Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility

Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.
Carcinogenesis (Impact Factor: 5.33). 12/2012; 34(3). DOI: 10.1093/carcin/bgs380
Source: PubMed


Several neuroblastoma (NB) susceptibility loci have been identified within LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1, and LIN28B by genome-wide association (GWA) studies including European American (EA) individuals. To validate and comprehensively evaluate the impact of the identified NB variants on disease risk and phenotype, we analyzed 16 single nucleotide polymorphisms (SNPs) in an Italian population (370 cases and 809 controls). We assessed their regulatory activity on gene expression in lymphoblastoid (LCLs) and NB cell lines. We evaluated the cumulative effect of the independent loci on NB risk and high-risk phenotype development in Italian and EAs (1627 cases and 2575 controls) populations. All NB susceptibility genes replicated in the Italian dataset except for DDX4 and IL31RA, and the most significant SNP was rs6435862 in BARD1 (P=8.4x10(-15)). BARD1 showed an additional and independent SNP association (rs7585356). This variant influenced BARD1 mRNA expression in LCLs and NB cell lines. No evidence of epistasis among the NB-associated variants was detected while a cumulative effect of risk variants on NB risk (EAs: P(trend)=6.9x10(-30), Italians: P(trend)=8.55x10(-13)) and development of high-risk phenotype (EAs: P(trend)=6.9x10(-13), Italians: P(trend)=2.2x10(-1)) was observed in a dose-dependent manner. These results provide further evidence that the risk loci identified in GWA studies contribute to NB susceptibility in distinct populations and strengthen the role of BARD1 as major genetic contributor to NB risk. This study shows that even in the absence of interaction the combination of several low-penetrance alleles has potential to distinguish sub-groups of patients at different risks of developing NB.

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    • "Furthermore, synteninnull mice show wound healing defects that are particularly marked in the cornea (Stepp et al. 2002, 2010). The 6p22.3 locus containing the long intergenic non-coding RNA gene LINC00340 (also known as FLJ22536 and CASC15) is gene poor (Fig. 2d) yet has previously shown association with aggressive neuroblastoma in GWAS studies (Capasso et al. 2013). The mechanisms through which non-coding RNAs act are poorly understood (Guttman et al. 2009; Gibb et al. 2011) but in the case of lincRNAs the mechanism may involve epigenetic regulation (Salta and De Strooper 2012). "
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