LMO family gene polymorphisms and Wilms tumor susceptibility in Chinese children: a five-center case-control study.

BACKGROUND: Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential. METHODS: We conducted this five-center case‒control study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association. RESULTS: We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II. CONCLUSION: Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions.

Role of FTO gene polymorphisms in Wilms tumor predisposition: A five-center case-control study.

BACKGROUND: Wilms tumor is the most frequently occurring renal malignancy in pediatrics. The FTO gene exhibits a featured genetic contribution to cancer development. Nonetheless, its single nucleotide polymorphism (SNP) contribution to Wilms tumor remains unknown. METHODS: In the present study, 402 Wilms tumor patients and 1198 healthy controls were successfully genotyped for FTO gene SNPs (rs1477196 G>A, rs9939609 T>A, rs7206790 C>G and rs8047395 A>G) using TaqMan SNP genotyping assays. Odds ratios (ORs) and 95% confidence intervals (CIs), generated from unconditional logistic regression, were applied to quantify the effects of FTO gene SNPs on Wilms tumor risk. RESULTS: We found that the rs8047395 A>G polymorphism was significantly correlated with an increased risk for Wilms tumor (GG versus AA/AG: adjusted OR = 1.38, 95% CI = 1.04-1.85, p = 0.027). Carriers with 1 and 1-2 risk genotypes are more susceptible of developing Wilms tumor than those without risk genotypes. Stratified analysis of rs8047395 and risk genotypes revealed more significant relationships with Wilms tumor risk in certain subgroups. Preliminary functional annotations revealed that the rs8047395 A allele increases expression levels of the FTO gene as determined by expression quantitative trait locus analysis. CONCLUSIONS: The present study provides evidence that rs8047395 may regulate FTO gene expression and thus confer susceptibility to Wilms tumor. The candidate FTO gene rs8047395 A>G polymorphism identified in this study warrants independent investigation.

METTL14 gene polymorphisms decrease Wilms tumor susceptibility in Chinese children.

BACKGROUND: Wilms tumor is a highly heritable malignancy. Aberrant METTL14, a critical component of N6-methyladenosine (m6A) methyltransferase, is involved in carcinogenesis. The association between genetic variants in the METTL14 gene and Wilms tumor susceptibility remains to be fully elucidated. We aimed to assess whether variants within this gene are implicated in Wilms tumor susceptibility. METHODS: A total of 403 patients and 1198 controls were analyzed. METTL14 genotypes were assessed by TaqMan genotyping assay. RESULT: Among the five SNPs analyzed, rs1064034 T > A and rs298982 G > A exhibited a significant association with decreased susceptibility to Wilms tumor. Moreover, the joint analysis revealed that the combination of five protective genotypes exerted significantly more protective effects against Wilms tumor than 0-4 protective genotypes with an OR of 0.69. The stratified analysis further identified the protective effect of rs1064034 T > A, rs298982 G > A, and combined five protective genotypes in specific subgroups. The above significant associations were further validated by haplotype analysis and false-positive report probability analysis. Preliminary mechanism exploration indicated that rs1064034 T > A and rs298982 G > A are correlated with the expression and splicing event of their surrounding genes. CONCLUSIONS: Collectively, our results suggest that METTL14 gene SNPs may be genetic modifiers for the development of Wilms tumor.

Impact of YTHDF1 gene polymorphisms on Wilms tumor susceptibility: A five-center case-control study.

BACKGROUND: Wilms tumor is the most frequent renal malignancy in children. YTHDF1 is associated with the development of several kinds of cancers, yet whether common variants of the YTHDF1 gene influence Wilms tumor risk is unknown. We present, here, a hospital-based case-control study specifically designed to investigate the role of YTHDF1 genetic variants on Wilms tumor. METHODS: We successfully genotyped samples of 408 Wilms tumor cases and 1198 controls which were collected from five hospitals across China. The unconditional logistic regression was adopted to analyze the contributions of YTHDF1 gene single nucleotide polymorphisms (SNPs) to the risk of Wilms tumor. The odds ratio (OR) and 95% confidence interval (CI) were generated to evaluate the conferring risk of YTHDF1 gene SNPs (rs6011668 C>T, rs6090311 A>G). RESULTS: Neither of the two SNPs could contribute to the risk of Wilms tumor. A negative association was also detected in the combined effects of protective genotypes on Wilms tumor risk. The stratification analysis revealed that compared with those with CC genotype, rs6011668 CT/TT genotype was associated with increased Wilms tumor risk in those ≤18 months (OR = 1.54, 95% CI = 1.02-2.30, p = 0.038), and with decreased Wilms tumor risk in those >18 months (OR = 0.70, 95% CI = 0.50-0.97, p = 0.034). CONCLUSION: Our present work sheds some light on the potential role of YTHDF1 gene polymorphisms on Wilms tumor risk.

LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four-centre case-control study.

Neuroblastoma ranks the most common seen solid tumour in childhood. Overexpression of LIN28A gene has been linked to the development of multiple human malignancies, but the relationship between LIN28A single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility is still under debate. Herein, we evaluated the correlation of four potentially functional LIN28A SNPs (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) and neuroblastoma susceptibility in 505 neuroblastoma patients and 1070 controls from four independent hospitals in China. The correlation strengths were determined by using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Among these SNPs, rs34787247 G>A exhibited a significant association with increased susceptibility in neuroblastoma (GA vs GG: adjusted OR = 1.30, 95% CI = 1.03-1.64; AA vs GG: adjusted OR = 2.51, 95% CI = 1.36-4.64, AA/GA vs GG: adjusted OR = 1.42, 95% CI = 1.12-1.80, AA vs GG/GA: adjusted OR = 2.39, 95% CI = 1.29-4.42). Furthermore, the combined analysis of risk genotypes revealed that subjects carrying three risk genotypes (adjusted OR = 1.64, 95% CI = 1.02-2.63) are more inclined to develop neuroblastoma than those without risk genotype, and so do carriers of 1-4 risk genotypes (adjusted OR = 1.26, 95% CI = 1.01-1.56). Stratification analysis further revealed risk effect of rs3811464 G>A, rs34787247 G>A and 1-4 risk genotypes in some subgroups. Haplotype analysis of these four SNPs yields two haplotypes significantly correlated with increased neuroblastoma susceptibility. Overall, our finding indicated that LIN28A SNPs, especially rs34787247 G>A, may increase neuroblastoma risk.

METTL3 polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study.

BACKGROUND: Wilms tumor is a common pediatric tumor worldwide. Methyltransferase like 3 (METTL3) is a core gene of the N6 -methyladenosine (m6 A) modification that widely affects the transcription of tumor-related genes in eukaryotes. METTL3 has been extensively investigated in various tumors but not Wilms tumor. METHODS: We describe a five-center case-control study with 414 patients and 1199 controls aiming to explore the associations between METTL3 polymorphisms (rs1061026 T>G, rs1061027 C>A, rs1139130 A>G and rs1263801 G>C) and Wilms tumor susceptibility. A TaqMan real-time polymerase chain reaction was performed for genotyping. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported as evaluation indicators to determine any associations. RESULTS: Referring to the preliminary analysis results, protective genotypes were identified as rs1061026 TG/GG, rs1061027 CA/AA, rs1139130 GG and rs1263801 GC/CC. The children with three protective genotypes were less likely to develop Wilms tumor than children without protective genotypes (adjusted OR = 0.68, 95% CI = 0.46-0.999, p = 0.0496). Similarly, stratified analysis of the subgroup aged > 18 months, carrying 3 or 4 protective genotypes, was a protective factor for Wilms tumor compared to carrying 0-2 protective genotypes (adjusted OR = 0.59 95% CI = 0.39-0.91, p = 0.016). However, we did not observe any other significant results. CONCLUSIONS: The combined effect of METTL3 polymorphisms reduce Wilms tumor susceptibility in Chinese children. This conclusion requires further verification.

ALKBH5 gene polymorphisms and Wilms tumor risk in Chinese children: A five-center case-control study.

