Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state
Nina Weichert-Leahey, … , John M. Maris, A. Thomas Look
Nina Weichert-Leahey, … , John M. Maris, A. Thomas Look
Published May 15, 2023
Citation Information: J Clin Invest. 2023;133(10):e166919. https://doi.org/10.1172/JCI166919.
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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 1

Evolutionary history of the G/T polymorphism at rs2168101.

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Evolutionary history of the G/T polymorphism at rs2168101. (A) Phylogene...
(A) Phylogenetic tree representing the evolutionary relationship between the LMO1 genes from the indicated species over the last 400 million years. Blue font denotes species that exclusively harbor a G at rs2168101. Orange font denotes that only humans demonstrate a G/T polymorphism at the rs2168101 locus. (B) Distribution of the G and T alleles of rs2168101 across Human Genome Diversity Project (HGDP) populations, as illustrated by their genome browser (http://popgen.uchicago.edu/ggv/). Circles create a pie chart in which blue represents the proportion of human populations from different parts of the world with a G at rs2168101 (human chromosome 11, position 8255408), and orange represents the proportion with a T. (C) Shown is a modified UCSC Genome Browser (https://genome.ucsc.edu/) window of the human LMO1 locus indicating the 2 alternative transcription start sites and the position of rs2168101 in the first intron (top), a vertebrate conservation track graphing PhyloP conservation scores (middle), and Multiz alignments of multiple vertebrate species (bottom), illustrating a high level of conservation in the noncoding region surrounding rs2168101. (D) The immediate sequence neighborhood surrounding rs2168101 in the first intron of LMO1 from multiple species is shown. The G at rs2168101 in the human consensus sequence is marked with a red box.