Breakthrough discovery reveals treatable form of familial mesothelioma

Researchers working independently at the University of Hawaii Cancer Center and the National Cancer Institute have discovered, and validated, a new variant of mesothelioma that may lead to more successful treatments. The studies have been published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer.

Mesothelioma is a rare and aggressive type of cancer that develops in the mesothelium, the thin layer of tissue that lines the lungs, heart, and abdomen. Asbestos exposure is the primary risk factor. Median survival time after diagnosis is typically 6 to 18 months.

In these new manuscripts, Dr. Michele Carbone of the University of Hawaii Cancer Center, and Dr. David Schrump of the National Cancer Institute, report that mesotheliomas caused by inherited germline BAP1 mutations are a different and much less aggressive compared to sporadic mesotheliomas and they discovered how to identify and diagnose these patients and how to best treat them.

They found that in addition to mesothelioma, these patients develop multiple tumors and therefore it is critical that they are enrolled in screening programs for early cancer detection. They propose to re-name these tumors as “low-grade-BAP1-associated-mesotheliomas”, L-BAM- to distinguish them from the very aggressive sporadic asbestos-induced mesotheliomas which are resistant to therapy.

The research team of Dr. Michele Carbone at the University of Hawaii Cancer Center discovered this variant of mesothelioma responds to therapy and these patient’s lives can be saved when these tumors are detected early on. Their new manuscript titled Clinical and Pathologic Phenotyping of mesotheliomas developing in carriers of Germline BAP1 Mutations Michele Carbone et al is in press in the JTO) https://www.sciencedirect.com/journal/journal-of-thoracic-oncology/articles-in-press.

During 1999-2024, the researchers 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.

Dr. Carbone’s research team identified 34 different germline inactivating mutations. Among 238 BAP1+/- carriers aged 27-81, 84 were diagnosed with mesothelioma (35%), 1/84 had evidence of asbestos exposure. No mesothelioma was recorded among 123 siblings/relatives who did not inherit BAP1+/- p<0.0001. The 84 BAP1+/- patients developed mesothelioma at a relatively young age; 45.2% developed multiple cancers. BAP1+/- patients had a florid, diffuse mesothelial hyperplasia often present in both pleural cavities, peritoneum and pericardium. Thoracoscopy and laparoscopy showed several multi-cavity ∼1-3 mm whitish flat lesions, imaging was usually negative for cancer. Histology revealed epithelioid cells lacking BAP1 nuclear staining arranged in tubulo-papillary and trabecular architectures, focally invading sub-mesothelial adipose tissue. These findings may lead to the diagnosis of stage IV metastatic mesothelioma. However, Carbone et al found that these tumors may 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 develop lesions visible by imaging, surgery and/or chemotherapy leads to survival of several years,may be cured. Deep invasion by mesothelioma cells with a solid architecture is rare: these cases have poor survival.” 

Dr. Michele Carbone, University of Hawaii Cancer Center

In an independent study conducted by the research team of Dr. David Schrump at the National Cancer Institute, National Institutes of Health, Bethesda, Md., 50 subjects with 32 germline BAP1 mutations underwent state-of-the-art computed tomographic imaging followed by video assisted thoracoscopies and diagnostic laparoscopies. Dr. Schrump and his team identified clinically occult mesotheliomas in 39 of 45 (87%) subjects affecting 63 of 81 (78%) hemi-thoraces and 27 of 32 (84%) peritoneal cavities. These mesotheliomas exhibited histological features distinct from sporadic mesotheliomas and slow clinical progression without therapeutic interventions (median follow-up: 21.8 months; range: 1.7 – 41.1 months). Laboratory experiments identified common as well as mutation-specific, cancer-associated epigenomic alterations in normal fibroblasts and peripheral blood mononuclear cells (PBMC) which correlated with cancer predilection in subjects with BAP1 Cancer Syndrome.

Overall, this prospective study demonstrated that subjects with germline BAP1 mutations have a strikingly high prevalence of subclinical mesotheliomas with unique histologic features and clinical characteristics. Furthermore, mesothelioma risk in subjects with BAP1 Cancer Syndrome may be a reflection of potentially quantifiable epigenetic changes in normal cells. These findings have already led to two ongoing protocols at the NCI (NCT05960773 and NCT06654050) to determine if oral epigenetic agents can abort progression of mesotheliomas to life threatening disease states in subjects with BAP1 Cancer Syndrome. The NCI experience is detailed in a comprehensive manuscript entitled Prospective Analysis of Mesotheliomas in Subjects with BAP1 Cancer Syndrome: Clinical Characteristics and Epigenetic Correlates of Disease which is also in press in JTO.

https://www.jto.org/article/S1556-0864(25)00984-0/fulltext

“This is a major step in the fight against mesothelioma, one of the most aggressive human cancers. It is also great relief to these families, who are now aware that their tumors can be treated and therefore most of them can live a normal life span,” said Dr. Carbone.

Dr. Carbone’s research progressed over years. Initially, studying a mesothelioma epidemic in 3 small villages in Cappadocia, Dr. Carbone proposed that familial mesothelioma was caused by genetics (Roushdy-Hammady et al. The Lancet 2001); next his team discovered the first gene responsible for familial mesothelioma (Testa et al Nature Genetics 2011); then they identified the mechanisms responsible for the potent tumor suppressor activity of BAP1 (Bononi et al Nature 2017; PNAS 2023) and discovered additional genes that when mutated in the germline may cause mesothelioma (Bononi et al PNAS 2020; Novelli et al., PNAS 2024).

The latest discovery is therefore the result of over 25 years of working with families affected by multiple cases of mesothelioma, he stated.