BACKGROUND: Wilms tumor is a frequently diagnosed renal cancer among children with unclear genetic causes. N6-methyladenosine (m6 A) modification genes play critical roles in tumorigenesis. However, whether genetic variations of m6 A modification genes predispose to Wilms tumor remain unclear. ALKBH5 (AlkB homolog 5), a crucial member of m6 A modification genes, encodes a demethylase that functions to reverse m6 A RNA methylation. METHODS: Herein, we evaluated the association of single nucleotide polymorphisms (SNPs) in the m6 A modification gene ALKBH5 and Wilms tumor susceptibility in a large multi-center case-control study. A total of 414 Wilms tumor cases and 1199 healthy controls were genotyped for ALKBH5 rs1378602 and rs8400 polymorphisms by TaqMan. RESULTS: No significant association was detected between these two polymorphisms and Wilms tumor risk. Moreover, 1, 2, and 1-2 protective genotypes (rs1378602 AG/AA or rs8400 GG) did not significantly reduce Wilms tumor risk, compared with risk genotypes only. Stratification analysis revealed a significant relationship between rs1378602 AG/AA genotypes and decreased Wilms tumor risk in children in clinical stage I diseases [adjusted odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.32-0.98, P = .042]. The presence of 1-2 protective genotypes was correlated with decreased Wilms tumor risk in subgroups of age > 18 months, when compared to the absence of protective genotypes (adjusted OR = 0.74, 95% CI = 0.56-0.98, P = .035). CONCLUSION: Collectively, our results demonstrate that ALKBH5 SNPs may exert a weak influence on susceptibility to Wilms tumor. This finding increases the understanding of the role of the m6 A gene in tumorigenesis of Wilms tumor.

The risk of new-onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants.

To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta-analysis of all available case-control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448-2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large-scale studies considering gene-environment interactions and functional research should be conducted to further investigate this association.

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop.

The tumour suppressor p53 plays an important role in tumourigenesis. Besides inducing apoptosis, it regulates cellular senescence, which constitutes an important barrier to tumourigenesis. The mechanism of regulation of cellular senescence by p53 and its downstream pathway are poorly understood. Here, we report that the ubiquitin domain-containing 1 (UBTD1) gene, a new downstream target of p53, induces cellular senescence and acts as a novel tumour suppressor by a mechanism that depends on p53. Expression of UBTD1 increased upon cellular senescence induced by serial passageing of cultures, as well as by exposure to DNA-damageing drugs that induce premature senescence. Over-expression of UBTD1 induces senescence in human fibroblasts and cancer cells and attenuation of the transformed phenotype in cancer cells. UBTD1 is down-regulated in gastric and colorectal cancer tissues, and its lower expression correlates with a more aggressive phenotype and worse prognosis. Multivariate analysis revealed that UBTD1 expression was an independent prognostic factor for gastric cancer patients. Furthermore, UBTD1 increased the stability of p53 protein, by promoting the degradation of Mdm2 protein. Importantly, UBTD1 and p53 function mutually depend on each other in regulating cellular senescence and proliferation. Thus, our data suggest that, upon DNA damage, p53 induction by UBTD1 creates a positive feedback mechanism to further increase p53 expression. Our results establish UBTD1 as a regulator of cellular senescence that mediates p53 function, and provide insights into the mechanism of Mdm2 inhibition that impacts p53 dynamics during cellular senescence and tumourigenesis.

Associations between polymorphisms of the XPC gene and lung cancer susceptibility: a meta-analysis.

Xeroderma pigmentosum complementation group C (XPC) gene plays a critical role in DNA damage recognition, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and cancer susceptibility. Numerous epidemiological studies have investigated the associations between XPC Lys939Gln and Ala499Val polymorphisms and lung cancer susceptibility, but the conclusions are inconclusive. We searched three electronic databases (MEDLINE, EMBASE and EBSCO) for eligible publications and performed a meta-analysis assessing the associations between XPC Lys939Gln and Ala499Val polymorphisms and lung cancer risk. We also analysed the genotype-mRNA expression correlation using the data of HapMap phase II release 23 with 270 individuals from 4 ethnicities for exploring biological plausibility of our findings. We included ten published studies of 3,882 cases and 5,219 controls for Lys939Gln, and five studies with 2,605 cases and 3,329 controls for Ala499Val. When all studies were pooled, we found a significantly increased overall lung cancer risk for Lys939Gln polymorphism (recessive model: OR = 1.14, 95 % CI = 1.01-1.29, P = 0.218 for heterogeneity). Stratification analysis also showed a higher lung cancer risk in Asian populations (recessive model: OR = 1.26, 95% CI = 1.04-1.52, P = 0.263 for heterogeneity). Interestingly, we found significant correlation between Lys939Gln genotypes and XPC mRNA expression for Asian populations as well. However, we did not observe any association between Ala499Val polymorphism and overall lung cancer risk, nor in further stratification analysis. This meta-analysis suggests that XPC Lys939Gln polymorphism may contribute to lung cancer risk, which needs further validation in single larger studies.

