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

doi:10.1093/jnci/djx093

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

Pharmacology

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22 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, P_meta = 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, P_replication = .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, P_meta = .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, P_meta = 1.51 × 10^-8; P_meta = .95). Our results indicate that common genetic variation predisposes to different neuroblastoma genotypes, including the likelihood of somatic MYCN-amplification.

Original language	English (US)
Article number	djx093
Journal	Journal of the National Cancer Institute
Volume	109
Issue number	10
DOIs	https://doi.org/10.1093/jnci/djx093
State	Published - Oct 1 2017

Funding

This work was supported in part by the Neuroblastoma Children’s Cancer Society (SLC); the Children’s Neuroblastoma Cancer Foundation (SLC); the Matthew Bittker Foundation (SLC); the Elise Anderson Neuroblastoma Research Fund (SLC); the Cancer Research Foundation (MAA); and the Conquer Cancer Foundation of the American Society of Clinical Oncology (MAA). Also, it was supported by the National Institutes of Health (R01CA124709, R00CA151869 to SJD, and K12CA139160 and T32GM007019 to MAA).

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "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.",

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

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AU - Diamond, Maura

AU - McDaniel, Lee

AU - Volchenboum, Samuel L.

AU - Stranger, Barbara Elaine

AU - Maris, John M.

AU - Diskin, Sharon J.

AU - Onel, Kenan

AU - Cohn, Susan L.

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Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma

Abstract

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ASJC Scopus subject areas

UN SDGs

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