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

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      DNA Repair*/genetics ; Tumor Suppressor Proteins*/genetics ; Tumor Suppressor Proteins*/metabolism ; Germ-Line Mutation* ; Ubiquitin-Protein Ligases*/genetics ; Ubiquitin-Protein Ligases*/metabolism ; Mesothelioma*/genetics ; Genetic Predisposition to Disease* ; Calcium Signaling*/genetics; Humans ; Female ; Male ; Middle Aged ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Apoptosis/genetics ; Fibroblasts/metabolism ; Asbestos/toxicity ; Genomic Instability
    • 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 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.
      Competing Interests: Competing interests statement:M.C. has a patent issued for “Methods for Diagnosing a Predisposition to Develop Cancer.” M.C. and H.Y. have a patent issued for “Using Anti-HMGB1 Monoclonal Antibody or other HMGB1 Antibodies as a Novel Mesothelioma Therapeutic Strategy”, and a patent issued for “HMGB1 As a Biomarker for Asbestos Exposure and Mesothelioma Early Detection.” M.C. is a board-certified pathologist who provides consultation for pleural pathology, including medical-legal.
    • References:
      J Mol Diagn. 2017 Sep;19(5):659-672. (PMID: 28736295)
      Redox Biol. 2019 Jul;25:101084. (PMID: 30612957)
      Carcinogenesis. 2015 Jan;36(1):76-81. (PMID: 25380601)
      J Thorac Oncol. 2023 Jun;18(6):694-697. (PMID: 37210180)
      Nat Rev Mol Cell Biol. 2018 Nov;19(11):713-730. (PMID: 30143745)
      Transl Lung Cancer Res. 2020 Feb;9(Suppl 1):S67-S76. (PMID: 32206572)
      J Thorac Oncol. 2018 May;13(5):606-623. (PMID: 29524617)
      J Thorac Oncol. 2022 Jul;17(7):921-930. (PMID: 35489694)
      BMC Cancer. 2022 Jun 1;22(1):599. (PMID: 35650591)
      Proc Natl Acad Sci U S A. 2021 Nov 30;118(48):. (PMID: 34815344)
      Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. (PMID: 29805046)
      J Clin Oncol. 2018 Oct 1;36(28):2863-2871. (PMID: 30113886)
      Mol Cell Biol. 2004 Nov;24(21):9305-16. (PMID: 15485900)
      J Thorac Oncol. 2022 Mar;17(3):461-466. (PMID: 34628055)
      Nat Protoc. 2013 Nov;8(11):2105-18. (PMID: 24113784)
      Front Pharmacol. 2022 Apr 25;13:871259. (PMID: 35548335)
      J Transl Med. 2023 Oct 25;21(1):749. (PMID: 37880686)
      PLoS One. 2011 Apr 19;6(4):e18828. (PMID: 21526190)
      Nature. 2017 Oct 19;550(7676):360-365. (PMID: 28976962)
      Cancer Genomics Proteomics. 2023 Sep-Oct;20(5):448-455. (PMID: 37643779)
      Cancer Res. 2009 Jan 1;69(1):111-9. (PMID: 19117993)
      Mol Cell. 2024 Feb 15;84(4):640-658.e10. (PMID: 38266639)
      J Clin Oncol. 2018 Oct 30;:JCO2018790352. (PMID: 30376426)
      Nat Rev Cancer. 2013 Mar;13(3):153-9. (PMID: 23550303)
      J Thorac Oncol. 2015 Apr;10(4):565-76. (PMID: 25658628)
      Nat Commun. 2021 Feb 23;12(1):1243. (PMID: 33623049)
      Oncogene. 1998 Mar 5;16(9):1097-112. (PMID: 9528852)
      Transl Lung Cancer Res. 2020 Feb;9(Suppl 1):S3-S27. (PMID: 32206567)
      Nat Methods. 2016 Feb;13(2):109-10. (PMID: 26820543)
      Oncogene. 2005 May 26;24(23):3726-36. (PMID: 15782130)
      J Thorac Oncol. 2022 Jul;17(7):873-889. (PMID: 35462085)
      FEBS Lett. 1997 Dec 22;420(1):25-7. (PMID: 9450543)
      Cancer Discov. 2020 Aug;10(8):1103-1120. (PMID: 32690542)
      Mol Cell Biol. 2003 Nov;23(21):7926-36. (PMID: 14560035)
