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

Flora Cimmino, Marianna Avitabile, Sharon J. Diskin, Zalman Vaksman, Piero Pignataro, Daniela Formicola, Antonella Cardinale, Alessandro Testori, Jan Koster, Carmen de Torres, Marcella Devoto, John M. Maris, Achille Iolascon, Mario Capasso

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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.

Original languageEnglish
Pages (from-to)2828-2837
Number of pages10
JournalInternational Journal of Cancer
Volume143
Issue number11
DOIs
Publication statusPublished - Dec 1 2018

Fingerprint

Neuroblastoma
Neoplasms
Genome-Wide Association Study
Single Nucleotide Polymorphism
Genetic Promoter Regions
Transcription Factors
Alleles
Binding Sites
Genome
Messenger RNA
Proteins

Keywords

  • BARD1
  • fine mapping
  • GWAS
  • neuroblastoma
  • SNP

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor. / Cimmino, Flora; Avitabile, Marianna; Diskin, Sharon J.; Vaksman, Zalman; Pignataro, Piero; Formicola, Daniela; Cardinale, Antonella; Testori, Alessandro; Koster, Jan; de Torres, Carmen; Devoto, Marcella; Maris, John M.; Iolascon, Achille; Capasso, Mario.

In: International Journal of Cancer, Vol. 143, No. 11, 01.12.2018, p. 2828-2837.

Research output: Contribution to journalArticle

Cimmino, F, Avitabile, M, Diskin, SJ, Vaksman, Z, Pignataro, P, Formicola, D, Cardinale, A, Testori, A, Koster, J, de Torres, C, Devoto, M, Maris, JM, Iolascon, A & Capasso, M 2018, 'Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor', International Journal of Cancer, vol. 143, no. 11, pp. 2828-2837. https://doi.org/10.1002/ijc.31822
Cimmino, Flora ; Avitabile, Marianna ; Diskin, Sharon J. ; Vaksman, Zalman ; Pignataro, Piero ; Formicola, Daniela ; Cardinale, Antonella ; Testori, Alessandro ; Koster, Jan ; de Torres, Carmen ; Devoto, Marcella ; Maris, John M. ; Iolascon, Achille ; Capasso, Mario. / Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor. In: International Journal of Cancer. 2018 ; Vol. 143, No. 11. pp. 2828-2837.
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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.",
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AU - Diskin, Sharon J.

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AU - Pignataro, Piero

AU - Formicola, Daniela

AU - Cardinale, Antonella

AU - Testori, Alessandro

AU - Koster, Jan

AU - de Torres, Carmen

AU - Devoto, Marcella

AU - Maris, John M.

AU - Iolascon, Achille

AU - Capasso, Mario

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