Dewei Luo

A functional polymorphism in Pre-miR-146a is associated with susceptibility to gastric cancer in a Chinese population.

MicroRNAs play an important role in regulating gene expression at the post-transcriptional level and are involved in numerous physiological processes. Aberrant expression of MicroRNAs is considered to participate in occurrence and progression of human cancers. A G>C polymorphism, rs2910164, which is located in the sequence of miR-146a precursor, could alter mature miR-146a expression and has been suggested to influence cancer risk. The present study was aimed to investigate whether this polymorphism has effects on susceptibility to gastric cancer in the Chinese population. We genotyped the miR-146a rs2910164 polymorphism using the TaqMan method in a two-stage case-control study comprising a total of 1686 gastric cancer patients and 1895 cancer-free subjects. The logistic regression was used to assess the genetic associations with gastric cancer risk. We found a significant association between rs2910164 polymorphism and increased gastric cancer risk [p = 0.038, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56; GG vs. CC/CG]. Similar results were observed in a follow-up replication study. Combined data from the two studies generated a more significant association [p = 0.001, OR = 1.27, 95% CI = 1.10-1.46; GG vs. CC/CG]. Besides, the increased risk associated with the rs2910164GG genotype was more evident in younger subjects (OR = 1.51, 95% CI = 1.25-1.81) rather than in older subjects. Our results suggest that the rs2910164 polymorphism in the sequence of miR-146a precursor may influence the susceptibility to gastric cancer in our Chinese population.

Hsa-miR-196a2 Rs11614913 Polymorphism Contributes to Cancer Susceptibility: Evidence from 15 Case-Control Studies

Background MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-196a2 rs11614913 polymorphism and cancer risk, which showed inconclusive results. Methodology/Principal Findings We conducted a meta-analysis of 15 studies that included 9,341 cancer cases and 10,569 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, individuals with the TC/CC genotypes were associated with higher cancer risk than those with the TT genotype (OR = 1.18, 95% CI = 1.03–1.34, P<0.001 for heterogeneity test). In the stratified analyses, we observed that the CC genotype might modulate breast cancer risk (OR = 1.11, 95%CI = 1.01–1.23, P heterogeneity = 0.210) and lung cancer risk (OR = 1.25, 95%CI = 1.06–1.46, P heterogeneity = 0.958), comparing with the TC/TT genotype. Moreover, a significantly increased risk was found among Asian populations in a dominant model (TC/CC versus TT, OR = 1.24, 95% CI = 1.07–1.43, P heterogeneity = 0.006). Conclusions These findings supported that hsa-miR-196a2 rs11614913 polymorphism may contribute to the susceptibility of cancers.

TERT polymorphisms modify the risk of acute lymphoblastic leukemia in Chinese children

Human telomerase reverse transcriptase (TERT) is essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality. We hypothesized that TERT polymorphisms are associated with risk of childhood acute lymphoblastic leukemia (ALL). We first conducted a case-control study of 570 ALL cases and 673 cancer-free controls of Chinese children, using the tagging single-nucleotide polymorphisms (tSNPs) approach. We then examined the functionality of the important SNPs. We found that TERT promoter region tSNP (rs2735940) and two intron region tSNPs (rs2736100 and rs10069690) were associated with risk of childhood ALL (P = 0.036, 0.011 and 0.022, respectively, in allele comparison). The in vitro luciferase assays in Jurkat cells showed an increased transcriptional activity of rs2735940 T allele compared with the C allele. Additional experiments with ALL bone marrow revealed that the rs2735940 T allele increased levels of the TERT messenger RNA. Notably, TERT intron 2 polymorphism (rs2736100) was associated with lower telomerase activity and longer telomeres. Our findings suggested that TERT promoter rs2735940 polymorphism may affect the TERT activity, and rs2736100 may be associated with telomere function, and thus, it is a potential biomarker for genetic susceptibility to ALL in Chinese children.

Genetic variation of CTNNB1 gene is associated with susceptibility and prognosis of gastric cancer in a Chinese population

