Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state
Nina Weichert-Leahey, Hui Shi, Ting Tao, Derek A. Oldridge, Adam D. Durbin, Brian J. Abraham, Mark W. Zimmerman, Shizhen Zhu, Andrew C. Wood, Deepak Reyon, J. Keith Joung, Richard A. Young, Sharon J. Diskin, John M. Maris, A. Thomas Look
Nina Weichert-Leahey, Hui Shi, Ting Tao, Derek A. Oldridge, Adam D. Durbin, Brian J. Abraham, Mark W. Zimmerman, Shizhen Zhu, Andrew C. Wood, Deepak Reyon, J. Keith Joung, Richard A. Young, Sharon J. Diskin, John M. Maris, A. Thomas Look
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Research Article Genetics Oncology

Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state

Abstract

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest–like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional cofactor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism, G/T, that affects a GATA motif in the first intron of LMO1. Here, we showed that WT zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma-initiation rate by preventing formation of the adrenergic cell state. This mechanism was conserved over 400 million years of evolution, separating zebrafish and humans.

Authors

Nina Weichert-Leahey, Hui Shi, Ting Tao, Derek A. Oldridge, Adam D. Durbin, Brian J. Abraham, Mark W. Zimmerman, Shizhen Zhu, Andrew C. Wood, Deepak Reyon, J. Keith Joung, Richard A. Young, Sharon J. Diskin, John M. Maris, A. Thomas Look

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Figure 3

Expression of the lmo family genes in zebrafish and human neuroblastoma.

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Expression of the lmo family genes in zebrafish and human neuroblastoma....
(A) RNA-Seq analysis was performed to measure the relative mRNA expression of lmo family genes in neuroblastomas arising in zebrafish with the indicated genotypes (GATA/GATA, n = 4; lmo1–/–, n = 3; and TATA/TATA, n = 2). mRNA expression levels for the indicated lmo family genes are represented by FPKM log-scale values. Expression under 1 FPKM is considered as nonexpressed. Statistical analysis was performed using the 2-tailed, unpaired t test. *P < 0.005. (B) Relative LMO1-4 mRNA expression levels measured by RNA-Seq in 153 primary human neuroblastoma samples (from TARGET), ranked from highest (left) to lowest levels of LMO1 expression (in FPKM). Expression correlation analysis demonstrated weak inverse correlation between LMO1 and the other 3 LMO family members (R ≥ –0.3, P < 0.05).