LMO1 polymorphisms reduce neuroblastoma risk in Chinese children: a two-center case-control study.
ABSTRACT: Previous genome-wide association and validation studies suggest that LIM domain only 1 (LMO1) gene polymorphisms affect neuroblastoma susceptibility. In this work, we used Taqman methodology to genotype four LMO1 polymorphisms (rs110419 A > G, rs4758051 G > A, rs10840002 A > G and rs204938 A > G) in 118 neuroblastoma cases and 281 controls from Northern China. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the association. We found that rs4758051 G > A was associated with a decreased neuroblastoma risk (AA vs. GG: adjusted OR = 0.28, 95% CI = 0.13-0.62; AG/AA vs. GG: adjusted OR = 0.62, 95% CI = 0.40-0.97; AA vs. GG/AG: adjusted OR = 0.33, 95% CI = 0.15-0.69). Likewise, carrying the rs10840002 G allele was also associated with a decreased neuroblastoma risk in this Northern Chinese population. In a combination analysis using Southern and Northern Chinese populations, we found that those carrying the rs110419 G, rs4758051 A or rs10840002 G allele were at decreased neuroblastoma risk, and this finding was supported by a false-positive report probability analysis. These results further verify that LMO1 polymorphisms are protective against neuroblastoma. Case-control studies with larger samples and using other ethnicities are still needed to confirm our conclusion.
Project description:Neuroblastoma is one of the most commonly diagnosed extracranial solid tumors in infancy; however, the etiology of neuroblastoma remains largely unknown. Previous genome-wide association study (GWAS) indicated that several common genetic variations (rs110419 A > G, rs4758051 G > A, rs10840002 A > G and rs204938 A > G) in the LIM domain only 1 (LMO1) gene were associated with neuroblastoma susceptibility. The aim of this study was to evaluate the correlation between the four GWAS-identified LMO1 gene polymorphisms and neuroblastoma risk in a Southern Chinese population. We genotyped the four polymorphisms in 256 neuroblastoma cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. False-positive report probability was calculated for all significant findings. We found that the rs110419 A > G polymorphism was associated with a significantly decreased neuroblastoma risk (AG vs. AA: adjusted OR = 0.65, 95% CI = 0.47-0.91; GG vs. AA: adjusted OR = 0.58, 95% CI = 0.36-0.91; AG/GG vs. AA: adjusted OR = 0.63, 95% CI = 0.46-0.86), and the protective effect was more predominant in children of age > 18 months, males, subgroups with tumor in adrenal gland and mediastinum, and patients in clinical stages III/IV. These results suggested that LMO1 gene rs110419 A > G polymorphism may contribute to protection against neuroblastoma. Our findings call for further validation studies with larger sample size.
Project description:Background: Neuroblastoma, a neuroendocrine tumor, stems from the developing sympathetic nervous system. Previous genome-wide association studies (GWASs) have discovered a number of neuroblastoma susceptibility genes in Caucasians including LIM domain only 1 (LMO1). Objective: We conducted a three-center case-control study including 313 cases and 716 controls with the purpose to evaluate the association between five GWAS-identified LMO1 variants (rs110419 A>G, rs4758051 G>A, rs10840002 A>G, rs204938 A>G, and rs2168101 G>T) and neuroblastoma susceptibility in eastern Chinese children. Methods: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. False positive report possibility (FPRP) analysis was performed to check whether significant results were noteworthy. Results: Significant associations with neuroblastoma risk were found for four (rs110419, rs4758051, rs10840002, and rs2168101) out of the five polymorphisms. Combined analysis demonstrated that carriers of 4-5 protective genotypes had a significantly decreased risk of neuroblastoma in comparison those with 0-3 protective genotypes (adjusted OR = 0.51, 95% CI = 0.39-0.68, P < 0.0001). Haplotype analysis of the five SNPs yield four significant haplotypes associated with neuroblastoma susceptibility. Conclusion: In conclusion, we confirmed LMO1 polymorphisms may reduce neuroblastoma risk in eastern Chinese populations.
Project description:Wilms' tumor is the most common childhood renal malignancy. A genome-wide association study identified LIM domain only 1 (LMO1) as having oncogenic potential. We examined the associations between LMO1 gene polymorphisms and susceptibility to Wilms' tumor. In this hospital-based, case-control study, we recruited 145 children with Wilms' tumor and 531 cancer-free children. Four polymorphisms (rs110419 A>G, rs4758051 G>A, rs10840002 A>G and rs204938 A>G) were genotyped using Taqman methodology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the associations between selected polymorphisms and Wilms' tumor susceptibility. Only rs110419 AG was found to be protective against Wilms' tumor (adjusted OR = 0.62, 95% CI = 0.41-0.94, P = 0.024) when compared to rs110419 AA. Wilms' tumor risk was markedly greater in children with 1-4 risk genotypes (nucleotide alterations) than in those with no risk genotypes (adjusted OR = 1.84, 95% CI = 1.25-2.69, P = 0.002). In a stratified analysis, the protective effect of rs110419 AG/GG was predominant in males. The association of 1-4 risk genotypes with Wilms' tumor risk was limited to subgroups of children who were >18 months old, female, and in clinical stages III+IV. Thus, LMO1 gene polymorphisms may contribute to Wilms' tumor risk, but this conclusion should be validated in other populations and larger studies.
Project description:<h4>Importance</h4>LIM domain only 1 (<i>LMO1</i>) gene polymorphisms were previously found to be implicated in the risk of several cancers. No available studies were performed regarding the predisposing effect of <i>LMO1</i> gene single nucleotide polymorphisms (SNPs) on central nervous system (CNS) tumor risk.<h4>Objective</h4>We aimed to determine whether the <i>LMO1</i> gene SNPs were associated with the risk of CNS tumor by applying a case-control study with 191 cases and 248 controls in China.<h4>Methods</h4>The contributions of <i>LMO1</i> gene SNPs to the risk of CNS tumor was evaluated by multinomial logistic regression.<h4>Results</h4>Based on the calculations of odds ratio (<i>OR</i>) and 95% confidence interval (<i>CI</i>), we failed to detect a significant relationship between each <i>LMO1</i> gene SNP (rs110419 A>G, rs4758051 G>A, rs10840002 A>G, rs204938 A>G, and rs2168101 G>T) and CNS tumor risk, respectively. A negative association was also found in the combined effects on these five SNPs and CNS tumor risk. The stratification analysis further demonstrated the individuals with rs204938 AG/GG genotype confer to increased risk of CNS tumor compared with those with an AA genotype in males (<i>OR</i>: 1.74, 95% <i>CI</i>: 1.01-2.98, <i>P =</i> 0.046).<h4>Interpretation</h4>We concluded that <i>LMO1</i> gene SNPs may not strong enough to influence the risk of CNS tumor in Chinese children. More studies are required to verify this association.
Project description:Neuroblastoma (NB), a neuroendocrine tumour, is one of the most prevalent cancers in children. The link between LMO1 polymorphisms and NB has been investigated by several groups, rendering inconclusive results. Here, with this comprehensive systematic review and up-to-date meta-analysis, we aim to distinctively elucidate the possible correlation between LMO1 polymorphisms and NB susceptibility. Eligible studies were systematically researched and identified using PubMed, Web of Science and Scopus databases up to 10 February 2019. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the associations. Our findings revealed that rs110419 and rs2168101 polymorphisms were significantly associated with a decreased risk of NB in all genetic models. In addition, the rs4758051 variant appeared protective against NB in homozygous, dominant and allele genetic models, whereas the rs10840002 variant markedly decreased the risk of NB in the allele model. In contrast, the rs204938 polymorphism showed a positive association with NB susceptibility in allele genetic models. In summary, our meta-analysis is the first to provide clear evidence of an association between specific polymorphisms of LMO1 and susceptibility to NB. Of note, additional larger well-designed studies would be helpful to further evaluate and confirm this association.
Project description:Neuroblastoma is one of the most commonly diagnosed solid cancers for children, and genetic factors may play a critical role in neuroblastoma development. Previous genome-wide association studies (GWASs) have identified nine genes associated with neuroblastoma susceptibility in Caucasians. To determine whether genetic variations in these genes are also associated with neuroblastoma susceptibility in Southern Chinese children, we genotyped 25 polymorphisms within these genes by the TaqMan method in 256 cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. We performed a meta-analysis to further evaluate the associations. Furthermore, we calculated the area under the receiver-operating characteristic curves (AUC) to assess which gene/genes may better predict neuroblastoma risk. We confirmed that CASC15 rs6939340 A>G, rs4712653 T>C, rs9295536 C>A, LIN28B rs221634 A>T, and LMO1 rs110419 A>G were associated with significantly altered neuroblastoma susceptibility. We also confirmed that rs6939340 A>G (G versus A: OR=1.30, 95% CI=1.13-1.50) and rs110419 G>A (A versus G: OR=1.37, 95% CI=1.19-1.58) were associated with increased neuroblastoma risk for all subjects. We also found that the combination of polymorphisms in CASC15, LIN28B, and LMO1 may be used to predict neuroblastoma risk (AUC=0.63, 95% CI=0.59-0.67). Overall, we verified five GWAS-identified polymorphisms that were associated with neuroblastoma susceptibility alteration for Southern Chinese population; however, these results need further validation in studies with larger sample sizes.
