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Ref Type Journal Article
PMID (37688570)
Authors Randall MP, Egolf LE, Vaksman Z, Samanta M, Tsang M, Groff D, Evans JP, Rokita JL, Layeghifard M, Shlien A, Maris JM, Diskin SJ, Bosse KR
Title BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
Journal Vol Issue Date Pages Journal Short Title
Journal of the National Cancer Institute 116 1 2024 Jan 10 138-148 J Natl Cancer Inst
URL
Abstract Text 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.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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BARD1 E287fs frameshift loss of function BARD1 E287fs results in a change in the amino acid sequence of the Bard1 protein beginning at aa 287 of 777, likely resulting in premature truncation of the functional protein (UniProt.org). E287fs results in decreased Bard1 expression and homology-directed repair activity, increased double-strand DNA breaks, and increased sensitivity to olaparib and cisplatin in cultured cells (PMID: 37688570).
BARD1 Q564* nonsense loss of function BARD1 Q564* results in a premature truncation of the Bard1 protein at amino acid 564 of 777 (UniProt.org). Q564* confers a loss of function to Bard1 as demonstrated by decreased homology-directed DNA repair activity in cell culture (PMID: 30925164), telomere abnormalities in patient cells, and increased sensitivity to olaparib and cisplatin treatment in cultured cells (PMID: 37688570).
BARD1 R112* nonsense loss of function BARD1 R112* results in a premature truncation of the Bard1 protein at amino acid 112 of 777 (UniProt.org). R112* results in Bard1 expression similar to wild-type but decreased homology-directed repair activity, increased double-strand DNA breaks, and increased sensitivity to olaparib and cisplatin in cultured cells (PMID: 37688570).
BARD1 R150* nonsense loss of function BARD1 R150* results in a premature truncation of the Bard1 protein at amino acid 150 of 777 (UniProt.org). R150* results in cisplatin sensitivity similar to wild-type Bard1 but decreased Bard1 expression and homology-directed repair activity, increased double-strand DNA breaks, and increased sensitivity to olaparib in cultured cells (PMID: 37688570).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BARD1 R150* neuroblastoma sensitive Cisplatin + Olaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Lynparza (Olaparib) and Platinol (cisplatin) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 R150* culture (PMID: 37688570). 37688570
BARD1 R112* neuroblastoma sensitive Cisplatin + Olaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Lynparza (Olaparib) and Platinol (cisplatin) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 R112* culture (PMID: 37688570). 37688570
BARD1 Q564* Advanced Solid Tumor sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) treatment inhibited viability of a cell line expressing BARD1 Q564* culture (PMID: 37688570). 37688570
BARD1 R112* neuroblastoma sensitive Olaparib Preclinical - Cell line xenograft Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 R112* in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37688570). 37688570
BARD1 E287fs neuroblastoma sensitive Cisplatin + Olaparib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Lynparza (Olaparib) and Platinol (cisplatin) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 E287fs culture (PMID: 37688570). 37688570
BARD1 E287fs neuroblastoma sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 E287fs culture (PMID: 37688570). 37688570
BARD1 Q564* Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a cell line expressing BARD1 Q564* in culture (PMID: 37688570). 37688570
BARD1 R112* neuroblastoma sensitive Cisplatin Preclinical - Cell culture Actionable In a preclinical study, Platinol (cisplatin) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 R112* culture (PMID: 37688570). 37688570
BARD1 E287fs neuroblastoma predicted - sensitive Olaparib Preclinical - Cell line xenograft Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 E287fs in culture but did not delay tumor growth in a cell line xenograft model (PMID: 37688570). 37688570
BARD1 R150* neuroblastoma sensitive Olaparib Preclinical - Cell line xenograft Actionable In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a neuroblastoma cell line expressing BARD1 R150* in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37688570). 37688570