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Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity
Authors:Bosse Kristopher R  Diskin Sharon J  Cole Kristina A  Wood Andrew C  Schnepp Robert W  Norris Geoffrey  Nguyen Le B  Jagannathan Jayanti  Laquaglia Michael  Winter Cynthia  Diamond Maura  Hou Cuiping  Attiyeh Edward F  Mosse Yael P  Pineros Vanessa  Dizin Eva  Zhang Yongqiang  Asgharzadeh Shahab  Seeger Robert C  Capasso Mario  Pawel Bruce R  Devoto Marcella  Hakonarson Hakon  Rappaport Eric F  Irminger-Finger Irmgard  Maris John M
Affiliation:Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
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.
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