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

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 , OR:1.79, 95% CI:1.62-1.98 and rs1048108: combined p = 7.27 × 10 , 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.

LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four‐centre case‐control study

“…24 Moreover, a fine-mapping analysis of BARD1 locus (2q35) also identified two independent genome-wide neuroblastoma-associated loci. 25 However, the present identified genetic variations could not fully account for the carcinogenesis of neuroblastoma. We are still on the discovery journey of unveiling more causative genetic alterations hidden in the bush.…”

Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma

“…Gain of function mutations in ALK in ~10% of cases has emerged as the only validated therapeutic target (4)(5)(6). Recent single-nucleotide polymorphism (SNP) based genome-wide association studies (GWAS) have identified several susceptibility neuroblastoma genes (CASC15, BARD1, LMO1, DUSP12, HSD17B12, DDX4/IL31RA, HACE1, LIN28B, NEFL) (7)(8)(9)(10)(11)(12) and BARD1 results to be the most strongly associated gene (10)(11)(12)(13). Many of the identified loci impart oncogenic dependencies in established tumors.…”

Association of PARP1 polymorphisms with response to chemotherapy in patients with high‐risk neuroblastoma

“…MYCN amplification and segmental chromosomal aberrations are, so far, the most reliable genomic biomarkers for the patients’ stratification and outcome prediction. Recently, genome‐wide association studies and high‐throughput sequencing‐based studies have highlighted that multiple DNA polymorphisms influence NB susceptibility and clinical phenotype and that recurrent mutations of single genes are infrequent in primary NB with activating mutations in ALK and inactivating mutations in ATRX , and TERT rearrangements being the most frequent . Gene expression‐based studies suggest that among high‐risk patients, gene signatures can identify children with higher risk disease who would benefit from new and more aggressive therapeutic approaches .…”