title: Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity.
abstract: The mechanisms underlying genetic susceptibility at loci discovered by genome-wide association study (GWAS) approaches in human cancer remain largely undefined. In this study, we characterized the high-risk neuroblastoma association at the BRCA1-related locus, BARD1, showing that disease-associated variations correlate with increased expression of the oncogenically activated isoform, BARD1β. In neuroblastoma cells, silencing of BARD1β showed genotype-specific cytotoxic effects, including decreased substrate-adherence, anchorage-independence, and foci growth. In established murine fibroblasts, overexpression of BARD1β was sufficient for neoplastic transformation. BARD1β stabilized the Aurora family of kinases in neuroblastoma cells, suggesting both a mechanism for the observed effect and a potential therapeutic strategy. Together, our findings identify BARD1β as an oncogenic driver of high-risk neuroblastoma tumorigenesis, and more generally, they illustrate how robust GWAS signals offer genomic landmarks to identify molecular mechanisms involved in both tumor initiation and malignant progression. The interaction of BARD1β with the Aurora family of kinases lends strong support to the ongoing work to develop Aurora kinase inhibitors for clinically aggressive neuroblastoma.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kristopher R
authors.initials: KR
authors.lastname: Bosse
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Cole
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wood
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schnepp
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Norris
authors.forename: Le B
authors.initials: le B
authors.lastname: Nguyen
authors.forename: Jayanti
authors.initials: J
authors.lastname: Jagannathan
authors.forename: Michael
authors.initials: M
authors.lastname: Laquaglia
authors.forename: Cynthia
authors.initials: C
authors.lastname: Winter
authors.forename: Maura
authors.initials: M
authors.lastname: Diamond
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mosse
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pineros
authors.forename: Eva
authors.initials: E
authors.lastname: Dizin
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pawel
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.forename: Irmgard
authors.initials: I
authors.lastname: Irminger-Finger
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases