Two Independent Studies Uncover a Novel, Less Aggressive Variant of Mesothelioma Linked to Germline BAP1 Mutations
In a groundbreaking development poised to redefine the landscape of mesothelioma research and treatment, two separate teams of researchers from the University of Hawaii Cancer Center and the National Cancer Institute (NCI) have identified and characterized a novel variant of mesothelioma associated with inherited germline mutations in the BAP1 gene. These pivotal studies, recently published in the prestigious Journal of Thoracic Oncology— the official journal of the International Association for the Study of Lung Cancer — illuminate a previously unrecognized subset of mesothelioma patients whose tumors exhibit markedly less aggressive clinical behavior and respond favorably to therapeutic interventions.
Mesothelioma is globally recognized as a highly aggressive and often fatal malignancy arising from the mesothelial lining of the lungs, heart, and abdominal cavity. Exposure to asbestos fibers remains the primary environmental risk factor, contributing to the development of sporadic, therapy-resistant tumor phenotypes characterized by rapid progression and median survival times typically ranging from six to eighteen months post-diagnosis. However, the research led by Dr. Michele Carbone and colleagues challenges this paradigm by demonstrating that mesothelioma developing in the context of inherited germline BAP1 mutations follows a distinctly different clinical course.
Dr. Carbone’s team conducted an extensive 25-year investigation of 47 families harboring germline BAP1 heterozygous mutations (BAP1+/-), transmitted in a Mendelian inheritance pattern. Through rigorous phenotypic profiling, clinical characterization, and molecular assessment, they identified 34 unique inactivating mutations in BAP1 among 238 carriers aged between 27 and 81. Strikingly, 35% (84 individuals) were diagnosed with mesothelioma, despite negligible asbestos exposure, while none of the 123 non-carrier siblings and relatives developed the disease. These patients manifested mesotheliomas at a comparatively young age and frequently developed multiple malignancies over time, underscoring a hereditary cancer predisposition linked to BAP1 dysfunction.
The pathological investigation revealed a consistent pattern of florid mesothelial hyperplasia encompassing the pleura, peritoneum, and pericardium, often silent on conventional imaging modalities such as CT scans. Advanced thoracoscopic and laparoscopic examination uncovered multiple sub-millimeter whitish flat lesions diffusely distributed across serous cavities. Histologically, these lesions comprised epithelioid cells devoid of nuclear BAP1 expression, arranged predominantly in tubulo-papillary and trabecular architectures with focal invasion into sub-mesothelial adipose tissue. Notably, despite histologic features suggestive of late-stage metastatic disease, the clinical course was indolent in the majority of cases, with many patients not requiring aggressive treatment modalities in early stages.
In recognition of these distinctive features, the investigators proposed the designation “low-grade-germline-mutant-BAP1-associated-mesothelioma” (L-BAM) to differentiate this entity from conventional sporadic mesotheliomas, which are typically high-grade, asbestos-induced, and refractory to chemotherapy. Importantly, patients exhibiting L-BAM demonstrated enhanced responsiveness to surgical resection and chemotherapy when lesions became detectable by imaging, resulting in prolonged survival—often measured in years rather than months—and in some cases, potential cure. Only a minority progressed to deep invasion and exhibited solid tumor morphology, conditions associated with poorer prognosis.
Complementing these clinical findings, an independent prospective study led by Dr. David Schrump at the National Cancer Institute conducted state-of-the-art diagnostic imaging followed by video-assisted thoracoscopic and laparoscopic procedures in 50 individuals possessing 32 distinct germline BAP1 mutations. The team detected clinically occult mesotheliomas in an overwhelming majority—87% of subjects—with involvement spanning 78% of hemi-thoraces and 84% of peritoneal cavities. These tumors shared unique histopathologic characteristics divergent from sporadic tumors and displayed slow progression over median follow-up exceeding 21 months, even in the absence of immediate therapeutic intervention.
Beyond clinical characterization, Dr. Schrump’s group explored the epigenetic landscape of these patients, employing laboratory analyses of normal fibroblasts and peripheral blood mononuclear cells (PBMCs) to reveal shared and mutation-specific epigenomic alterations correlated with increased cancer risk under the umbrella of BAP1 Cancer Syndrome. Such findings suggest that epigenetic dysregulation plays a critical role in disease pathogenesis and may serve as a biomarker for risk stratification and early intervention.
These combined insights have propelled translational research efforts, prompting the initiation of two ongoing clinical protocols at the NCI (NCT05960773 and NCT06654050) aimed at testing the efficacy of oral epigenetic agents in arresting mesothelioma progression in carriers of BAP1 mutations. By targeting the underlying molecular alterations before tumors advance to life-threatening stages, these interventions hold promise for transforming patient outcomes in a population historically burdened by dismal prognoses.
“This discovery represents a monumental advance in mesothelioma research,” stated Dr. Carbone. “For decades, mesothelioma was regarded almost invariably as an untreatable disease with poor survival. Now, the identification of L-BAM and its relatively benign clinical behavior offers hope for families carrying BAP1 mutations—enabling early diagnosis, tailored treatment, and the potential for normal life expectancy.”
Dr. Carbone attributes this breakthrough to over 25 years of dedicated research spanning epidemiological studies in endemic regions of Cappadocia, genetic investigations revealing the heritable nature of familial mesothelioma, and molecular elucidation of BAP1’s tumor suppressor functions. Initial studies reported in The Lancet (2001) highlighted a familial clustering of mesothelioma, followed by the landmark identification of BAP1 mutations by Testa et al. (Nature Genetics, 2011). Subsequent work by Carbone and collaborators delineated the complex tumor suppressor mechanisms orchestrated by BAP1, incorporating studies published in Nature (2017) and Proceedings of the National Academy of Sciences (PNAS, 2020, 2023, 2024).
These findings challenge the longstanding narrative that asbestos exposure is the predominant driver of all mesotheliomas, underscoring the importance of genetic predisposition and molecular biomarkers in shaping disease trajectories. The revelation of a less aggressive, therapy-responsive tumor variant rekindles optimism for improved surveillance strategies and personalized medicine approaches that could mitigate morbidity and mortality associated with mesothelioma.
Furthermore, the research provides a compelling rationale for integrating advanced diagnostic techniques—including high-resolution imaging and minimally invasive endoscopic assessments—into routine screening protocols for individuals harboring germline BAP1 mutations. Early detection of subtle mesothelial lesions, often undetectable by conventional imaging, coupled with a nuanced understanding of tumor biology, could tailor interventions that arrest malignant transformation before dissemination.
In the broader context, this research exemplifies the power of combining genetic, histopathological, clinical, and epigenetic data to unravel the heterogeneity of cancer phenotypes. As the first evidence of a genetically defined, “low-grade” mesothelioma subtype emerges, it sets the stage for revising clinical guidelines and therapeutic algorithms, highlighting the necessity for multidisciplinary collaboration among oncologists, geneticists, pathologists, and thoracic surgeons.
Mesothelioma’s traditional label as an invariably fatal cancer is thus poised for redefinition; patients with germline BAP1 mutations may now be empowered with knowledge and access to targeted therapies that fundamentally alter their disease course. Continued research into the molecular underpinnings and therapeutic vulnerabilities of L-BAM will undoubtedly refine and expand treatment paradigms, translating scientific discovery into tangible clinical benefits for affected families worldwide.
Subject of Research: Inherited germline BAP1 mutations and their association with a novel, less aggressive variant of mesothelioma (Low-grade BAP1-associated mesothelioma, L-BAM)
Article Title: Clinical and Pathologic Characterization of a Novel Germline BAP1-Associated Low-Grade Mesothelioma
News Publication Date: September 2, 2025
Web References:
https://www.sciencedirect.com/journal/journal-of-thoracic-oncology/articles-in-press
References:
– Carbone M et al., Clinical and Pathologic Phenotyping of Mesotheliomas Developing in Carriers of Germline BAP1 Mutations, Journal of Thoracic Oncology (in press)
– Schrump DS et al., Prospective Analysis of Mesotheliomas in Subjects with BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease, Journal of Thoracic Oncology (in press)
– Roushdy-Hammady I et al., Familial Mesothelioma in Cappadocia: The Lancet 2001
– Testa JR et al., Germline BAP1 Mutations in Familial Mesothelioma, Nature Genetics 2011
– Bononi A et al., Mechanistic Insights into BAP1 Tumor Suppressor Activity, Nature 2017; PNAS 2023
– Bononi A et al., Additional Germline Mutations in Mesothelioma, PNAS 2020; Novelli R et al., PNAS 2024
Keywords: Mesothelioma, BAP1 Cancer Syndrome, germline mutations, low-grade mesothelioma, thoracic oncology, epigenetic alterations, familial cancer predisposition, targeted therapy, early detection, tumor suppressor gene, carcinogenesis, pleural malignancy
