Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma.

Abstract

BACKGROUND:

Neuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system.

METHODS:

We first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) compared to thoracic sympathetic ganglia (n = 118). We also evaluated association of common germline variation with these primary sites in 1027 European-American neuroblastoma patients.

RESULTS:

We observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (odds ratio = 1.89, 95% confidence interval = 1.04 to 3.43), and among cases without MYCN amplification (odds ratio = 2.86, 95% confidence interval = 1.48 to 5.49). Common germline single nucleotide polymorphisms (SNPs) in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites.

CONCLUSIONS:

Neuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.

• Authors: Derek A Oldridge, Bao Truong, Douglas Russ, Steven G DuBois, Zalman Vaksman, Yael P Mosse, Sharon J Diskin, John M Maris, Katherine K Matthay
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 111 Issue 11 Pg. 1192-1201 (11 01 2019) ISSN: 1460-2105 [Electronic] United States
• PMID: 30793172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Biomarkers, Tumor
• N-Myc Proto-Oncogene Protein

Topics

• Adrenal Gland Neoplasms (genetics, pathology)
• Biomarkers, Tumor (genetics)
• Chromosome Aberrations
• Cohort Studies
• Gene Amplification
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genomics (methods)
• Humans
• Infant
• Mutation
• N-Myc Proto-Oncogene Protein (genetics)
• Neuroblastoma (genetics, pathology)
• Polymorphism, Single Nucleotide
• Prognosis
• Thoracic Neoplasms (genetics, pathology)