wu, F.V. Hernandez, H. Wang, R. Wang, S. Shiffka, N. Shah, S.R. Carr, C.D. Hoang, A.M. Blakely, A. Lebensohn, K. Mishra, S. Xi, M.R. Zhang, T. Tolunay, S. Gara, A. Absher, D. Francis, A. Rowland, M. Connolly, S. Jacobs, S. Orfgen, K. Driscoll, A. Ghafoor, X. Lu, G.G. Malouf, H. Yang, M. Carbone, R. Hassan, E. Jones, M. Miettinen, D.S. Schrump
• Journal: Journal of Thoracic Oncology
• Published: 2025;20(11):1699-1715
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Although mesotheliomas are the most common malignancies identified in BAP1 cancer syndrome (BCS), the prevalence and natural history of the neoplasms have not been elucidated. Protocol NCT04431024 was initiated to prospectively evaluate whether high-resolution computed tomography (CT) imaging and minimally invasive surgical evaluation could facilitate detection and surveillance of mesotheliomas in subjects with germline BAP1 mutations.

Methods: Subjects above or equal to 33 years of age with or without prior malignancies underwent CT imaging followed by bilateral thoracoscopies and laparoscopies. CT imaging and intraoperative findings were objectively scored; surgical biopsies were interpreted by two expert pathologists. Skin, peripheral blood mononuclear cells, plasma, serum, and tumor biopsies were collected for correlative research studies.

Results: A total of 50 subjects with 32 germline BAP1 mutations were enrolled between March 2021 and July 2024. Median follow-up was 21.8 months (range: 1.7-41.1 mo). Furthermore, 16 sites of prior mesothelioma in 15 patients were excluded from the analysis. Surgical evaluation identified diffuse mesotheliomas in 39 of 45 subjects (87%), affecting 63 of 81 hemi-thoraces (78%) and 27 of 32 peritoneal cavities (84%); these mesotheliomas exhibited unique histologic features and slow clinical progression without therapeutic interventions. CT scans were unreliable for detecting or ruling out these mesotheliomas. Common and mutation specific, cancer-associated epigenomic alterations were identified in dermal fibroblasts and peripheral blood mononuclear cells, which correlated with cancer predilection in subjects with BCS.

Conclusions: Adult subjects with germline BAP1 mutations exhibit a high prevalence of subclinical, multicompartment mesotheliomas, which may be manifestations of systemic epigenetic burdens. These findings establish a paradigm for longitudinal assessment of subjects with BCS and support further efforts to identify and validate epigenetic biomarkers for the detection and surveillance of mesotheliomas and other malignancies arising in these individuals.

Published by Elsevier Inc.

In plain English

This prospective study at the U.S. National Cancer Institute enrolled 50 people with inherited BAP1 mutations between March 2021 and July 2024. Chest and abdominal surgery was planned regardless of CT, but five people had none and some areas went unexamined. Asbestos exposure was not objectively quantified. Of 45 who had surgery, 39 (87%) had diffuse mesothelioma, including 25 of 30 never previously diagnosed. Excluding areas already known to be affected, mesothelioma was found in 63 of 81 chest sides and 27 of 32 abdomens. These newly found plaque-like tumors were all low grade. On study-team review, CT showed suspicious findings in 37% of affected areas. Fifteen people re-examined after one year showed slow or no apparent progression. All people in one comparison had newly found mesothelioma. Some had no earlier BAP1-related cancer; others had an active or earlier one, which could be mesothelioma. Separate 10-marker DNA methylation sets in skin and blood cells, linked to the same genes, told these groups apart with about 90% predictive performance within this cohort. The authors concluded that CT has limited use for finding or ruling out early mesothelioma in these people. They noted possible lead-time bias and limited sample size.

