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

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 ( gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missen...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 121; no. 29; p. e2405231121
Main Authors Novelli, Flavia, Yoshikawa, Yoshie, Vitto, Veronica Angela Maria, Modesti, Lorenzo, Minaai, Michael, Pastorino, Sandra, Emi, Mitsuru, Kim, Jin-Hee, Kricek, Franz, Bai, Fang, Onuchic, José N, Bononi, Angela, Suarez, Joelle S, Tanji, Mika, Favaron, Cristina, Zolondick, Alicia A, Xu, Ronghui, Takanishi, Yasutaka, Wang, Zhanwei, Sakamoto, Greg, Gaudino, Giovanni, Grzymski, Joseph, Grosso, Federica, Schrump, David S, Pass, Harvey I, Atanesyan, Lilit, Smout, Jan, Savola, Suvi, Sarin, Kavita Y, Abolhassani, Hassan, Hammarström, Lennart, Pan-Hammarström, Qiang, Giorgi, Carlotta, Pinton, Paolo, Yang, Haining, Carbone, Michele
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 16.07.2024
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Summary: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 ( 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 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 -silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of activity and revealed that heterozygous germline 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.
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ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2405231121