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

• Published in: Proceedings 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
• Language: English
• Published: United States National Academy of Sciences 16.07.2024
• Subjects: Apoptosis; Apoptosis - genetics; Asbestos; Asbestos - toxicity; BRCA1 protein; Ca2+-transporting ATPase; Calcium; Calcium Signaling - genetics; Calcium signalling; Carcinogenesis; Carcinogens; Cell culture; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA Repair - genetics; Female; Fibroblasts - metabolism; Genetic Predisposition to Disease; Genomic Instability; Germ-Line Mutation; Humans; Male; Medicin och hälsovetenskap; Mesothelioma; Mesothelioma - genetics; Middle Aged; Mutation; p53 Protein; Tissue culture; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; gene × environment; genetics; cancer prevention; carcinogenesis; mesothelioma
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2405231121

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.