@article{84a8459463ff400b891d4df7d5276a18,
title = "Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism",
abstract = "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. 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 < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.",
author = "Oldridge, {Derek A.} and Wood, {Andrew C.} and Nina Weichert-Leahey and Ian Crimmins and Robyn Sussman and Cynthia Winter and McDaniel, {Lee D.} and Maura Diamond and Hart, {Lori S.} and Shizhen Zhu and Durbin, {Adam D.} and Abraham, {Brian J.} and Lars Anders and Lifeng Tian and Shile Zhang and Wei, {Jun S.} and Javed Khan and Kelli Bramlett and Nazneen Rahman and Mario Capasso and Achille Iolascon and Gerhard, {Daniela S.} and {Guidry Auvil}, {Jaime M.} and Young, {Richard A.} and Hakon Hakonarson and Diskin, {Sharon J.} and {Thomas Look}, A. and Maris, {John M.}",
note = "Funding Information: Acknowledgements This work was supported in part by NIH grants R01-CA124709 (J.M.M.), R01-CA180692 (J.M.M. and A.T.L.), R00-CA151869 (S.J.D.), RC1MD004418 to the TARGET consortium, 1K99CA178189 (S.Z.), T32-HG000046 (D.A.O.), R01-CA109901 (R.A.Y.), the Giulio D{\textquoteright}Angio Endowed Chair (J.M.M.), the PressOn Foundation (J.M.M.), Andrew{\textquoteright}s Army Foundation (J.M.M.), the Abramson Family Cancer Research Institute (J.M.M.), the Brooke Mulford Foundation (J.M.M.), the University of Pennsylvania Genome Frontiers Institute, an Alex{\textquoteright}s Lemonade Stand Foundation Innovation Award (A.T.L.), young investigator awards from Alex{\textquoteright}s Lemonade Stand Foundation (S.Z., A.C.W.) and the CureSearch for Children{\textquoteright}s Cancer Foundation (S.Z.), grant from the German Cancer Aid 110801 (N.W.-L.), St Baldrick{\textquoteright}s Foundation Fellow award (A.C.W.), George L. Ohrstrom Jr foundation (A.C.W.), Wellcome Trust Senior Investigator Award Ref:100210/Z/12/Z (N.R.) and NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR (N.R.), Fondazione Italiana per la Lotta al Neuroblastoma (M.C.), Associazione Oncologia Pediatrica e Neuroblastoma (M.C.), and Associazione Italiana per la Ricerca sul Cancro (M.C.). We gratefully acknowledge the Children{\textquoteright}s Oncology Group (COG) for providing the specimens and clinical data from neuroblastoma patients and thank patients and families for participating in the COG, the UK-based Factors Associated with Childhood Tumors (FACT), and Italian cooperative group studies. We thank A. Renwick who performed the Taqman analyses and A. Zachariou for recruiting participants to the FACT study. We thank G. Blobel for scientific advice and discussion, and generously providing equipment and reagents for ChIP experiments, N. Saeki and H. Sasaki for providing the LMO1 cDNA clone, and Y. Nakatan for providing the lentiviral vector pOZ-FHN. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = dec,
day = "17",
doi = "10.1038/nature15540",
language = "English (US)",
volume = "528",
pages = "418--421",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7582",
}