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: Prospective clinical protocol (NCT04431024). Participants had CT imaging followed by planned surgical examination (thoracoscopy and laparoscopy) with biopsies and repeat surveillance. The study also included laboratory analysis of DNA methylation in skin fibroblasts and blood cells.
• Who was studied: 50 patients carrying 32 unique germline BAP1 mutations (BAP1 cancer syndrome), accrued at the National Cancer Institute between March 2021 and July 2024. There were 24 males and 26 females, with a median age of 51.2 years (range 29.9 to 73.3). Five did not have surgery, leaving 45 assessable patients.
• Exposure: Germline BAP1 mutations. Asbestos exposure was not objectively quantified in these subjects.
• Main results:
  • Five patients did not undergo surgical evaluation and were excluded from the clinical analysis. The reasons were medical contraindications, patient refusal or logistics.
  • Of the 45 assessable patients, 15 already had confirmed mesothelioma in 16 compartments at baseline. These compartments were excluded from later analysis. Six further compartments were never evaluated during surgery.
  • Surgical evaluation found diffuse mesothelioma in 39 of 45 assessable subjects (87%).
  • Compartments already known to have mesothelioma and those not evaluated were excluded. Of the remaining compartments, 90 of 113 (80%) were confirmed to have mesothelioma. This included 63 of 81 hemi-thoraces (78%) and 27 of 32 abdominal cavities (84%).
  • Of 30 patients with no prior diagnosis of mesothelioma, 25 (83%) were found to have diffuse mesotheliomas at surgery. These involved 64 of 84 cavities (76%).
  • 14 of 15 subjects (93%) with a prior history of mesothelioma were found to have additional disease.
  • Of 43 subjects who had more than one cavity examined, 34 (79%) had synchronous, subclinical multicompartment mesotheliomas.
  • Of the 90 cavities with confirmed mesothelioma, 33 (37%) had CT findings suspicious for mesothelioma on review by the study team. Overall, CT had a sensitivity of 37% and a specificity of 70%.
  • For subclinical pleural and peritoneal mesotheliomas, CT had a positive predictive value of 82% and a negative predictive value of 22%.
  • The plaque-like lesions were all low grade (nuclear grade 1 or 2). They were typically 0.5 to 1.0 mm thick and showed loss of BAP1. The authors separately described more aggressive, infiltrative tumors with higher nuclear atypia.
  • Fifteen patients had repeat laparoscopy and thoracoscopy 1 year after the first evaluation. Mesothelioma was still present, with slow or no apparent progression.
  • In fibroblast DNA methylation analysis, patients from separate families who shared the same BAP1 mutation clustered together.
  • In fibroblasts, ten DNA methylation probes had a predictive performance of about 90% within this cohort for distinguishing two groups. Both groups had newly detected mesothelioma. M1 (n = 16) had no prior BAP1-associated malignancy. M2 (n = 22) had active or prior BAP1 malignancies, including mesothelioma.
  • In blood cells (PBMCs), a different set of 10 probes, linked to the same 10 gene loci, also had a predictive performance of 90% for distinguishing M1 and M2 subjects.
• The authors' conclusion: The authors concluded that CT scans have limited utility for either detecting or ruling out early-stage mesotheliomas in subjects with BAP1 cancer syndrome.
• Limitations the authors state:
  • Lead-time bias cannot be ruled out when judging the slower progression of these mesotheliomas.
  • The findings cannot be directly compared with subjects whose mesotheliomas do not arise from germline BAP1 mutations. The prevalence and natural history of subclinical sporadic mesotheliomas are unknown.
  • The sample size was too small to identify a statistically significant DNA methylation signature distinguishing cancer-free subjects from those with malignancy. Only two subjects were cancer-free (M0).
  • The authors were unable to reliably obtain and culture normal pleura, so fibroblasts were used instead.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, BAP1 Tumor Predisposition Syndrome, Neoplasm, Bilateral, CT Scan, Fibroblast, Biomarker.

Related studies

• 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)
• Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations — M.G. Zauderer, M. Bott, et al. (2013)
• Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases — R. Pilarski, C.M. Cebulla, et al. (2014)
• Case report: Onychopapilloma in a patient with BAP1 tumor predisposition syndrome-a useful clinical marker? — E. Sjøstrøm, L.B. Ahlborn, et al. (2026)
• Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s — M. Carbone, E.G. Flores, et al. (2015)
• BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs — M. Carbone, L.K. Ferris, et al. (2012)

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