TY - JOUR
T1 - Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor
AU - Cimmino, Flora
AU - Avitabile, Marianna
AU - Diskin, Sharon J.
AU - Vaksman, Zalman
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
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054395119&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30132831
U2 - https://doi.org/10.1002/ijc.31822
DO - https://doi.org/10.1002/ijc.31822
M3 - Article
C2 - 30132831
SN - 0020-7136
VL - 143
SP - 2828
EP - 2837
JO - International journal of cancer. Journal international du cancer
JF - International journal of cancer. Journal international du cancer
IS - 11
ER -