Jiao Zhang

Association of Common Genetic Variants in Pre-microRNAs and Neuroblastoma Susceptibility: A Two-Center Study in Chinese Children

Neuroblastoma is a commonly occurring extracranial pediatric solid tumor without defined etiology. Polymorphisms in pre-miRNAs have been demonstrated to associate with the risk of several cancers. So far, no such polymorphism has been investigated in neuroblastoma. With this in mind, we performed a two-center case-control study to assess the association of genetic variants in pre-miRNAs and neuroblastoma susceptibility in Chinese children, including 393 cases and 812 controls. We found that miR-34b/c rs4938723 T > C polymorphism was significantly associated with decreased neuroblastoma risk (TC versus TT: adjusted odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.39–0.67; TC/CC versus TT: adjusted OR = 0.62, 95% CI = 0.48–0.79). We also observed the significant association between the miR-218 rs11134527 A > G polymorphism and decreased neuroblastoma risk (AG versus AA: adjusted OR = 0.73, 95% CI = 0.56–0.96). Stratified analysis further demonstrated that the protective effect of the rs4938723 T > C polymorphism remained prominent in the subgroups, regardless of age, gender, and clinical stages. In term of sites of origin, this polymorphism significantly reduced the risk of tumors originating from the adrenal gland. We further validated the significant results using false-positive report probability analyses. Overall, the miR-34b/c rs4938723 T > C and miR-218 rs11134527 A > G polymorphisms displayed a protective role from neuroblastoma. These findings need further validation.

LMO1 polymorphisms reduce neuroblastoma risk in Chinese children: a two-center case-control study

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.

LINC00673 rs11655237 C>T confers neuroblastoma susceptibility in Chinese population

Neuroblastoma, which accounts for approximately 10% of all pediatric cancer-related deaths, has become a therapeutic challenge and global burden attributed to poor outcomes and mortality rates of its high-risk form. Previous genome-wide association studies (GWASs) identified the LINC00673 rs11655237 C>T polymorphism to be associated with the susceptibility of several malignant tumors. However, the association between this polymorphism and neuroblastoma susceptibility is not clear. We genotyped LINC00673 rs11655237 C>T in 393 neuroblastoma patients in comparison with 812 age-, gender-, and ethnicity-matched healthy controls. We found a significant association between the LINC00673 rs11655237 C>T polymorphism and neuroblastoma risk (TT compared with CC: adjusted odds ratio (OR) =1.80, 95% confidence interval (CI) =1.06–3.06, P=0.029; TT/CT compared with CC: adjusted OR =1.31, 95% CI =1.02–1.67, P=0.033; and T compared with C: adjusted OR =1.29, 95% CI =1.06–1.58, P=0.013). Furthermore, stratified analysis indicated that the rs11655237 T allele carriers were associated with increased neuroblastoma risk for patients with tumor originating from the adrenal gland (adjusted OR =1.51, 95% CI =1.06–2.14, P=0.021) and International Neuroblastoma Staging System (INSS) stage IV disease (adjusted OR =1.60, 95% CI =1.12–2.30, P=0.011). In conclusion, we verified that the LINC00673 rs11655237 C>T polymorphism might be associated with neuroblastoma susceptibility. Prospective studies with a large sample size and different ethnicities are needed to validate our findings.

Functional Polymorphisms at ERCC1/XPF Genes Confer Neuroblastoma Risk in Chinese Children

Variations in nucleotide excision repair pathway genes may predispose to initiation of cancers. However, polymorphisms of ERCC1/XPF genes and neuroblastoma risk have not been investigated before. To evaluate the relevance of polymorphisms of ERCC1/XPF genes in influencing neuroblastoma susceptibility, we genotyped four polymorphisms in ERCC1/XPF genes using a Chinese population of 393 cases and 812 controls. The results showed that ERCC1 rs2298881 and rs11615 predisposed to enhanced neuroblastoma risk [CA vs. AA: adjusted odds ratio (OR) = 1.94, 95% confidence interval (CI) = 1.30–2.89, P = 0.0012; CC vs. AA: adjusted OR = 2.18, 95% CI = 1.45–3.26, P = 0.0002 for rs2298881, and AG vs. GG: adjusted OR = 1.31, 95% CI = 1.02–1.69, P = 0.038 for rs11615]. Moreover, XPF rs2276466 was also associated with increased neuroblastoma risk (GG vs. CC: adjusted OR = 1.66, 95% CI = 1.02–2.71, P = 0.043). In the combined analysis of ERCC1, we found that carriers with 2–3 risk genotypes were more likely to get risk of neuroblastoma, when compared to those with 0–1 risk genotype (adjusted OR = 1.75; 95% CI = 1.25–2.45, P = 0.0012). Our study indicates that common genetic variations in ERCC1/XPF genes predispose to neuroblastoma risk, which needs to be further validated by ongoing efforts.