XPC gene polymorphisms contribute to bladder cancer susceptibility: a meta-analysis.

Numerous studies have investigated the association between three polymorphisms (Lys939Gln, Ala499Val and PAT-/+) of Xeroderma pigmentosum group C (XPC) gene and bladder cancer susceptibility; however, the findings are inconclusive. In order to acquire a more precise estimation of the relationship, we performed a meta-analysis based on 10 studies including 3,934 cases and 4,269 controls for Lys939Gln, five studies including 2,113 cases and 2,249 controls for Ala499Val, and seven studies including 2,834 cases and 3,048 controls for PAT-/+ polymorphism. We searched publications from EMBASE, MEDLINE, and Chinese Biomedical. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model according to the between-study heterogeneity. We found that all studied polymorphisms were individually associated with increased overall cancer risks, as shown by ORs (95% CIs) below: the Lys939Gln (Gln/Gln vs. Lys/Lys: OR = 1.39, 95% CI = 1.08-1.79; recessive model: OR = 1.42, 95% CI = 1.11-1.83; and allele comparing: OR = 1.12, 95% CI = 1.003-1.24), the Ala499Val (Val/Val vs. Ala/Ala: OR = 1.82, 95% CI = 1.19-2.79; recessive model: OR = 1.70, 95% CI = 1.18-2.46; and allele comparing: OR = 1.23, 95% CI = 1.01-1.50), and the PAT-/+ (+/+ vs. -/-: OR = 1.36, 95% CI = 1.03-1.79 and recessive model: OR = 1.34, 95% CI = 1.06-1.70). Furthermore, stratification analyses demonstrated an increased risk for Asian populations as to the Lys939Gln and PAT-/+ whereas for Caucasian populations as to the Ala499Val polymorphism in the homozygous and recessive models. Despite some limitations, this meta-analysis suggests that XPC polymorphisms are associated with bladder cancer risk, but this association warrants further validation in well-designed studies with large sample sizes.

Smoking and hOGG1 Ser326Cys polymorphism contribute to lung cancer risk: evidence from a meta-analysis.

The human 8-oxoguanine DNA glycosylase (hOGG1) gene plays an important role in the repair of oxidatively damaged DNA base lesions and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contributes to cancer susceptibility. Numerous studies have investigated the association between hOGG1 Ser326Cys polymorphism and lung cancer susceptibility; however, the conclusions are still inconclusive. We searched eligible publications from MEDLINE, EMBASE, and CBM and performed a meta-analysis to assess the associations between hOGG1 Ser326Cys polymorphism and lung cancer risk. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to estimate risk associations, and false-positive report probability (FPRP) analysis was also carried out to evaluate significant findings. A total of 31 investigations with 10,220 cases and 12,284 controls were identified. When all studies were pooled, a significantly increased overall lung cancer risk was found (Cys/Cys vs. Ser/Ser: OR = 1.24, 95 % CI = 1.05-1.47, P = 0.013; recessive model: OR = 1.22, 95 % CI = 1.05-1.41, P = 0.008, and Cys vs. Ser: OR = 1.11, 95 % CI = 1.02-1.21, P = 0.022), and further stratification analysis showed that the association was stronger in Asians, never smokers, and more-cigarette takers. These results were confirmed by FPRP analysis. Despite some limitations, this meta-analysis provides solid evidence that hOGG1 Ser326Cys polymorphism may contribute to lung cancer risk, particularly for Asian populations, never smokers, and more-cigarette takers. Nevertheless, these findings warrant further validation in single large investigations.

