ArticleJournal of the National Cancer Institute2024
BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
Article in Journal of the National Cancer Institute, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 23 citations in OpenAlex.
- A comprehensive survey of genetic variants in neuroblastoma.Journal, genetic engineering & biotechnology · 2026Article
- Prevalence and Clinical Significance of Adult-Onset Cancer Predisposition Variants in Pediatric Oncology.medRxiv : the preprint server for health sciences · 2026Article
- Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric central nervous system tumors.Nature communications · 2025Article
- BARD1: A Friend or Foe in Pancreatic Ductal Adenocarcinoma?International journal of molecular sciences · 2025Review
- The Non-Coding Regulatory Variant rs2863002 at chr11p11.2 Increases Neuroblastoma Risk by Affecting HSD17B12 Expression and Lipid Metabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Detecting likely germline variants during tumor-based molecular profiling.The Journal of clinical investigation · 2025Review
- GermlineCancers · 2025Article
- Germline pathogenic variation impacts somatic alterations and patient outcomes in pediatric CNS tumors.medRxiv : the preprint server for health sciences · 2025Article
- Expanding the Genomic Landscape of HBOC and Cancer Risk Among Mutation Carriers.International journal of molecular sciences · 2025Article
- Study on the molecular mechanism of UBA52 and BARD1 regulating hepatocellular carcinoma through the PI3 K/AKT signaling pathway.Discover oncology · 2025Article
- Rare germline structural variants increase risk for pediatric solid tumors.Science (New York, N.Y.) · 2025Article
- A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.Genetics · 2024Article
- A maternal germline mutator phenotype in a family affected by heritable colorectal cancer.medRxiv : the preprint server for health sciences · 2024Article
- Response to PARP Inhibition inThe New England journal of medicine · 2024Article
- Developmental origins shape the paediatric cancer genome.Nature reviews. Cancer · 2024Review
- Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Rare germline structural variants increase risk for pediatric solid tumors.bioRxiv : the preprint server for biology · 2024Article
- Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.Journal of the National Cancer Institute · 2024Article
- Clinical Response to a PARP Inhibitor and Chemotherapy in a Child with BARD1-Mutated Refractory Neuroblastoma: A Case Report.Research square · 2023Article
- Reply to Li and Colleagues.Journal of the National Cancer Institute · 2023Article
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13 authors at 3 institutions in 2 countries.
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Abstract
backgroundHigh-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.
methodsWe 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.
resultsBoth 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.
conclusionsTaken 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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