METTL14 Gene Polymorphisms Confer Neuroblastoma Susceptibility: An Eight-Center Case-Control Study

Association between NER pathway gene polymorphisms and neuroblastoma risk in an eastern Chinese population

Association of ERCC1 and XPF polymorphisms with pediatric glioma susceptibility.

The etiology of hepatoblastoma is largely unknown due to the rarity of this disease. Nucleotide excision repair (NER), a versatile system in repairing DNA damage, is highly implicated in carcinogenesis. However, it remains unclear whether single nucleotide polymorphisms (SNPs) of genes in the NER pathway are related to hepatoblastoma risk. A total of 313 Chinese children diagnosed with hepatoblastoma and 1446 controls were recruited from seven hospitals across China. TaqMan assay was adopted to genotype 19 SNPs in NER pathway genes including ERCC1, XPA, XPC, XPD, XPF and XPG. Of them, only two SNPs in XPC gene predisposed to hepatoblastoma risk. The XPC rs2607775 polymorphism significantly contributed to hepatoblastoma risk (dominant model: adjusted OR=1.44, 95% CI=1.01-2.05, P=.046). However, XPC rs1870134 conferred a significantly decreased risk of hepatoblastoma in recessive model (adjusted OR=0.50, 95% CI=0.26-0.98, P=.042). Stratified analysis revealed that rs2607775 CG/GG genotype, rs1870134 CC genotype and four to five risk genotypes were associated with the risk of hepatoblastoma under certain subgroups. The significant relationships were confirmed by haplotype analyses and false-positive report probability analyses. In addition, expression quantitative trait locus analysis suggested that rs2607775 G increased expression of XPC mRNA. Collectively, our discover a promising candidate XPC gene as a biomarker for the risk of hepatoblastoma.

Neuroblastoma tightly linked with genetic abnormality. The core genes responsible for RNA N1-methyladenosine (m1A) modification are critical in tumor development. Nevertheless, few reports revealed the function of m1A modification core gene polymorphisms and the neuroblastoma risk. We carried out this study to verify the association of 12 single-nucleotide polymorphisms (SNPs) with neuroblastoma susceptibility. This study recruited 898 cases with newly diagnosed neuroblastoma and 1734 Healthy controls from eight medical centers. We selected 12 SNPs from m1A modification genes ALKBH1, TRMT6, TRMT61B, and TRMT10C, and genotypes were determined by the TaqMan method. We used univariable and multivariable logistic regression models to analyze the association of SNPs with neuroblastoma risk, followed by stratified analysis. Statistical analysis showed that TRMT6 rs236170 GG (AOR = 1.23, 95% CI = 1.02–1.50, P = 0.034), rs451571 CC (AOR = 1.46, 95% CI = 1.01–2.11, P = 0.043), rs236188 AA (AOR = 2.65, 95% CI = 1.16–6.07, P = 0.021), rs236110 AA (AOR = 1.91, 95% CI = 1.29–2.82, P = 0.001), and ALKBH1 rs6494 AA (AOR = 4.27, 95% CI = 1.31–13.93, P = 0.016), rs176942 GG (AOR = 1.98, 95% CI = 1.35–2.89, P = 0.0005) were neuroblastoma risk variants; the ALKBH1 rs1048147 CC (AOR = 0.80, 95% CI = 0.68–0.94, P = 0.007) was inverse associated with neuroblastoma risk. The eQTL analysis showed that functional annotation of rs6494 T > A may be potential function variants through decreasing ALKBH1 gene expression mRNA, rs451571 T > C, rs236188 G > A, rs236110 C > A are associated with neuroblastoma risk through increasing the expression of its nearby genes RP5-967N21.11 and lowering the expression of MCM8. Our research showed some SNPs in the m1A modification core genes are related to neuroblastoma.Clinical perspectives(i) Few reports have revealed the function of m1A modification core gene polymorphisms in neuroblastoma risk.(ii) After genotyping 12 SNPs with potential functions in four m1A modification core genes in children with neuroblastoma and healthy controls, we found several neuroblastoma predisposition loci, including TRMT6 rs236170, rs451571, rs236188, rs236110, and ALKBH1 rs6494, rs176942, and rs1048147. The eQTL assessment demonstrated that rs6494 T > A may be a potential functional variant by decreasing ALKBH1 mRNA expression.(iii) Our research is the first to reveal m1A modification core gene SNPs and neuroblastoma risk.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-14984-2.

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.

