Common variations in BARD1 influence susceptibility to high-risk neuroblastoma

Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Nature Genetics (Impact Factor: 29.65). 06/2009; 41(6):718-23. DOI: 10.1038/ng.374
Source: PubMed

ABSTRACT We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (P(allelic) = 2.35 x 10(-9)-2.25 x 10(-8)). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (P(allelic) = 7.90 x 10(-7)-2.77 x 10(-4)). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 x 10(-18) and 2.74 x 10(-16), respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma.

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    ABSTRACT: BARD1 has been shown to play tumor suppressive roles in human cancer. We performed this meta-analysis and firstly evaluated the association between three common BARD1 polymorphisms (Arg378Ser, Val507Met and Pro24Ser) and cancer susceptibility. We performed this meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, EMBASE, Cochrane Library, OVID and Web of Science databases was done from database inception to August 2014. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between BARD1 polymorphisms and cancer risk. On the basis of 10 studies about BARD1 polymorphisms and cancer, we found that BARD1 Val507Met (G/A) polymorphism was associated with decreased cancer susceptibility (allelic model: OR = 0.76, 95% CI: 0.66-0.87, P < 0.00001; dominant model: OR = 0.77, 95% CI: 0.65-0.91, P < 0.00001; recessive model: OR = 0.64, 95% CI: 0.55-0.74, P < 0.00001; homozygote comparison: OR = 0.58, 95% CI: 0.49-0.70, P < 0.00001; heterozygote comparison: OR = 0.85, 95% CI: 0.74-0.99 , P = 0.0008). BARD1 Pro24Ser (C/T) polymorphism was also associated decreased cancer risk in allelic model (OR = 0.72, 95% CI: 0.60-0.88, P = 0.0009), dominant model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), recessive model (OR = 0.70, 95% CI: 0.56-0.87 , P = 0.004), homozygote comparison (OR = 0.55, 95% CI: 0.39-0.78, P = 0.0007) and heterozygote comparison (OR = 0.75, 95% CI: 0.62-0.91, P = 0.004). And in our sensitivity analysis, when deleting the study performed by Capasso in 2009, we found that BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006). In conclusion, BARD1 Arg378Ser, Val507Met and Pro24Ser may be associated with decreased cancer risk. More studies with larger samples and gene-environment interactions are needed to confirm our findings.
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    ABSTRACT: Neuroblastoma (NB) is the third most common pediatric cancer. Although NB accounts for 7% of pediatric malignancies, it is responsible for more than 10% of childhood cancer-related mortality. Prognosis and treatment are determined by clinical and biological risk factors. Estimated 5-year survival rates for patients with non-high-risk and high-risk NB are more than 90% and less than 50%, respectively. Recent clinical trials have continued to reduce therapy for patients with non-high-risk NB, including the most favorable subsets who are often followed with observation approaches. In contrast, high-risk patients are treated aggressively with chemotherapy, radiation, surgery, and myeloablative and immunotherapies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Pediatric Clinics of North America 02/2015; 62(1):225-256. DOI:10.1016/j.pcl.2014.09.015 · 2.20 Impact Factor
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    ABSTRACT: The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.


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May 27, 2014