Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity Academic Article uri icon

Overview

MeSH Major

  • Cell Transformation, Neoplastic
  • Genetic Predisposition to Disease
  • Neuroblastoma
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases

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.

publication date

  • April 15, 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3328617

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-11-3703

PubMed ID

  • 22350409

Additional Document Info

start page

  • 2068

end page

  • 78

volume

  • 72

number

  • 8