TRMT6 gene rs236110 C > A polymorphism increases the risk of Wilms tumor.

tRNA methyltransferase 6 (TRMT6)is an enzyme catalyzing N1-methyladenosine, a reversible modification in RNA, including tRNA, mRNA, rRNA, and lncRNA. Increasing evidence has shown the implications of this post-transcriptional modification and its regulators in carcinogenesis. However, its roles in Wilms tumor haven't been reported. In this study, four TRMT6 gene polymorphisms (rs236170 A > G, rs451571 T > C, rs236188 G > A, and rs236110 C > A) were tested for association with susceptibility to Wilms tumor, the most frequently diagnosed pediatric renal tumor. TaqMan method was adopted to analyze the genotypes of these polymorphisms in 414 cases and 1199 controls. Among the four TRMT6 gene polymorphisms, only the rs236110 C > A displayed a significant association with the risk of Wilms tumor [AA vs. CC, adjusted odds ratio (OR) = 1.93, 95 % confidence interval (CI) = 1.14-3.27, P = 0.015]. This association was confirmed under the recessive models (AA vs. CC/CA, OR = 1.92, 95 % CI = 1.14-3.23, P = 0.015). Furthermore, after stratifying by age, gender, and clinical stage, we mainly detected significant associations for the rs236110 C > A in children older than 18 months, boys, and those with stage IV or III + IV diseases. The rs236110 A allele was significantly associated with decreased expression of MCM8. In conclusion, we identified the rs236110 C > A in the TRMT6 gene as a Wilms tumor susceptibility locus, and this polymorphism warrants more validation studies to be translated into individualized risk prediction strategies for children.

WDR4 gene polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study.

Wilms tumor is the most common embryonal renal malignancy in children. WDR4 is an indispensable noncatalytic subunit of the RNA N7-methylguanosine (m7G) methyltransferase complex and plays an essential role in tumorigenesis. However, the relationship between polymorphisms in the WDR4 gene and susceptibility to Wilms tumor remains to be fully investigated. We performed a large case-control study involving 414 patients and 1199 cancer-free controls to investigate whether single nucleotide polymorphisms (SNPs) in the WDR4 gene are associated with Wilms tumor susceptibility. WDR4 gene polymorphisms (rs2156315 C > T, rs2156316 C > G, rs6586250 C > T, rs15736 G > A, and rs2248490 C > G) were genotyped using the TaqMan assay. In addition, unconditioned logistic regression analysis was performed, odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between WDR4 gene SNPs and Wilms tumor susceptibility as well as the strength of the associations. We found that only the rs6586250 C>T polymorphism was significantly associated with an increased risk of Wilms tumor (adjusted OR=2.99, 95% CI = 1.28-6.97, P = 0.011 for the rs6586250 TT genotype; adjusted OR=3.08, 95% CI = 1.33-7.17, P = 0.009 for the rs6586250 CC/CT genotype). Furthermore, the stratification analysis revealed that patients with the rs6586250 TT genotype and carriers with 1-5 risk genotypes exhibited statistically significant associations with increased Wilms tumor risk in specific subgroups. However, the rs2156315 CT/TT genotype was identified as having a protective effect against Wilms tumor in the age >18 months subgroup compared with the rs2156315 CC genotype. In brief, our study demonstrated that the rs6586250 C > T polymorphism of the WDR4 gene was significantly associated with Wilms tumor. This finding may contribute to the understanding of the genetic mechanism of Wilms tumor.

Polymorphisms in the XPG gene and risk of gastric cancer in Chinese populations.

