Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism.
Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism.
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DOI：
10.1038/nature15540
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发表时间：
2015-12-17
期刊：
影响因子：
64.8
通讯作者：
Maris JM
中科院分区：
文献类型：
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作者：
Oldridge DA;Wood AC;Weichert-Leahey N;Crimmins I;Sussman R;Winter C;McDaniel LD;Diamond M;Hart LS;Zhu S;Durbin AD;Abraham BJ;Anders L;Tian L;Zhang S;Wei JS;Khan J;Bramlett K;Rahman N;Capasso M;Iolascon A;Gerhard DS;Guidry Auvil JM;Young RA;Hakonarson H;Diskin SJ;Look AT;Maris JM
神经母细胞瘤是一种儿科恶性肿瘤，通常发生在儿童早期，来源于发育中的交感神经系统。临床表型范围从预后良好的局部肿瘤到广泛转移性疾病，尽管进行了强化治疗，长期生存率仍约为40%。先前的全基因组关联研究（GWAS）确定了LMO 1基因位点的常见多态性，这些多态性与肿瘤细胞中的神经母细胞瘤易感性和对LMO 1的致癌成瘾高度相关。在这里，我们试图发现该基因座的致病DNA变异及其导致神经母细胞瘤肿瘤发生的机制。我们首先估算了LMO 1基因座上所有可能的基因型，然后将高度相关的单核苷酸多态性（SNP）映射到染色质可及性、进化保守性和转录因子结合位点。SNP rs 2168101 G>T是最高度相关的变体（组合P=7.47×10-29，比值比0.65，95%CI：0.60-0.70），并且位于由LMO 1的第一内含子内的组蛋白H3赖氨酸27的广泛乙酰化定义的超级增强子中。与肿瘤形成相关的祖先G等位基因位于保守的加塔转录因子结合基序中。我们发现，新进化的保护性TATA等位基因与神经母细胞瘤原发性肿瘤中总LMO 1表达降低（P=0.028）相关，并消除GATA 3结合（P<0.0001）。我们通过RNA测序（P<0.0001）和报告基因分析（P=0.002）证实，在该SNP杂合的肿瘤中，等位基因不平衡有利于含G链。这些发现表明，最近进化的多态性内的超级增强子元件在LMO 1的第一个内含子的影响神经母细胞瘤的易感性，通过不同的加塔转录因子结合和直接调制的LMO 1表达顺式，这导致肿瘤细胞的致癌依赖性。
Neuroblastoma is a pediatric malignancy that typically arises in early childhood and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumors with excellent outcomes to widely metastatic disease where long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study (GWAS) identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumor cells. Here we sought to discover 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. SNP rs2168101 G>T was the most highly associated variant (combined P=7.47×10-29, Odds Ratio 0.65, 95% CI: 0.60-0.70) and resided 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 tumor 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 tumors and ablates GATA3 binding (P<0.0001). We demonstrate allelic imbalance favoring the G-containing strand in tumors heterozygous for this SNP as demonstrated both by RNA sequencing (P<0.0001) and reporter assays (P=0.002). These findings show 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 tumor cells.