Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov;20(11):1683-1698.
doi: 10.1016/j.jtho.2025.06.020. Epub 2025 Jun 27.

Clinical and Pathologic Phenotyping of Mesotheliomas Developing in Carriers of Germline BAP1 Mutations

Michele Carbone  1 , Michael Minaai  2 , Muaiad Kittaneh  3 , Thomas Krausz  4 , Markku M Miettinen  5 , Qiang Pan Hammarström  6 , Lennart Hammarström  6 , Hassan Abolhassani  6 , Ian Pagano  2 , Ronghui Xu  2 , Flavia Novelli  2 , Giovanni Gaudino  2 , Sandra Pastorino  2 , Kavita Y Sarin  7 , Robert T Ripley  8 , Harvey I Pass  9 , David S Schrump  10 , Haining Yang  2
Affiliations

Clinical and Pathologic Phenotyping of Mesotheliomas Developing in Carriers of Germline BAP1 Mutations

Michele Carbone et al. J Thorac Oncol. 2025 Nov.

Abstract

Introduction: Mesothelioma is frequent among carriers of inactivating heterozygous germline BAP1 mutations (BAP1+/-). We studied whether the natural history and the pathology of mesotheliomas in BAP1+/- carriers differed from sporadic, not genetically related, mesotheliomas.

Methods: During 1999 to 2024, we studied 47 families carrying BAP1+/- transmitted in a Mendelian fashion. We characterized these mutations, collected family history, clinical records, prepared family pedigrees, and diagnosed their mesotheliomas.

Results: We identified 34 different germline inactivating mutations. Among 238 BAP1+/- carriers aged 27 to 81 years, 84 were diagnosed with mesothelioma (35%) and one of 84 had evidence of asbestos exposure. No mesothelioma was recorded among 123 siblings, first- or second-degree relatives who did not inherit BAP1+/- (p < 0.0001). The 84 patients with BAP1+/- developed mesothelioma at a relatively young age; 45.2% developed multiple cancers. Patients with BAP1+/- had a florid, diffuse mesothelial hyperplasia often present in both pleural cavities, peritoneum and pericardium. Thoracoscopy and laparoscopy results revealed several multicavity approximately 1 to 3 mm whitish flat lesions, but imaging result was usually negative for cancer. Histology results revealed epithelioid cells lacking BAP1 nuclear staining arranged in tubulopapillary and trabecular architectures, focally invading submesothelial adipose tissue. These findings may lead to the diagnosis of stage IV metastatic mesothelioma. However, we found that these tumors remain indolent for years, and, at this early stage, patients do not require aggressive therapy. We refer to these tumors as "low-grade-germline-mutant-BAP1-associated-mesotheliomas, L-BAM" to distinguish them from aggressive, therapy-resistant, sporadic mesotheliomas. For the 1/3 of patients who developed lesions visible by imaging, surgery, chemotherapy, or a combination of both led to survival of several years, and some were cured. Deep invasion by mesothelioma cells with a solid architecture is rare: these cases have poor survival.

Conclusions: Compared with sporadic mesotheliomas, mesotheliomas developing in BAP1+/- carriers are a different disease, biologically, histologically, and clinically; these patients require a tailored clinical approach.

Keywords: BAP1; Diagnosis; Mesothelioma; Prognosis.

PubMed Disclaimer

Conflict of interest statement

Disclosure This work receives funding through the National Institutes of Health and the National Cancer Institute (NCI) and the U.S. Department of Defense grants to Drs. Carbone and Yang and by donations to the University of Hawaii Foundation. Drs. Carbone and Yang report receiving funding from the NCI 1R01CA290173-01 (Drs. Yang, Carbone, and Ripley), 1R01CA237235-01A1 (Drs. Carbone and Yang), and 1R01CA198138 (Dr. Carbone); the National Institute of Environmental Health Sciences 1R01ES030948-01 (Drs. Carbone and Yang); the U.S. Department of Defense W81XWH-16-1-0440 (Drs. Yang, Carbone, and Pass); the UH Foundation through donations that they received from Barry and Virginia Weinman; the Riviera United-4-a Cure (Drs. Carbone and Yang); the Melohn Family Endowment; the Honeywell International Inc.; Richard L. and Susan Fried; Richard and Ray Turbin; the Germaine Hope Brennan Foundation; and the Maurice and Joanna Sullivan Family Foundation (Dr. Carbone). Drs. Carbone and Yang have a patent issued for “Using Anti-HMGB1 Monoclonal Antibody or other HMGB1 Antibodies as a Novel Mesothelioma Therapeutic Strategy” and a patent issued for “HMGB1 As a Biomarker for Asbestos Exposure and Mesothelioma Early Detection.” Dr. Carbone is a board-certified pathologist and provides consultation for pleural pathology, including medical-legal. Drs. Pass and Yang report receiving funding from the Early Detection Research Network NCI 5U01CA214195-04. Dr. Pass reports receiving funding from Genentech, Belluck, and Fox LLP. The funding sources did not have any role in the work presented here. Pharma had no role in any aspect of this research and the related manuscript.

References

    1. Roushdy-Hammady I, Siegel J, Emri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet. 2001;357(9254):444–5. - PubMed
    1. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nature genetics. 2011;43(10):1022–5. - PMC - PubMed
    1. Carbone M, Arron ST, Beutler B, et al. Tumour predisposition and cancer syndromes as models to study gene-environment interactions. Nature reviews Cancer. 2020;20(9):533–49. - PMC - PubMed
    1. Carbone M, Harbour JW, Brugarolas J, et al. Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer. Cancer discovery. 2020;10(8):1103–20. - PMC - PubMed
    1. Carbone M, Adusumilli PS, Alexander HR Jr., et al. Mesothelioma: Scientific clues for prevention, diagnosis, and therapy. CA Cancer J Clin. 2019;69(5):402–29. - PMC - PubMed