DNA repair genes play an important role in maintaining stability and integrity of genomic DNA. Polymorphisms in nucleotide excision repair genes may cause variations in DNA repair capacity phenotype and thus contribute to cancer risk. In this case-control study of 1,125 gastric cancer cases and 1,196 cancer-free controls, we investigated the association between three functional single nucleotide polymorphisms (SNPs, rs2296147T > C, rs2094258C > T and rs873601G > A) in the xeroderma pigmentosum group G (XPG) gene and gastric cancer risk. We used the Taqman assays to genotype these three SNPs and logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found that only the rs873601A variant genotypes were associated with a significant higher risk for gastric adenocarcinoma (adjusted OR = 1.30, 95% CI = 1.03-1.64 for AA vs. GG and adjusted OR = 1.23, 95% CI = 1.01-1.49 for AA vs. GG/AG). Stratification analysis indicated that this risk was more pronounced in subgroups of older age (>59 years), males, ever-smokers, and patients with NGCA. All these were not found for the other two SNPs (rs2296147T > C and rs2094258C > T). We then performed expression analysis using gastric cancer adjacent normal tissues from 141 patients and found that the A variant allele was associated with non-significantly reduced expression of XPG mRNA (P(trend) = 0.107). Further analysis using mRNA expression data from the HapMap suggested that the A allele was associated with significantly reduced expression of XPG mRNA in normal cell lines for 45 Chinese (P(trend) = 0.003) as well as for 261 subjects with different ethnicities (P(trend) = 0.001). These support the hypothesis that functional XPG variants may contribute to the risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings.

H19 gene polymorphisms and Wilms tumor risk in Chinese children: a four-center case-control study.

BACKGROUND: Wilms tumor is the most common pediatric renal cancer. However, genetic bases behind Wilms tumor remain largely unknown. H19 is a critical maternally imprinted gene. Previous studies indicated that single nucleotide polymorphisms (SNPs) in the H19 can modify the risk of several human malignancies. Epigenetic errors at the H19 locus lead to biallelic silencing in Wilms tumors. Genetic variations in the H19 may be related to Wilms tumor susceptibility. METHODS: We conducted a four-center study to investigate whether H19 SNP was a predisposing factor to Wilms tumor. Three polymorphisms in the H19 (rs2839698 G > A, rs3024270 C > G, rs217727 G > A) were genotyped in 355 cases and 1070 cancer-free controls, using Taqman method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. RESULTS: We found that all of these three polymorphisms were significantly associated with Wilms tumor risk alterations. The rs2839698 G > A polymorphism (AG vs. GG: adjusted OR = 0.74, 95% CI = 0.57-0.96, p = 0.024; AA vs. GG: adjusted OR = 1.52, 95% CI = 1.05-2.22, p = 0.027), the rs3024270 C > G polymorphism (CG vs. CC: adjusted OR = 0.61, 95% CI = 0.46-0.81, p = 0.0007; and the rs217727 polymorphism (AG vs. GG: adjusted OR = 0.76, 95% CI = 0.58-0.99, p = 0.035). The Carriers of 1, 2, and 1-2 risk genotypes were inclined to develop Wilms tumor compared with those without risk genotype (adjusted OR = 1.36, 95% CI = 1.02-1.80, p = 0.037; adjusted OR = 1.84, 95% CI = 1.27-2.67, p = 0.001; adjusted OR = 1.50, 95% CI = 1.17-1.92, p = 0.002, respectively). The stratified analysis further revealed that rs2839698 AA, rs217727 AA, and 1-2 risk genotypes could strongly increase Wilms tumor risk among children above 18 months of age, males, and with clinical stage I+II disease. CONCLUSION: Our findings indicate that genetic variations in the H19 may confer Wilms tumor risk.

The contribution of YTHDF2 gene rs3738067 A>G to the Wilms tumor susceptibility.

YTHDF2 is responsible for maintaining the dynamic N6-methyladenosine (m6A) modification balance and influences a variety of cancers. We tested whether YTHDF2 gene rs3738067 A>G polymorphism is related to Wilms tumor by genotyping samples of Chinese children (450 cases and 1317 controls). However, the rs3738067 A>G polymorphism showed no statistical significance with Wilms tumor susceptibility. Stratification analysis also revealed that there was no remarkable association of rs3738067 variant AG/GG genotype with Wilms tumor risk in every subgroup (age, gender, and clinical stages). In all, the results indicated YTHDF2 gene rs3738067 A>G polymorphism could not alter Wilms tumor risk significantly.

YTHDC1 gene polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study.

