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.

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. - ISSN 0020-7136. - 143:11(2018), pp. 2828-2837. [10.1002/ijc.31822]

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;Pignataro, Piero;Formicola, Daniela;CARDINALE, ANTONELLA;TESTORI, ALESSANDRO;Iolascon, Achille;Capasso, Mario
2018

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.
2018
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. - ISSN 0020-7136. - 143:11(2018), pp. 2828-2837. [10.1002/ijc.31822]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/750300
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