UNLABELLED Gastric cancer is the second leading cause of cancer-related death worldwide with a low 5-year survival (S5y) after initial diagnosis. Although aberrant Wnt/β-catenin (CTNNB1) signaling has been observed in multiple human cancers, there is no information on the role of CTNNB1 polymorphisms in gastric cancer risk and S5y. We performed a genetic association study to analyse the correlation between the five tagged SNPs (tSNPs) (rs4135385, rs1798808, rs1880481, rs11564465 and rs2293303) of CTNNB1 and gastric cancer risk and survival. A total of 944 patients with complete follow-up information and 848 cancer-free controls were enrolled in this study. The rs1880481 polymorphism was correlated with decreased risk of gastric cancer [AC/AA vs. CC: adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.63-0.91], whereas the three other SNPs showed opposite effect (AG/AA vs. GG: adjusted OR = 1.31, 95% CI = 1.08-1.57 for rs4135385; GG vs. AA/AG: 2.09, 1.02-4.28 for rs11564475; TT vs. CC/CT 4.87, 2.72-8.71 for rs2293303). We further investigated if these tSNPs were related to the S5y of gastric cancer, and the results displayed that only the SNP rs4135385 AG/AA genotypes were significantly associated with a favorable gastric cancer survival compared with the GG genotype [adjusted hazard ratio (HR) = 0.80, 95% CI = 0.66-0.97], and the association was more prominent among patients with non-cardia gastric cancer (NCGC) than those with cardia gastric cancer (CGC) (Log-rank P = 0.007 for NCGC and 0.417 for CGC). Our results indicated that the genetic variants of CTNNB1 could be used as predictors of gastric cancer susceptibility and prognosis.

A functional polymorphism C‐1310G in the promoter region of Ku70/XRCC6 is associated with risk of renal cell carcinoma

The DNA repair gene Ku70 plays a key role in the DNA double strand break (DSB) repair system. Defects in DSB repair capacity can lead to genomic instability. We hypothesized that the Ku70 C‐1310G polymorphism (rs2267437) was associated with risk of renal cell carcinoma (RCC). We genotyped the Ku70 C‐1310G polymorphism in a case–control study of 620 patients and 623 controls in a Chinese population and assessed the effects of C‐1310G polymorphism on RCC susceptibility and survival. We then examined the functionality of this polymorphism. Compared with the Ku70‐1310CC genotype, the CG and CG/GG genotypes had a significantly increased risk of RCC [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.16–1.87 for CG and OR = 1.47, 95% CI = 1.16–1.86 for CG/GG]. However, the C‐1310G polymorphism did not influence the survival of RCC. The in vivo experiments with normal renal tissues revealed statistically significantly lower Ku70 mRNA expression in samples with CG/GG genotypes relative to those with the CC genotype (P < 0.05). In vitro luciferase assays in various cell lines showed lower luciferase activity for the −1310G allele than for the −1310C allele. These results suggest that the Ku70 C‐1310G polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC in Chinese populations. Larger studies are warranted to validate our findings.

Tagging SNPs in the ERCC4 gene are associated with gastric cancer risk.

ERCC4 plays an essential role in the nucleotide excision repair (NER) pathway, which is involved in the removal of a wide variety of DNA lesions. To determine whether the ERCC4 tagging SNPs (tSNPs) are associated with risk of gastric cancer, we conducted a hospital-based case-control study of 350 cases and 468 cancer-free controls. In the logistic regression (LR) analysis, we found a significantly decreased risk of gastric cancer associated with the rs744154 GC/CC genotypes [adjusted odds ratio (OR)=0.56, 95% confidence interval (CI)=0.42-0.75, false discovery rate (FDR) P=0.003] compared with the wild-type GG genotype. Haplotype-based association study revealed that the CGC haplotype that containing the rs744154 C allele can decrease the risk of gastric cancer compared with the most common haplotype GGT (adjusted OR=0.61, 95% CI=0.46-0.81). Using the multifactor dimensionality reduction (MDR) analysis, we identified that the SNP rs744154 and smoking status were the best two predictive factors for gastric cancer with a testing accuracy of 55.76% and a perfect cross-validation consistency (CVC) of 10 (P=0.001). Furthermore, the smokers with the rs744154 GC/CC genotypes showed a decreased risk of gastric cancer (adjusted OR=0.55, 95% CI=0.35-0.85) compared with the smokers with the GG genotype using multivariate LR analysis. The above findings consistently suggested that genetic variants in the ERCC4 gene may play a protective role in the etiology of gastric cancer, even in the smokers.

A common variant near TERC and telomere length are associated with susceptibility to childhood acute lymphoblastic leukemia in Chinese

Abstract Telomeres are involved in maintaining chromosomal stability, cellular immortality and tumorigenesis. A recent genome-wide association study has identified an association between telomere length and two common variants (rs12696304 and rs16847897) at 3q26 that includes TERC. We hypothesized that the two variants and relative telomere length (RTL) would be predictors of the risk of childhood acute lymphoblastic leukemia (ALL). A case–control study of 570 cases and 673 cancer-free controls among Chinese children was performed. We found that there was a protective relationship between the second and third quartiles of RTL and risk of ALL [adjusted odds ratio (OR) with 95% confidence interval (95% CI) by quartile: 0.65 (0.47–0.91), 0.56 (0.40–0.79)], compared with the first quartile (shortest) RTL. Moreover, rs16847897 CG genotype increased the risk of childhood ALL by 29% compared with the CC genotype. Our findings indicate that extreme telomere length may be a potential predictor for future risk of ALL, and TERC rs16847897 may contribute to the development of childhood ALL.