CASC15 gene polymorphisms reduce neuroblastoma risk in Chinese children

In this case-control study, we analyzed the association between three single nucleotide polymorphisms (SNPs) in the CASC15 gene (rs6939340 A>G, rs4712653 T>C, and rs9295536 C>A) and neuroblastoma susceptibility in the Guangdong and Henan populations of China. We genotyped and analyzed 118 cases and 281 control subjects from Henan province and combined them with previously published data from the Guangdong population. In the Henan population, only the rs6939340 G>A variant homozygote AA was associated with decreased neuroblastoma risk [AA vs. GG: adjusted odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23-0.98; P=0.045]. All three polymorphisms, individually and in combination, were associated with decreased neuroblastoma susceptibility in the Guangdong population. Moreover, subjects carrying 1-3 of these protective genotypes had lower neuroblastoma susceptibility than non-carriers (adjusted OR=0.65, 95% CI=0.51-0.84, P=0.0007). These results show that all three genetic variants of CASC15 identified in a genome-wide association study (GWAS) decrease neuroblastoma risk in two distinct Chinese populations.

LMO1 super-enhancer polymorphism rs2168101 G>T correlates with decreased neuroblastoma risk in Chinese children

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.

XPA gene polymorphisms and risk of neuroblastoma in Chinese children: a two-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.

Polymorphisms in MYCN gene and neuroblastoma risk in Chinese children: a 3-center case–control study

Introduction Neuroblastoma 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 methods To 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. Results The 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. Conclusion This study demonstrates a weak impact of MYCN gene polymorphisms on neuroblastoma risk, which should be further validated.

HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children: HOTAIR Polymorphisms and Neuroblastoma

Neuroblastoma is the most frequently diagnosed extracranial solid tumor in children. Previous studies have shown that single‐nucleotide polymorphisms in some genes are associated with the risk of multiple cancers, including neuroblastoma. Although Hox transcript antisense intergenic RNA (HOTAIR) gene polymorphisms have been investigated in a variety of cancers, to the authors knowledge the relationships between HOTAIR gene polymorphisms and neuroblastoma susceptibility have not been reported to date. The objective of the current study was to evaluate the correlation between HOTAIR gene polymorphisms and neuroblastoma risk in Chinese children.

RAN/RANBP2 polymorphisms and neuroblastoma risk in Chinese children: a three-center case-control study

The genetic etiology of sporadic neuroblastoma remains largely obscure. RAN and RANBP2 genes encode Ras-related nuclear protein and Ran-binding protein 2, respectively. These two proteins form Ran-RanBP2 complex that regulate various cellular activities including nuclear transport. Aberrant functions of the two proteins are implicated in carcinogenesis. Given the unknown role of RAN/RANBP2 single nucleotide polymorphisms (SNPs) in neuroblastoma risk, we performed a multi-center case-control study in Chinese children to assess the association of the RAN/RANBP2 SNPs with neuroblastoma risk. We analyzed three potentially functional SNPs in RAN gene (rs56109543 C>T, rs7132224 A>G, rs14035 C>T) and one in RANBP2 (rs2462788 C>T) in 429 cases and 884 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the association between these four polymorphisms and neuroblastoma risk. No single variant was found to statistically significantly associate with neuroblastoma risk. However, individuals with 3 protective genotypes were less likely to develop neuroblastoma, in comparison to non-carriers (adjusted OR=0.33; 95% CI=0.12-0.96; P=0.042), as well as those with 0-2 protective genotypes (adjusted OR=0.33; 95% CI=0.11-0.94; P=0.038). Stratified analysis revealed no significant association for any of the four polymorphisms. Further studies are warranted to validate the weak impact of RAN/RANBP2 SNPs on neuroblastoma risk.