Guo-Chang Liu

BARD1 Gene Polymorphisms Confer Nephroblastoma Susceptibility

BRCA1-associated RING domain protein 1 (BARD1) is a tumor suppressor, which forms a heterodimer with BRCA1. Three BARD1 gene polymorphisms (rs7585356 G > A, rs6435862 T > G and rs3768716 A > G) were initially identified as high-risk neuroblastoma susceptibility loci by a previous GWAS. Because of the general tumor-suppressing function of BARD1, we hypothesized that these BARD1 gene polymorphisms might modify the susceptibility to nephroblastoma. We genotyped these polymorphisms in 145 cases and 531 controls using Taqman methods. Out of three polymorphisms, only the rs7585356 G > A polymorphism was significantly associated with increased susceptibility to nephroblastoma [AA vs. GG: adjusted odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.01–3.12]. Combined analysis of three polymorphisms indicated that subjects with 3 risk genotypes exhibited significantly elevated nephroblastoma risk, when compared with subjects with 0–2 risk genotypes (adjusted OR = 1.72, 95% CI = 1.02–2.89). Stratified analysis revealed that in term of clinical stage, rs7585356 AA carriers were associated with increased risk of developing clinical stage I + II nephroblastoma. The presence of three risk genotypes was significantly associated with nephroblastoma risk in females and clinical stage I + II nephroblastoma. Our results suggested that BARD1 rs7585356 G > A may be associated with nephroblastoma risk.

The correlation between LIN28B gene potentially functional variants and Wilms tumor susceptibility in Chinese children

Wilms tumor (WT) is the most common urologic cancer in children. However, genetic bases underlying WT remain largely unknown. Previous studies indicated that Lin28 homolog B (LIN28B) level is significantly elevated in some WTs. Enforced expression of Lin28b during kidney development could induce WT. Genetic variations in the LIN28B gene may be related to WT susceptibility.

NFKB1 -94insertion/deletion ATTG polymorphism and cancer risk: Evidence from 50 case-control studies

Nuclear factor-kappa B1 (NF-κB1) is a pleiotropic transcription factor and key contributor to tumorigenesis in many types of cancer. Numerous studies have addressed the association of a functional insertion (I)/deletion (D) polymorphism (-94ins/delATTG, rs28362491) in the promoter region of NFKB1 gene with the risk of various types of cancer; however, their conclusions have been inconsistent. We therefore conducted a meta-analysis to reevaluate this association. PubMed, EMBASE, China National Knowledge infrastructure (CNKI), and WANFANG databases were searched through July 2016 to retrieve relevant studies. After careful assessment, 50 case-control studies, comprising 18,299 cases and 23,484 controls were selected. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to determine the strength of the association. The NFKB1 -94ins/delATTG polymorphism was associated with a decreased risk of overall cancer in the homozygote model (DD vs. II): OR = 0.75, 95% CI = 0.64-0.87); heterozygote model (ID vs. II): OR = 0.91, 95% CI = 0.83-0.99; recessive model (DD vs. ID/II): OR = 0.81, 95% CI = 0.71-0.91; dominant model (ID/DD vs. II): OR = 0.86, 95% CI = 0.78-0.95; and allele contrast model (D vs. I): OR = 0.88, 95% CI = 0.81-0.95). Subgroup and stratified analyses revealed decreased risks for lung cancer, nasopharyngeal carcinoma, prostate cancer, ovarian cancer, and oral squamous cell carcinoma, and this association held true also for Asians (especially Chinese subjects) in hospital-based studies, and in studies with quality scores less than nine. Well-designed, large-scale case-control studies are needed to confirm these results.

Association between TP53 gene Arg72Pro polymorphism and Wilms’ tumor risk in a Chinese population

Wilms’ tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms’ tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms’ tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms’ tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003–4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms’ tumor risk in Chinese children. These findings need further validations in other populations with larger sample size.

Base Excision Repair Gene Polymorphisms and Wilms Tumor Susceptibility

Base excision repair (BER) is the main mechanism to repair endogenous DNA lesions caused by reactive oxygen species. BER deficiency is linked with cancer susceptibility and premature aging. Single nucleotide polymorphisms (SNPs) within BER genes have been implicated in various human malignancies. Nevertheless, a comprehensive investigation of their association with Wilms tumor susceptibility is lacking. In this study, 145 cases and 531 sex and age-matched healthy controls were recruited. We systematically genotyped 18 potentially functional SNPs in six core BER pathway genes, using a candidate SNP approach. Logistic regression was employed to evaluate odds ratio (OR) and 95% confidence interval (CI) adjusted for age and gender. Several SNPs showed protective effects against Wilms tumor. Significant associations with Wilms tumor susceptibility were shown for hOGG1 rs1052133 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.96, P = .030), FEN1 rs174538 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.95, P = .027; recessive: adjusted OR = 0.54, 95% CI = 0.32–0.93 P = .027), and FEN1 rs4246215 (dominant: adjusted OR = 0.55, 95% CI = 0.38–0.80, P = .002) polymorphisms. Stratified analysis was performed by age, gender, and clinical stage. Moreover, there was evidence of functional implication of these significant SNPs suggested by online expression quantitative trait locus (eQTL) analysis. Our findings indicate that common SNPs in BER genes modify susceptibility to Wilms tumor.

