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

Abstract

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 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 European American (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 = 8.4 × 10(-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, whereas a cumulative effect of risk variants on NB risk (European Americans: P (trend) = 6.9 × 10(-30), Italians: P (trend) = 8.55 × 10(13)) and development of high-risk phenotype (European Americans: P (trend) = 6.9 × 10(-13), Italians: P (trend) = 2.2 × 10(-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 subgroups of patients at different risks of developing NB.

Evaluation of GWAS-identified SNPs at 6p22 with neuroblastoma susceptibility in a Chinese population

“…This study indicated that three SNPs in the FLJ22536 gene mapping to chromosome 6p22 were significantly associated with neuroblastoma susceptibility [8]. The association of 6p22 locus with neuroblastoma susceptibility has been replicated in subsequent studies using diverse populations, including African-Americans [13] and Italians [14].…”

“…Latorre et al [13] investigated the association of all these three polymorphisms in 390 African-American neuroblastoma patients and 2500 healthy controls; however, they failed to prove the association with altered neuroblastoma susceptibility for any of three SNPs. Capasso et al [14] attempted to test the association between two polymorphisms (rs6939340 A>G and rs4712653 T>C) and neuroblastoma susceptibility with 370 cases and 809 controls in an Italian population; they confirmed a significant association between both of these two polymorphisms and neuroblastoma susceptibility. As far as we knew, no validation study was performed among Asians except ours; we found that all of these three SNPs were associated with decreased neuroblastoma susceptibility in the current study.…”

“…They found that three polymorphisms located at the 6p22 and within the predicted gene FLJ22536 were associated with neuroblastoma susceptibility, and they also validated these results using additional 720 patients and 2128 control subjects. Later on, two validation studies were performed to verify the association between these FLJ22536 genetic variants and neuroblastoma risk for African-Americans [13] and Italian population [14]. Latorre et al [13] investigated the association of all these three polymorphisms in 390 African-American neuroblastoma patients and 2500 healthy controls; however, they failed to prove the association with altered neuroblastoma susceptibility for any of three SNPs.…”

“…Although the association with rs6939340 A>G, rs4712653 T>C, and rs9295536 C>A polymorphisms in the FLJ22536 gene has been replicated in previous studies involving African-Americans [13] and European descents [14], it remains unclear whether these polymorphisms also confer neuroblastoma susceptibility in Asians. Given the possible variations in minor allele frequency (MAF) and pattern of linkage disequilibrium across races, genetic susceptibility to neuroblastoma may largely differ between Asians and Caucasians.…”

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

“…Familial neuroblastoma is rare (approximately 1%), and most of these cases harbour germline mutations in ALK 1. In contrast, the genetic bases of sporadic neuroblastoma remain largely unknown 2, 3. Through a genomewide association study (GWAS) of sporadic neuroblastoma, we have reported common single nucleotide polymorphisms (SNPs) associated with neuroblastoma susceptibility at CASC15 4, BARD1 5, LMO1 6, DUSP12 7, HSD17B12 7, DDX4/IL31RA 7, HACE1 8 and LIN28B 8 loci.…”