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

• 成果类型: Article
• 署名作者: Novelli, Flavia; Yoshikawa, Yoshie; Vitto, Veronica Angela Maria; Modesti, Lorenzo; Minaai, Michael; Pastorino, Sandra; Emi, Mitsuru; Kim, Jin-Hee; Kricek, Franz; Bai, Fang; Onuchic, Jose 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; Hammarstrom, Lennart; Pan-Hammarstrom, Qiang; Giorgi, Carlotta; Pinton, Paolo; Yang, Haining; Carbone, Michele
• 署名单位: University of Hawaii System; Cancer Research Center of Hawaii; Hyogo Medical University; University of Ferrara; ShanghaiTech University; Rice University; University of Hawaii System; University of Hawaii Manoa; Nevada System of Higher Education (NSHE); Desert Research Institute NSHE; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); New York University; Stanford University; Karolinska Institutet
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15367
• DOI: 10.1073/pnas.2405231121
• 发表日期: 2024-07-16
• 关键词: bap1 mutations; susceptibility; asbestos; brca1; p53; immunohistochemistry; apoptosis; gene

摘要

We report that similar to 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 BARD1 V523A 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.