Neuroblastoma is a common fatal pediatric cancer of the developing sympathetic nervous system, which accounts for ~10% of all pediatric cancer deaths. To investigate genetic risk factors related to neuroblastoma, many genome-wide association studies have been performed, and single nucleotide polymorphisms (SNPs) within HACE1 gene have been identified to associate with neuroblastoma risk. However, the association of the HACE1 SNPs with neuroblastoma needs to be validated in Southern Chinese children. We genotyped five SNPs located in the HACE1 gene (rs4336470 C>T, rs9404576 T>G, rs4079063 A>G, rs2499663 T>C, and rs2499667 A>G) in 256 Southern Chinese patients in comparison with 531 ethnically matched healthy controls. Single locus analysis showed no significant association between any of HACE1 SNPs and neuroblastoma risk in Southern Chinese children. However, when all the risk genotypes were combined, we found a borderline significant trend toward an increased neuroblastoma risk with 4–5 risk genotypes (adjusted odds ratio =1.36, 95% confidence interval =0.98–1.89, P=0.065). Moreover, stratified analysis found that carriers of 4–5 risk genotypes tended to develop neuroblastoma in the retroperitoneal region and have more aggressive tumors, progressing to advanced clinical stages III/IV, when compared with those of 0–3 risk genotypes. In conclusion, HACE1 gene may have weak effect on neuroblastoma risk in Southern Chinese children. Large well-designed studies are needed to strengthen our findings.

Neuroblastoma is the most common seen solid tumor in children less than one year old. Given that polymorphisms in the lncRNA H19 gene are observed in several types of human malignancies, there likely to be similar events that contribute to the pathogenesis of neuroblastoma. We hypothesize that single nucleotide polymorphisms (SNPs) in the H19 gene might predispose to neuroblastoma. Here, we genotyped three SNPs (rs2839698 G>A, rs3024270 C>G, rs217727 G>A) from H19 gene in a Chinese population (700 subjects with neuroblastoma and 1516 control subjects) enrolled from six hospitals and examined the effect of individual and combined SNPs on the risk of neuroblastoma. Odds ratios (ORs) and 95% confidence intervals (CIs) calculated from logistic regression were adopted to assess such association, adjusted for age and gender. Among them, 700 controls and 1514 cases were successfully genotyped. None of these three SNPs were found to be relevant to the risk of neuroblastoma, either in overall analysis or stratification analysis. Findings from this study excluded the participation of lncRNA H19 gene SNPs in the risk of neuroblastoma. More independent case-control studies are encouraged to better elucidate this relationship.

To evaluate the potential association between single nucleotide polymorphisms in the RAS gene and neuroblastoma risk, we examined four candidate SNPs within this gene. Our hospital-based case-control study included 402 cases and 473 controls. Four SNPs (rs12587 G > T, rs7973450 A > G, and rs7312175 G > A in KRAS and rs2273267 A > T in NRAS) were genotyped using the TaqMan assay. The association between RAS gene polymorphisms and neuroblastoma susceptibility was assessed through odds ratios and 95% confidence intervals. None of the four candidate SNPs exhibited a significant attribution to neuroblastoma risk. However, the concurrent presence of 2-3 KRAS risk genotypes significantly conferred an increased susceptibility to neuroblastoma (adjusted odds ratio [AOR] = 2.55, 95% confidence interval [CI] 1.33-4.89; P = 0.005). Further stratified analyses indicated that carriers of the KRAS rs12587 TT genotype tended to be more predisposed to neuroblastoma in males and in the subgroup with tumors originating from other sites. Additionally, the co-occurrence of 2-3 KRAS risk genotypes was found to be linked to an increased neuroblastoma risk in subgroups of individuals older than 18months, males, tumors originating from retroperitoneum, mediastinum, or other sites, and those with tumors at clinical stage III + IV, respectively. In summary, a single KRAS gene polymorphism may be weakly associated with an increased risk of childhood neuroblastoma in Jiangsu province, China, while the presence of more KRAS risk genotypes may increase the contribution to the risk of neuroblastoma.

Alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes have been indicated in several malignancies, including hepatocellular carcinoma (HCC). They play an important role in the progression of cancer. However, the impact of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes on the recurrence of HCC has not been investigated. In this study, we genotyped 17 SNPs in genes encoding TCA cycle key enzymes and analyzed their association with recurrence-free survival (RFS) in a cohort of 492 Chinese HCC patients by Cox proportional hazard model and survival tree analysis. We identified 7 SNPs in SDHC, SDHD, FH, and IDH2 genes to be significantly associated with the RFS of HCC patients. Moreover, all these SNPs were associated with the early recurrence (within 2 years after surgery) risk of diseases. Cumulative effect analysis showed that these SNPs exhibited a dose-dependent effect on the overall and early recurrence. Further stratified analysis suggested that number of risk genotypes modified the protective effect on HCC recurrence conferred by transcatheter arterial chemoembolization treatment. Finally, the survival tree analysis revealed that SNP rs10789859 in SDHD gene was the primary factor contributing to HCC recurrence in our population. To the best of our knowledge, we for the first time observed the association between SNPs in genes encoding TCA cycle key enzymes and HCC recurrence risk. Further observational and functional studies are needed to validate our findings and generalize its clinical usage.

