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Nature. 2015 Dec 17;528(7582):418-21. doi: 10.1038/nature15540. Epub 2015 Nov 11.

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

Author information

1
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
2
Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, Auckland Region 1142, New Zealand.
4
Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
5
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
6
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
7
Whitehead Institute for Biomedical Research and MIT, Boston, Massachusetts 02142, USA.
8
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
9
Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
10
Thermo Fisher Scientific, Austin, Texas 78744, USA.
11
The Institute of Cancer Research, London SM2 5NG, UK.
12
University of Naples Federico II, 80131 Naples, Italy.
13
CEINGE Biotecnologie Avanzate, 80131 Naples, Italy.
14
Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA.
15
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
16
Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA.

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.

PMID:
26560027
PMCID:
PMC4775078
DOI:
10.1038/nature15540
[Indexed for MEDLINE]
Free PMC Article

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