Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling

Our plain-English summary of Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling, by F. Novelli, Y. Yoshikawa, V.A.M. Vitto, et al (Proceedings of the National Academy of Sciences of the United States of America, 2024).

The study

• Authors: F. Novelli, Y. Yoshikawa, V.A.M. Vitto, L. Modesti, M. Minaai, S. Pastorino, M. Emi, J.H. Kim, F. Kricek, F. Bai, J.N. Onuchic, A. Bononi, J.S. Suarez, M. Tanji, C. Favaron, A.A. Zolondick, R. Xu, Y. Takanishi, Z. Wang, G. Sakamoto, G. Gaudino, J. Grzymski, F. Grosso, D.S. Schrump, H.I. Pass, L. Atanesyan, J. Smout, S. Savola, K.Y. Sarin, H. Abolhassani, L. Hammarström, Q. Pan-Hammarström, C. Giorgi, P. Pinton, H. Yang, M. Carbone
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2024;121(29):e2405231121
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

In plain English

This was a genetic screening and laboratory study. The authors examined germline (inherited) DNA from 61 people with young-onset mesothelioma and no evidence of asbestos exposure, and from 264 people with sporadic mesothelioma in the USA, Japan and Italy. Three of the 61 (4.9%) carried rare BARD1 variants that computer scores predicted to be damaging. Three of the 264 sporadic patients carried such variants, all in the US group. The authors put this at about 1.8% of all mesothelioma patients. No survival information was available for the sporadic group. The BARD1 carriers studied had statistically significantly longer survival than people with sporadic mesothelioma, with a median of 3.0 years (95% confidence limits 2.6 to 23.0). In the laboratory, fibroblasts from one woman with peritoneal mesothelioma, alive over 23 years later, showed more DNA damage and signs of reduced cell death. Mesothelial cells with lowered BARD1 showed similar changes after crocidolite asbestos exposure. They formed more transformed foci when exposed to crocidolite with TNFα. The authors concluded they had linked germline BARD1 mutations to mesothelioma in young patients. The other missense variants were not tested because cells from those patients were unavailable.

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: Genetic sequencing study of mesothelioma patients' germline DNA combined with laboratory (in vitro) experiments on patient-derived fibroblasts and on primary human mesothelial cells in which BARD1 was experimentally reduced
• Who was studied: Two groups. The first was 61 patients who developed mesothelioma younger than 55 with no evidence of asbestos exposure. The second was 264 sporadic mesothelioma patients: 101 from the USA, 131 from Japan and 32 from Italy. Survival information was not available for the second group. The laboratory work used fibroblasts from one female BARD1V523A carrier with diffuse peritoneal mesothelioma, and benign mesothelial cells obtained from pleural fluid of patients with nonmalignant conditions.
• Exposure: In the laboratory, BARD1-reduced primary human mesothelial cells were exposed to crocidolite asbestos at 5 micrograms per square centimetre. In the transformation (foci) assay this was done in the presence of TNFα. Fibroblasts were exposed to 1 Gy ionizing radiation or to hydrogen peroxide. The main exposure studied in patients was inherited BARD1 variants. The young-patient group had no evidence of asbestos exposure.
• Main results:
  • In the young-patient group, 3 of 61 (4.9%) carried rare heterozygous germline BARD1 variants with CADD scores above 20.
  • In the same young-patient group, 27 of 61 (44.2%) carried pathogenic BAP1 variants.
  • Among the 264 sporadic mesothelioma patients, three carried rare BARD1 mutations with CADD scores above 20, all in the US group.
  • The authors estimated that about 1.8% of all mesothelioma patients, and 4.9% of those younger than 55, carried rare germline BARD1 variants.
  • Survival information was not available for the sporadic group. The BARD1 carriers studied had statistically significantly (P less than 0.05) improved survival compared to sporadic mesothelioma. Their median survival was 3.0 years, with 95% confidence limits of 2.6 to 23.0.
  • The BARD1V523A carrier whose cells were studied had diffuse peritoneal mesothelioma and had survived more than 23 years.
  • BARD1V523A fibroblasts showed a significant increase in micronuclei, a sign of chromosome damage, after ionizing radiation (P less than 0.05).
  • Mesothelial cells with BARD1 silenced had a significantly higher frequency of micronuclei after asbestos exposure than control cells.
  • The authors interpreted reduced BARD1 binding to p53 as leading to lower p53 levels and reduced apoptosis (programmed cell death).
  • Mesothelial cells with BARD1 silenced formed more transformed foci when exposed to crocidolite asbestos in the presence of TNFα.
  • Experiments with purified proteins indicated that BARD1, p53 and SERCA2 form a three-part protein complex.
  • In the TCGA mesothelioma dataset, 37 patients with low BARD1 expression in their tumours had significantly longer median survival than patients with high BARD1 expression (P = 0.009679).
• The authors' conclusion: The authors concluded that they had linked germline BARD1 mutations to the development of mesothelioma in young patients.
• Limitations the authors state:
  • Functional laboratory studies were done only for the BARD1V523A variant. The other missense variants were not tested because cells from those patients were not available.
  • Survival information was not available for the 264 sporadic mesothelioma patients.
  • Two BARD1 variants found in several patients (p.Arg658Cys and p.Ser241Cys) were left out of the counts. They are common in some populations, and the authors were unsure whether they cause disease.
  • ClinVar classifications did not help the authors judge whether the variants were pathogenic.

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, Germline Mutation, Fibroblast, Apoptosis, Mesothelial Cells, Carcinogenesis.

Related studies

• Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma — M. Betti, E. Casalone, et al. (2017)
• Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma — A. Bononi, K. Goto, et al. (2020)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• Germline BAP1 mutations predispose also to multiple basal cell carcinomas — A. de la Fouchardière, O. Cabaret, et al. (2015)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)

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