BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.

Autor:	Randall MP; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Egolf LE; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Vaksman Z; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Current affiliation: New York Genome Center, New York, NY., Samanta M; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Tsang M; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Groff D; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Evans JP; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Current affiliation: Genomics and Data Sciences, Spark Therapeutics, Philadelphia, PA., Rokita JL; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Layeghifard M; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada., Shlien A; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada., Maris JM; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Diskin SJ; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Bosse KR; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2024 Jan 10; Vol. 116 (1), pp. 138-148.
DOI:	10.1093/jnci/djad182
Abstrakt:	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. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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