Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism

A causal variant is identified at the LMO1 oncogene locus that drives the genetic association of LMO1 with neuroblastoma susceptibility; the causal SNP disrupts a GATA transcription factor binding site within a tissue-specific super-enhancer element in the first intron of LMO1 , thereby affecting LMO1 expression. LMO1 oncogene involvement in neuroblastoma Polymorphisms at the oncogene LMO1 locus have previously been identified as being highly associated with susceptibility to neuroblastoma, a paediatric cancer. John Maris and colleagues now identify a causal variant at this locus, driving the LMO1 genetic association with neuroblastoma susceptibility. The authors show that the causal single nucleotide polymorphism disrupts a GATA transcription factor binding site in a tissue-specific super-enhancer element within the first intron of LMO1 , thereby affecting expression of the LMO1 oncogene. Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells 1 . Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10 −29 , odds ratio 0.65, 95% confidence interval 0.60–0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1 . The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression ( P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding ( P