A previous genome-wide association study (GWAS) identified four genetic polymorphisms (rs1027702 near DUSP12, rs10055201 in IL31RA, rs2619046 in DDX4, and rs11037575 in HSD17B12 gene) that were associated with neuroblastoma susceptibility, especially for low-risk subjects. The aim of this study was to examine the association between these four polymorphisms and neuroblastoma susceptibility in a Southern Chinese population composed of 256 cases and 531 controls. Overall, among all the polymorphisms, single-locus analysis only revealed significant association between the HSD17B12 rs11037575 C>T polymorphism and neuroblastoma susceptibility (CT vs CC: adjusted odds ratio [OR] =0.71, 95% confidence interval [CI] =0.51–0.97, P=0.030). Moreover, stratified analysis indicated that the rs11037575 T allele was associated with decreased neuroblastoma risk among the children aged 0–18 months (adjusted OR =0.60, 95% CI =0.37–0.97, P=0.036); regarding the tumor site, this polymorphism protected against tumor in the mediastinum (adjusted OR =0.59, 95% CI =0.37–0.94, P=0.025). When risk genotypes were combined, we found that girls with two to four risk genotypes were at a significantly increased risk of neuroblastoma (adjusted OR =1.65, 95% CI =1.03–2.64, P=0.039). In terms of clinical stages, individuals with two to four risk genotypes had a tendency toward the development of stage III/IV diseases (adjusted OR =1.69, 95% CI =1.12–2.54, P=0.012). In conclusion, we verified that the HSD17B12 rs11037575 T allele might negatively associate with neuroblastoma risk. These findings need further validation by prospective studies with larger sample size and different ethnicities.

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

Neuroblastoma is a malignant tumor arising from the developing sympathetic nervous system, which mainly affects children. Variations in XPA gene have been shown to confer cancer susceptibility. However, no investigation has been reported regarding the association between XPA polymorphisms and neuroblastoma risk. This study was conducted to measure the association of XPA polymorphisms with neuroblastoma susceptibility in Chinese children. In this hospital-based case-control study with 393 cases and 812 controls, we genotyped two polymorphisms (rs1800975 T>C, and rs3176752 G>T) in XPA gene to access their contributions to neuroblastoma risk by TaqMan methods. The strength of the association with neuroblastoma risk was estimated by odds ratios (ORs) and 95% confidence intervals (CIs). No single polymorphism was found to predispose to neuroblastoma susceptibility. When risk genotypes were combined, we found that carriers of 1-2 risk genotypes had significantly increased neuroblastoma risk (adjusted OR=1.28; 95% CI=1.001-1.64, P=0.049), when compared to non-carriers. Stratification analysis by age, gender, sites of origin and clinical stages failed to show any significant association. Our study provides cues that XPA gene polymorphisms may exert a weak effect in neuroblastoma risk. This finding needs further validations by larger sample size studies.