Wilms tumor is a common pediatric tumor with abundant genetic drivers. YTHDC1 is an important reader of the N6-methyladenosine modification that widely regulates eukaryotic transcripts. YTHDC1 has been associated with the occurrence and development of some tumors. However, this is the first study on YTHDC1 gene polymorphisms and Wilms tumor susceptibility. In brief, we conducted a five-center case-control study to explore the associations between YTHDC1 polymorphisms (rs2293596 T > C, rs2293595 T > C, and rs3813832 T > C) and Wilms tumor susceptibility in Chinese children. A total of 404 cases and 1198 controls were successfully genotyped using TaqMan real-time PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were used as the evaluation indicators. We found that children with the 2-3 risk genotypes were more likely to develop Wilms tumor than those with the 0-1 risk genotypes (adjusted OR = 1.28, 95% CI = 1.01-1.62, P = 0.042). However, no other statistically significant results were found in this research study. The combined effect of YTHDC1 polymorphisms significantly increases Wilms tumor susceptibility. Our results need to be verified in different populations after increasing the sample size and controlling for confounding factors.

HMGA2 Gene rs8756 A>C Polymorphism Reduces Neuroblastoma Risk in Chinese Children: A Four-Center Case-Control Study.

BACKGROUND: Neuroblastoma, mainly affecting children, is a lethal malignancy arising from the developing sympathetic nervous system. The genetic etiology of neuroblastoma remains mostly obscure. High mobility group AT-hook 2 (HMGA2), an oncogenic gene, is up-regulated in many tumors. Single nucleotide polymorphisms (SNPs) often modify cancer susceptibility. However, no studies are investigating the association between HMGA2 SNPs and neuroblastoma susceptibility. METHODS: We conducted a four-center case-control study to evaluate the association between three HMGA2 polymorphisms (rs6581658 A>G, rs8756 A>C and rs968697 T>C) and neuroblastoma susceptibility in a Chinese population with 505 cases and 1070 controls. Logistic regression was performed to evaluate the strength of the association. RESULTS: We found that the rs8756 AC/CC genotypes were associated with a reduced neuroblastoma risk when compared to rs8756 AA genotype [Adjusted odds ratio (OR)=0.74, 95% confidence interval (CI)=0.56-0.99, P=0.039]. Carriers with 3 protective genotypes have lower neuroblastoma susceptibility than those without or with 0-2 protective genotypes. The stratified analysis revealed that the protective effects of rs8756 AC/CC genotypes were more predominant among children of age > 18 months, males, and subgroups with the tumor in the mediastinum. Furthermore, haplotype analysis uncovered that haplotype ACC significantly reduced neuroblastoma risk. CONCLUSION: Our study indicated HMGA2 rs8756 A>C polymorphism is significantly associated with decreased neuroblastoma risk.

WTAP Gene Variants Confer Hepatoblastoma Susceptibility: A Seven-Center Case-Control Study.

Hepatoblastoma is a rare disease, and its etiology remains to be revealed. Wilms tumor suppressor-1-associated protein (WTAP) plays a critical role in tumorigenesis. However, whether single nucleotide polymorphisms (SNPs) of the WTAP gene predispose to hepatoblastoma risk awaits to be investigated. With the use of the TaqMan assay, we evaluated the genotype frequencies of three WTAP SNPs (rs7766006 G > T, rs9457712 G > A, and rs1853259 A > G) in Chinese children with 313 hepatoblastoma patients and 1,446 controls. Among these three SNPs, only the rs7766006 T allele exhibited a significant association with hepatoblastoma risk (GT versus GG: adjusted odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.53-0.92, p = 0.009; GT/TT versus GG: adjusted OR = 0.73, 95% CI = 0.57-0.95, p = 0.017). Combined analysis indicated that subjects with two risk genotypes showed significantly higher hepatoblastoma risk, compared to individuals without a risk genotype (adjusted OR = 1.38, 95% CI = 1.02-1.88, p = 0.037). The stratified analysis revealed that the rs1853259 GG genotype, the rs7766006 GT/TT genotype, and two risk genotypes modified hepatoblastoma risk in certain subgroups. The significant results were validated by haplotype analyses and false-positive report probability analyses. Furthermore, the expression quantitative trait locus analysis indicated that rs7766006 T was associated with decreased expression of WTAP mRNA. Collectively, our results suggest that WTAP SNPs may be genetic modifiers for the development of hepatoblastoma.