Dataset Information

LMO1 Super-Enhancer rs2168101 G>T Polymorphism Reduces Wilms Tumor Risk.

ABSTRACT: Wilms tumor is one of the most prevalent pediatric malignancies in childhood cancer worldwide. A genome-wide association study recognized that LIM domain only 1 (LMO1) increases the risk of oncogenic potential. An association has been found that LMO1 gene polymorphisms are associated with the susceptibility to Wilms tumor. One hundred forty-five children with Wilms tumor and 531 cancer-free children were included in this hospital-based case-control study. Five potentially functional polymorphisms in the LMO1 gene (rs2168101 G>T, rs1042359 A>G, rs11041838 G>C, rs2071458 C>A and rs3750952 G>C) were genotyped by the TaqMan method. The association between selected polymorphisms and Wilms tumor susceptibility was measured by calculating the odds ratio (OR) and the 95% confidence interval (CI). Only rs2168101 G>T polymorphism was found to have a significant protective effect against Wilms tumor (GT vs. GG: adjusted OR=0.58, 95% CI=0.39-0.88, P=0.010; GT/TT vs. GG: adjusted OR=0.67, 95% CI=0.46-0.97, P=0.034). Moreover, carriers of 3-5 protective genotypes had significantly lower tumor risk than carriers of 0-2 protective genotypes (adjusted OR=0.62, 95% CI=0.42-0.91, P=0.022). The stratified analysis showed that the protective effect of rs2168101 GT/TT was predominant in males, and rs2071458 GT/TT was predominant in females. Regarding the combined risk genotypes, the analysis indicated that the 3-5 protective genotypes collectively decreased Wilms tumor risk in females. These results suggest that LMO1 gene rs2168101 G>T polymorphism may help prevent Wilms tumor, but this conclusion should be verified in other populations and additional studies.

SUBMITTER: Li G

PROVIDER: S-EPMC6547990 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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<i>LMO1</i> Super-Enhancer rs2168101 G>T Polymorphism Reduces Wilms Tumor Risk.

Li Guoyuan G Jia Wei W Yin Zijun Z Zhu Jinhong J Liu Guochang G Xia Huimin H He Jing J Fu Wen W

Journal of Cancer 20190421 8

Wilms tumor is one of the most prevalent pediatric malignancies in childhood cancer worldwide. A genome-wide association study recognized that LIM domain only 1 (LMO1) increases the risk of oncogenic potential. An association has been found that <i>LMO1</i> gene polymorphisms are associated with the susceptibility to Wilms tumor. One hundred forty-five children with Wilms tumor and 531 cancer-free children were included in this hospital-based case-control study. Five potentially functional polym ...[more]

PMID: 31205537

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Project description: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.

Dataset Information

LMO1 Super-Enhancer rs2168101 G>T Polymorphism Reduces Wilms Tumor Risk.

Publications

<i>LMO1</i> Super-Enhancer rs2168101 G>T Polymorphism Reduces Wilms Tumor Risk.

Similar Datasets

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