Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma

Abstract

To investigate genetic predispositions for MYCN-amplified neuroblastoma, we performed a meta-analysis of three genome-wide association studies totaling 615 MYCN-amplified high-risk neuroblastoma cases and 1869 MYCN-nonamplified non-high-risk neuroblastoma cases as controls using a fixed-effects model with inverse variance weighting. All statistical tests were two-sided. We identified a novel locus at 3p21.31 indexed by the single nucleotide polymorphism (SNP) rs80059929 (odds ratio [OR] = 2.95, 95% confidence interval [CI] = 2.17 to 4.02, Pmeta = 6.47 × 10-12) associated with MYCN-amplified neuroblastoma, which was replicated in 127 MYCN-amplified cases and 254 non-high-risk controls (OR = 2.30, 95% CI = 1.12 to 4.69, Preplication = .02). To confirm this signal is exclusive to MYCN-amplified tumors, we performed a second meta-analysis comparing 728 MYCN-nonamplified high-risk patients to identical controls. rs80059929 was not statistically significant in MYCN-nonamplified high-risk patients (OR = 1.24, 95% CI = 0.90 to 1.71, Pmeta = .19). SNP rs80059929 is within intron 16 in the KIF15 gene. Additionally, the previously reported LMO1 neuroblastoma risk locus was statistically significant only in patients with MYCN-nonamplified high-risk tumors (OR = 0.63, 95% CI = 0.53 to 0.75, Pmeta = 1.51 × 10-8; Pmeta = .95). Our results indicate that common genetic variation predisposes to different neuroblastoma genotypes, including the likelihood of somatic MYCN-amplification.

Figure 1.

Specific genomic loci associated with the development of MYCN-amplified high-risk neuroblastoma. A) Manhattan plot showing single nucleotide polymorphisms (SNPs) statistically significantly associated with MYCN-amplified neuroblastoma. B) LocusZoom (22) plot of novel loci identified at 3p21.31 shows that the most strongly associated SNP is located in intron 16 within the KIF15 gene locus. C) Forest plot shows the P value and odds ratio with 95% confidence interval for rs80059929 from each set and meta-analysis. Error bars indicate 95% confidence intervals. All statistical tests were two-sided. D) Manhattan plot showing SNPs statistically significantly associated with MYCN-nonamplified high-risk neuroblastoma. E) LocusZoom of previously identified loci on chromosome 11 shows the SNPs in LMO1 that were not associated with the development of MYCN-amplified disease. F) Forest plot shows the P value and odds ratio with 95% confidence interval for rs2168101 from each set and meta-analysis. Error bars indicate 95% confidence intervals. All statistical tests were two-sided. MAF = minor allele frequency; OR = odds ratio.