Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma

Eric A. Hungate, Mark A. Applebaum, Andrew D. Skol, Zalman Vaksman, Maura Diamond, Lee McDaniel, Samuel L. Volchenboum, Barbara Elaine Stranger, John M. Maris, Sharon J. Diskin, Kenan Onel, Susan L. Cohn

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10 Scopus citations

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.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume109
Issue number10
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hungate, E. A., Applebaum, M. A., Skol, A. D., Vaksman, Z., Diamond, M., McDaniel, L., Volchenboum, S. L., Stranger, B. E., Maris, J. M., Diskin, S. J., Onel, K., & Cohn, S. L. (2017). Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma. Journal of the National Cancer Institute, 109(10). https://doi.org/10.1093/jnci/djx093