Article ; Online: BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
Journal of the National Cancer Institute
2024 Volume 116, Issue 1, Page(s) 138–148
Abstract: Background: High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common ... ...
| Abstract | Background: High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common single nucleotide polymorphisms and rare, pathogenic or likely pathogenic germline loss-of-function variants in BARD1 enriched in neuroblastoma patients. The functional implications of these findings remain poorly understood. Methods: We correlated BARD1 genotype with expression in normal tissues and neuroblastomas, along with the burden of DNA damage in tumors. To validate the functional consequences of germline pathogenic or likely pathogenic BARD1 variants, we used CRISPR-Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 loss-of-function variants (R112*, R150*, E287fs, and Q564*) and quantified genomic instability in these cells via next-generation sequencing and with functional assays measuring the efficiency of DNA repair. Results: Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using isogenic heterozygous BARD1 loss-of-function variant cellular models, we functionally validated this association with inefficient DNA repair. BARD1 loss-of-function variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites, and enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. Conclusions: Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications. |
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| MeSH term(s) | Humans ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Genome-Wide Association Study ; Haploinsufficiency ; Ubiquitin-Protein Ligases/genetics ; BRCA1 Protein/genetics ; DNA Repair/genetics ; Neuroblastoma/pathology |
| Chemical Substances | Tumor Suppressor Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; BRCA1 Protein ; BARD1 protein, human (EC 2.3.2.27) |
| Language | English |
| Publishing date | 2024-02-26 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2992-0 |
| ISSN | 1460-2105 ; 0027-8874 ; 0198-0157 |
| ISSN (online) | 1460-2105 |
| ISSN | 0027-8874 ; 0198-0157 |
| DOI | 10.1093/jnci/djad182 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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