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 6

Human TATA/TATA neuroblastomas resemble zebrafish TATA/TATA tumors with low LMO1 expression and a mesenchymal phenotype.

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Human TATA/TATA neuroblastomas resemble zebrafish TATA/TATA tumors with ...
(A) Relative LMO1 mRNA expression levels (in FPKM) in 124 human neuroblastoma samples with the indicated genotypes at rs2168101: TATA/TATA, GATA/TATA, or GATA/GATA. Each neuroblastoma sample is assigned to either low (pink), intermediate (light red) or high risk (purple). Statistical analysis was performed using the 2-tailed, Welch’s t test. *P < 0.005. (B and C) Adrenergic and mesenchymal gene set signature scores were generated using GSVA based on the previously published expression profiles by Von Groningen, et al. (8). Higher positive scores indicate upregulation of the corresponding signature, whereas, lower negative scores indicate downregulation. GATA/GATA and GATA/TATA tumors were combined into 1 group (blue) and compared with the TATA/TATA tumors (tan). (D and E) UMAP representing the whole transcriptome landscape of 124 human neuroblastoma samples (dots) in a 2-dimensional space combined with the adrenergic (D) and mesenchymal (E) gene signatures. Relative Z-score-transformed expression for each signature (according to the heat scale) is shown for each tumor (points) and overall density (contours). Clusters 1–4 represent tumors falling into similar density contours based on the adrenergic signature (D) or mesenchymal signature (E). (F–H) Combination of UMAP dimensionality reduction analysis and expression levels of LMO1 (F), LMO2 (G), and LMO3 (H). Relative Z-score of log2-transformed expression for LMO1 (F), LMO2, (G) or LMO3 (H) (according to the heat scale) is shown for each tumor (points) and overall density (contours). (I) MYCN status for all 124 human neuroblastoma samples.