Project description:Neuroblastoma is one of the most frequently occurring childhood cancers. The rs2168101 G>T polymorphism observed in the LMO1 gene is located at a conserved GATA transcription factor binding motif. This polymorphism was reported to be significantly associated with neuroblastoma susceptibility. However, whether this and other functional polymorphisms can affect neuroblastoma risk of Chinese children remains unknown. We conducted a two-center hospital-based case-control study with a total of 374 cases and 812 controls to assess the role of five LMO1 gene polymorphisms in the neuroblastoma risk. We confirmed that rs2168101 G>T was significantly associated with decreased neuroblastoma risk for both northern and southern Chinese children and the combined subjects [GT vs. GG: adjusted odds ratio (OR)=0.57, 95% confidence interval (CI)=0.44-0.74, P<0.0001; TT vs. GG: adjusted OR=0.29, 95% CI=0.15-0.56, P=0.0002; GT/TT vs. GG: adjusted OR=0.53, 95% CI=0.41-0.68, P<0.0001; and TT vs. GT/GG: adjusted OR=0.36, 95% CI=0.19-0.69, P=0.002] after adjustment for age and gender. This association was further confirmed by performing a stratifying analysis and a false-positive report probability analysis. Similar results were observed for the rs3750952 G>C polymorphism. In summary, the current study confirmed that the potentially functional LMO1 rs2168101 G>T and rs3750952 G>C polymorphisms were associated with neuroblastoma susceptibility. This research requires further validation with larger sample sizes and inclusion of different ethnicities.
Project description:Neuroblastoma is a childhood cancer of the sympathetic nervous system that accounts for approximately 10% of all paediatric oncology deaths. To identify genetic risk factors for neuroblastoma, we performed a genome-wide association study (GWAS) on 2,251 patients and 6,097 control subjects of European ancestry from four case series. Here we report a significant association within LIM domain only 1 (LMO1) at 11p15.4 (rs110419, combined P = 5.2?×?10(-16), odds ratio of risk allele = 1.34 (95% confidence interval 1.25-1.44)). The signal was enriched in the subset of patients with the most aggressive form of the disease. LMO1 encodes a cysteine-rich transcriptional regulator, and its paralogues (LMO2, LMO3 and LMO4) have each been previously implicated in cancer. In parallel, we analysed genome-wide DNA copy number alterations in 701 primary tumours. We found that the LMO1 locus was aberrant in 12.4% through a duplication event, and that this event was associated with more advanced disease (P?<?0.0001) and survival (P = 0.041). The germline single nucleotide polymorphism (SNP) risk alleles and somatic copy number gains were associated with increased LMO1 expression in neuroblastoma cell lines and primary tumours, consistent with a gain-of-function role in tumorigenesis. Short hairpin RNA (shRNA)-mediated depletion of LMO1 inhibited growth of neuroblastoma cells with high LMO1 expression, whereas forced expression of LMO1 in neuroblastoma cells with low LMO1 expression enhanced proliferation. These data show that common polymorphisms at the LMO1 locus are strongly associated with susceptibility to developing neuroblastoma, but also may influence the likelihood of further somatic alterations at this locus, leading to malignant progression.
Project description:Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and the most frequently diagnosed cancer in the first year of life. Previous genome-wide association studies (GWAS) of Caucasian and African populations have shown that common single nucleotide polymorphisms (SNPs) in several genes are associated with the risk of developing NB, while few studies have been performed on Chinese children. Herein, we examined the association between the genetic polymorphisms in candidate genes and the risk of NB in Chinese children. In total, 127 SNPs in nine target genes, revealed by GWAS studies of other ethnic groups and four related lincRNAs, were genotyped in 549 samples (244 NB patients and 305 healthy controls). After adjustment for gender and age, there were 21 SNPs associated with NB risk at the two-sided P < 0.05 level, 11 of which were located in LMO1. After correction for multiple comparisons, only rs204926 in LMO1 remained significantly different between cases and controls (OR = 0.45, 95% CI: 0.31-0.65, adjusted P = 0.003). In addition, 16 haplotypes in four separate genes were significantly different between case and control groups at an unadjusted P value < 0.05, 11 of which were located in LMO1. A major haplotype, ATC, containing rs204926, rs110420, and rs110419, conferred a significant increase in risk for NB (OR = 1.82, 95% CI: 1.41-2.36, adjusted P < 0.001). The major finding of our study was obtained for risk alleles within the LMO1 gene. Our data suggest that genetic variants in LMO1 are associated with increased NB risk in Chinese children.
Project description:Background:Neuroblastoma is one of the most common extracranial solid pediatric tumors. KRAS plays an important role in regulating cell proliferation, differentiation, and apoptosis. Single nucleotide polymorphisms (SNPs) in KRAS have been shown to modify susceptibility to multiple tumors, but no specific molecular epidemiology study was reported regarding neuroblastoma. Methods:We conducted a four-center case-control study to explore the association between KRAS gene polymorphisms (rs12587 G>T, rs7973450 A>G, rs7312175 G>A) and neuroblastoma susceptibility with 505 Chinese children and 1070 matched controls. Results:We found that rs7973450 A>G was associated with significantly increased neuroblastoma risk [GG vs. AA: adjusted odds ratio (OR)=4.26, 95% confidence interval (CI)=1.28-14.19, P=0.018; GG vs. AA/AG: adjusted OR=4.27, 95% CI=1.28-14.24, P=0.018]. The stratified analysis further demonstrated that rs7973450 GG genotype carriers had a higher risk to develop neuroblastoma in the subgroups of males, tumor originated from the adrenal gland and clinical stages III+IV. Conclusions:Overall, our results suggested that rs7973450 A>G was associated with increased neuroblastoma risk.