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

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 contr

SUBMITTER: Randall MP 

PROVIDER: S-EPMC10777668 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature