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Int J Cancer. 2018 Dec 1;143(11):2828-2837. doi: 10.1002/ijc.31822. Epub 2018 Oct 4.

Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor.

Author information

1
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.
2
CEINGE Biotecnologie Avanzate, Naples, Italy.
3
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA.
4
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
5
IRCCS SDN, Naples, Italy.
6
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
7
Hospital Sant Joan de Déu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain.
8
Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA.
9
Department of Biostatistics, Epidemiology and Informatics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Abstract

A previous genome-wide association study (GWAS) identified common variation at the BARD1 locus as being highly associated with susceptibility to high-risk neuroblastoma, but the mechanisms underlying this association have been not extensively investigated. Here, we performed a fine mapping analysis of BARD1 locus (2q35) using GWAS data from 556 high-risk neuroblastoma patients and 2,575 controls of European-American ancestry, and identified two independent genome-wide neuroblastoma-associated loci. Functional single-nucleotide polymorphism (SNP) prioritization identified two causative variants that independently contributed to neuroblastoma risk, and each replicated robustly in multiple independent cohorts comprising 445 high-risk cases and 3,170 controls (rs17489363: combined p = 1.07 × 10-31 , OR:1.79, 95% CI:1.62-1.98 and rs1048108: combined p = 7.27 × 10-14 , OR:0.65, 95% CI:0.58-0.73). Particularly, the T risk allele of rs17489363 in the canonical promoter region of full-length BARD1 altered binding site of the transcription factor HSF1 and correlated with low expression of full-length BARD1 mRNA and protein. Low-level expression of full-length BARD1 associated with advanced neuroblastoma. In human neuroblastoma cells, attenuating full-length BARD1 increased proliferation and invasion capacity. In conclusion, we have identified two potentially causative SNPs at the BARD1 locus associated with predisposition to high-risk neuroblastoma, and have shown that full-length BARD1 may act as tumor suppressor.

KEYWORDS:

BARD1; GWAS; SNP; fine mapping.; neuroblastoma

PMID:
30132831
PMCID:
PMC6258207
[Available on 2019-12-01]
DOI:
10.1002/ijc.31822
[Indexed for MEDLINE]

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