Background: Substantial preclinical data corroborate the critical role of estrogen in prostate cancer development; however, epidemiological studies found no associations between circulating estrogen levels and prostate cancer risk. It was hypothesized that intraprostatic estrogen milieu may play a more important role than circulating estrogen in prostate carcinogenesis. Since it is difficult to obtain data on prostatic estrogen levels, we tested the hypothesis indirectly by investigating associations of prostate cancer risk with genetic variations of enzymes that are involved in estrogen synthesis, metabolism and function, and may affect intraprostatic estrogen milieu. Methods: A panel of 36 potentially functional single nucleotide polymorphisms (SNPs) in estrogen-related genes was assembled based on information obtained in the literature. After removing SNPs with call rate <95% (1 SNP) or minor allele frequency <3% (10 SNPs), a total of 25 SNPs in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined for associations with prostate cancer risk using data and DNA samples from 1617 cases and 1731 controls in the Prostate Cancer Prevention Trial (PCPT). Cases and controls were frequency-matched on age, treatment arm and family history. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately in the placebo and finasteride arms, adjusting for age, race and family history. Results were similar when restricting analysis to white men only. Results: Panels of SNPs that were significantly associated with prostate cancer risk were different according to treatment arm, showing rs1801132 in ESR1, rs700518 in CYP19A1, and rs4124874 in UGT1A6 in the placebo arm and rs2445765 in CYP19A1 and rs4680 in COMT in the finasteride arm. When stratified by circulating estrogen and androgen levels, significant associations were only observed in either the high or low category of serum hormone levels; no SNPs were significantly associated with prostate cancer risk in both categories. CYP19A1 was the only gene harboring SNPs that were significantly associated with prostate cancer risk in both the placebo (rs700518) and finasteride arms (rs2445765). In haplotype analysis using all three CYP19A1 SNPs genotyped in the study (rs700518, rs2445765 and rs700519), compared with non-risk haplotype (GCC), certain CYP19A1 haplotypes were significantly associated with increased prostate cancer risk in both arms. Conclusion: Associations between prostate cancer risk and SNPs in genes involved in estrogen metabolism and function are complicated, and markedly modified by other factors such as finasteride treatment or circulating hormone levels. Supported by grant U10CA37429, 5UM1CA182883 and P01CA108964 from the NCI. Citation Format: Li Tang, Mary Platek, Song Yao, Cathee Till, Phyllis Goodman, Catherine M. Tangen, Yue Wu, Elizabeth A. Platz, Marian L. Neuhouse, Frank Z. Stanczyk, Juergen K. Reichardt, Regina M. Santella, Ann Hsing, William D. Figg, Scott M. Lippman, Ian M. Thompson, Christine B. Ambrosone. Associations between genetic polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1274. doi:10.1158/1538-7445.AM2017-1274

IntroductionNeuroblastoma is an embryonal tumor of the sympathetic nervous system. The MYCN oncogene is amplified in some neuroblastoma patients and correlated with poor prognosis. However, less is known regarding the relationship between MYCN gene single-nucleotide polymorphisms (SNPs) and neuroblastoma risk.Patients and methodsTo investigate the contribution of MYCN gene polymorphisms to neuroblastoma risk, we performed a 3-center case–control study by genotyping 4 SNPs in the MYCN gene from 429 cases and 884 controls.ResultsThe results showed that only rs57961569 G>A was associated with neuroblastoma risk (GA vs GG: adjusted odds ratio =0.76, 95% confidence interval =0.60–0.98, P=0.033), while the other 3 SNPs were not (rs9653226 T>C, rs13034994 A>G, and rs60226897 G>A). Stratified analysis revealed that rs57961569 GG carriers were more likely to develop neuroblastoma in the following subgroups: children older than 18 months, tumor derived from the adrenal gland, and clinical stages III + IV. The increased neuroblastoma risk associated with the rs9653226 variant CC genotypes was more evident in the following subgroups: females, tumor derived from the adrenal gland, and clinical stages III + IV. The presence of 2–3 risk genotypes had a significant relationship with the following subgroups: tumor derived from the adrenal gland and clinical stages III + IV.ConclusionThis study demonstrates a weak impact of MYCN gene polymorphisms on neuroblastoma risk, which should be further validated.

Neuroblastoma is the predominant extracranial solid tumor occurring in children, and genetic factors like genetic polymorphism play a crucial role in its etiology. In this study, we investigated the associations between three NEFL polymorphisms (rs11994014 G>A, rs2979704 T>C, and rs1059111 A>T) and neuroblastoma susceptibility in a cohort of 402 neuroblastoma patients and 473 controls from Jiangsu Province. Genotyping was determined using the TaqMan method. Genotype distributions between cases and controls were assessed via both univariate and multivariate logistic regression models to assess the associations between NEFL polymorphisms and neuroblastoma risk. Stratified analyses were performed based on age, sex, clinical stage, and site of origin to explore potential effect modifications and subgroup-specific associations. In the overall analysis, no significant associations were found between any of the three NEFL polymorphisms and neuroblastoma risk. When subjects were grouped on the basis of the number of risk genotypes, no significant alteration in susceptibility was observed in children carrying three risk genotypes compared with controls carrying fewer risk genotypes. Stratified analyses based on age, sex, clinical stage, and site of origin also revealed no significant results. Our findings suggest that NEFL polymorphisms do not significantly modify neuroblastoma susceptibility in this population, suggesting that the previously reported neuroblastoma susceptibility loci in NEFL in Caucasians may not be consistent across different populations. Further research, including larger, more diverse cohorts, is necessary to clarify the potential role of NEFL and other genetic factors in neuroblastoma etiology.