      JAMA Netw Open. 2023 Aug 1;6(8):e2327351. (PMID: 37556141)
      PLoS Genet. 2019 Mar 29;15(3):e1008049. (PMID: 30925164)
      J Transl Med. 2018 Jul 13;16(1):194. (PMID: 30001711)
      Nat Genet. 2011 Aug 28;43(10):1022-5. (PMID: 21874000)
      Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
      Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33466-33473. (PMID: 33318203)
      Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9008-9013. (PMID: 30975761)
      Lancet. 2001 Feb 10;357(9254):444-5. (PMID: 11273069)
      Nat Rev Cancer. 2020 Sep;20(9):533-549. (PMID: 32472073)
      Nat Genet. 2009 Jun;41(6):718-23. (PMID: 19412175)
      Cancer Res. 1999 Dec 1;59(23):5922-6. (PMID: 10606236)
      Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894. (PMID: 30371827)
      Eur J Cancer. 2022 Mar;163:44-54. (PMID: 35032816)
      Nature. 2017 Jun 22;546(7659):549-553. (PMID: 28614305)
      Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1779-84. (PMID: 25624484)
      PLoS One. 2013 Aug 16;8(8):e71016. (PMID: 23976973)
      Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276)
      JAMA Oncol. 2016 Apr;2(4):482-90. (PMID: 26720728)
      NPJ Precis Oncol. 2022 Jun 29;6(1):49. (PMID: 35768576)
      CA Cancer J Clin. 2019 Sep;69(5):402-429. (PMID: 31283845)
      Nat Rev Cancer. 2007 Feb;7(2):147-54. (PMID: 17251920)
      Hum Mutat. 2022 Aug;43(8):1012-1030. (PMID: 34859531)
      J Cell Biol. 1999 Sep 6;146(5):905-16. (PMID: 10477747)
      Cell Signal. 2015 Sep;27(9):1763-71. (PMID: 26022179)
      Mol Cell. 2001 Dec;8(6):1255-66. (PMID: 11779501)
      Int J Mol Sci. 2020 Jun 17;21(12):. (PMID: 32560575)
      Genes Chromosomes Cancer. 2002 Mar;33(3):235-42. (PMID: 11807980)
      Genes (Basel). 2020 Jul 15;11(7):. (PMID: 32679805)
    • Grant Information:
      R01 CA198138 United States CA NCI NIH HHS; S10 OD028515 United States OD NIH HHS; 853057 International ERC_ European Research Council; IG-19803 Italian Association for Cancer Research; PRIN2017E5L5P3 t AROSE, Progetti di Rilevante Interesse Nazionale; C-1792 Welch Foundation (The Welch Foundation); GR-2013-02356747 Italian Ministry of Health; R01 ES030948 United States ES NIEHS NIH HHS; 5U01CA214195-04 the Early Detection Research Network NCI; 1R01ES030948-01 HHS | NIH | National Institute of Environmental Health Sciences (NIEHS); IG-23670 Italian Association for Cancer Research; 1R01CA237235-01A1 HHS | NIH | National Cancer Institute (NCI); 1R01CA198138 US Department of Defence; R01 CA237235 United States CA NCI NIH HHS; PHY-2019745 NSF; U01 CA214195 United States CA NCI NIH HHS; PRIN20177E9EPY AROSE, Progetti di Rilevante Interesse Nazionale
    • Contributed Indexing:
      Keywords: cancer prevention; carcinogenesis; gene × environment; genetics; mesothelioma
    • Accession Number:
      EC 2.3.2.27 (BARD1 protein, human)
      0 (Tumor Suppressor Proteins)
      EC 2.3.2.27 (Ubiquitin-Protein Ligases)
      0 (Tumor Suppressor Protein p53)
      1332-21-4 (Asbestos)
      0 (TP53 protein, human)
    • Publication Date:
      Date Created: 20240711 Date Completed: 20240711 Latest Revision: 20240807
    • Publication Date:
      20240807
    • Accession Number:
      PMC11260134
    • Accession Number:
      10.1073/pnas.2405231121
    • Accession Number:
      38990952