LINC00473 antagonizes the tumour suppressor miR-195 to mediate the pathogenesis of Wilms tumour via IKKα

Although dramatic improvements of overall survival has achieved in patients with favourable histology Wilms tumour, disease recurrence is still the main cause of cancer‐related death in childhood. Long non‐coding RNAs (lncRNAs) as oncogenes or tumour suppressors are dysregulated during carcinogenesis. However, the role of lncRNAs in the pathogenesis of Wilms tumour is unknown. Here, an lncRNA LINC00473 signature that functioned as oncogene was identified in Wilms tumour.

Associations between LMO1 gene polymorphisms and Wilms’ tumor susceptibility

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.

Comparison of laparoscopic excision versus open transvesical excision for symptomatic prostatic utricle in children

PURPOSE The aims of this study were to report our clinical experience with laparoscopic excision (LE) and to compare the outcomes of LE versus open transvesical excision (OTE) for the management of prostatic utricle (PU) in children. PATIENTS AND METHODS This was a retrospective single-center study of 14 children who underwent OTE or LE for managing symptomatic PU between April 2003 and December 2014. Age, utricle size, operative time, estimated blood loss, duration of hospital stay, indwelling time of the urethral catheter, presence of residual postoperative utricular stump, and complications were compared between the two groups. RESULTS There were no significant differences in age or utricle size between the two groups. Compared to the OTE group, the LE group experienced shorter operative times, lower estimated blood losses, and shorter hospital stays. Indwelling time of the urethral catheter was nearly 8days in the OTE group and 6days in the LE group. All patients had a follow-up visit between 6months and 2years after surgery. Two patients in the OTE group had transient UTI. Postoperative VCUG showed minimal residual utricular stump for 3 patients in the OTE group. However, no patient in either group required further operative therapy. CONCLUSIONS LE is a safe and feasible procedure for symptomatic PU in children. Compared to OTE, LE can provide minimally invasive access for achieving good exposure with good short-term outcomes.

Axl promotes the proliferation, invasion and migration of Wilms’ tumor and can be used as a prognostic factor

Purpose Overexpression of Axl has been reported in many tumors, where it promotes tumorigenesis and progression, as well as correlates with the prognosis of different malignancies. However, Axl expression and its function have rarely been reported in Wilms’ tumor (WT). This study aimed to reveal the clinical significance of Axl expression in patients with WT and determine its mechanisms. Materials and methods We analyzed the expression of Axl and its correlations with various clinicopathological features in 72 WT tissues and 72 adjacent non-cancerous tissues by immunohistochemistry. Cox proportional hazards regression models were used to investigate the correlations between Axl expression and the prognosis of WT patients. Fresh frozen samples from 20 WT patients were examined using Western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). In WT cell line, after Axl knockdown by sh-Axl and growth arrest-specific 6 (Gas6) stimulation, the cell proliferation, migration and invasion abilities were detected by methyl-thiazolyl-tetrazolium (MTT), clone-forming, wound-healing and transwell assays. Meanwhile, the tumor-forming ability was tested on nude mice xenograft models. Finally, the expression of several proteins in signal pathways was quantified by WB assays. Results Compared with the adjacent non-cancerous tissues, the expression of Axl was significantly higher in WT tissues (P<0.05). High expression of Axl was associated with tumor recurrence or lung metastasis of WT patients and was a prognostic factor for WT patients (P<0.05). In vitro assays, the proliferation, migration and invasion of WT cells decreased with Axl knockdown and significantly increased with Axl activation by Gas6 (P<0.05). In vivo assays, the ability of tumorigenicity in WT cells reduced dramatically after Axl knockout (P<0.05). Moreover, PI3K–Akt pathway proteins decreased with Axl knockdown. Conclusion Our results suggest that Axl is highly expressed in WT and is a prognostic factor, which could promote the progression of WT in vitro and in vivo. It may also be a potential biomarker for WT.

MicroRNA‑92a‑3p inhibits the cell proliferation, migration and invasion of Wilms tumor by targeting NOTCH1

Dysregulation of miR-92a-3p has been shown to contribute to many tumorigenic processes, and is correlated with tumor progression and prognosis. However, the association between miR-92a-3p and the clinicopathological features of Wilms tumorand its regulatory mechanism remain unknown. In the present study, we demonstrated that miR-92a-3p was downregulated in Wilms tumor tissues and was significantly correlated with the lung metastasis of patients with Wilms tumor. Furthermore, miR-92a-3p mimics suppressed Wilms tumor cell proliferation, migration and invasion by in vitro assays. In addition, miR-92a-3p knockdown promoted tumor progression. Moreover, miR-92a-3p was shown to target directly the 3′-UTR of NOTCH1 mRNA by Dual-Luciferase reporter assays in Wilms tumor cells. miR-92a-3p mimics decreased the expression of mRNA and protein of NOTCH1. miR-92a-3p inhibitor enhanced NOTCH1 expression by using western blotting and qPCR. In Wilms tumor tissues, NOTCH1 was highly expressed when compared with that in adjacent non-tumor tissues. NOTCH1 expression was found to be negatively correlated with miR-92a-3p in tumor tissues. Knockdown of NOTCH1 expression reversed the promotive effect of miR-92a-3p inhibitor on the cell proliferation, migration and invasion in Wilms tumor. In conclusion, miR-92a-3p blocks the progression of Wilms tumor by targeting NOTCH1.