Genetic Predisposition to Neuroblastoma Results from a Regulatory Polymorphism that Promotes the Adrenergic Cell State

Abstract

AbstractChildhood 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 co-factor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism G/T that affects aGATA motif in the first intron of LMO1. Here we show that wild-type zebrafish with theGATA genotype develop adrenergic neuroblastoma, while knock-in of the protectiveTATA allele at this locus reduces the penetrance of MYCN-driven tumors, which are restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrates thatTATA/TATA tumors also exhibit a mesenchymal cell state and are low risk at diagnosis. Thus, conversion of the regulatoryGATA to aTATA allele in the first intron ofLMO1reduces the neuroblastoma initiation rate by preventing formation of the adrenergic cell state, a mechanism that is conserved over 400 million years of evolution separating zebrafish and humans.