Abstract C008: Expanding the spectrum of pathogenic germline BARD1 variants in children with neuroblastoma

Abstract

Pathogenic germline variants in BARD1 are strongly associated with neuroblastoma, and emerging evidence from our group and others suggests that heterozygous loss-of-function BARD1 variants may confer sensitivity to PARP inhibition, analogous to BRCA1-deficient cancers. This potential therapeutic vulnerability underscores the importance of identifying the full spectrum of pathogenic BARD1 variants in children with this embryonal tumor. We analyzed germline whole genome and exome sequencing data from TARGET and Gabriel Miller Kids First (GMKF) neuroblastoma cohorts (n=1,232) and identified 12 pathogenic/likely pathogenic germline variants along with an additional 25 missense variants of uncertain significance (VUS), none of which have been previously studied in neuroblastoma. Using published BARD1 saturation genome editing data, we prioritized 2 of the 25 VUS predicted to impair BARD1 function (BARD1(NM_000465.4):c.2167C>G p.(His723Asp) and BARD1(NM_000465.4):c.2006C>G p.(Pro669Arg)). Both of these variants localize to the C-terminal BRCT domain, which mediates poly-ADP-ribose (PAR) dependent recruitment of the BARD1/BRCA1 heterodimer to DNA damage sites, consistent with the established role of defective DNA damage repair in neuroblastoma predisposition. Multiple in silico algorithms predict both variants to be deleterious. Functional and structural studies are underway to determine whether these BRCT-domain variants impair homologous recombination and confer sensitivity to PARP inhibition. To further define the spectrum of germline BARD1 variants, we are expanding our analysis to an additional 784 individuals with high-risk neuroblastoma undergoing whole genome sequencing. These studies will improve interpretation of rare germline BARD1 variants in neuroblastoma and may identify patients with BARD1-associated homologous recombination deficiency who could benefit from PARP inhibitor based therapy.