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

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 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 a GATA motif in the first intron of LMO1. Here we show that wild-type zebrafish with the GATA genotype develop adrenergic neuroblastoma, while knock-in of the protective TATA 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 that TATA/TATA tumors also exhibit a mesenchymal cell state and are low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduces 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. ### Competing Interest Statement RAY is a founder and shareholder of Syros Pharmaceuticals, which is discovering and developing therapeutics directed at transcriptional pathways in cancer. BJA is a shareholder of Syros Pharmaceuticals. ATL is a founder and shareholder of Light Horse Therapeutics, which is discovering and developing small molecules to disrupt oncogenic protein complexes. JMM is a founder of Tantigen BIO and HULA Therapeutics, two companies focused on discovery and development of immunotherapies for childhood cancers. No other potential conflicts of interest are declared. J.K.J. has financial interests in Beam Therapeutics, Chroma Medicine (f/k/a YKY, Inc), Editas Medicine, Excelsior Genomics, Pairwise Plants, Poseida Therapeutics, SeQure Dx, Inc, Transposagen Biopharmaceuticals, and Verve Therapeutics (f/k/a Endcadia). J.K.J. interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. J.K.J. is a coinventor on various patents and patent applications that describe gene editing and epigenetic editing technologies.