Search

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI‐interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome‐wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6‐methyladenosine (m6A) and facilitated RNA‐binding protein interactions between EIF2S3 at 5′‐untranslated region (UTR) and YTHDF2/YBX3 at 3′‐UTR to promote DUSP1 circularization. This m6A‐dependent mRNA‐looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen‐activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER‐mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa. [ABSTRACT FROM AUTHOR]

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification‐related single nucleotide polymorphisms (RNAm‐SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm‐SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'‐O‐Me, m5C, m7G, A‐to‐I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm‐SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm‐SNPs involving m6A, m1A, and A‐to‐I modifications were associated with bladder cancer risk. Among them, m6A‐related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10−4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10−9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm‐SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention. [ABSTRACT FROM AUTHOR]

Background: Alternative splicing (AS)‐related single nucleotide polymorphisms (SNPs) are associated with risk of cancers, but the potential mechanism has not been fully elucidated. Methods: Two‐stage case–control studies comprising 1630 cases and 2504 controls were conducted to investigate the association between the AS‐SNPs and bladder cancer susceptibility. A series of assays were used to evaluate the functional effect of AS‐SNPs on bladder cancer risk. Results: We observed that SNP rs558814 A>G located in lncRNA BCLET (Bladder Cancer Low‐Expressed Transcript, ENSG00000245498) can decrease the risk of bladder cancer (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.76–0.92, p = 3.26 × 10−4). Additionally, the G allele of rs558814 had transcriptional regulatory effects and facilitated the expression of BCLET transcripts, including BCLET‐long and BCLET‐short. We also found decreased BCLET expression in bladder cancer tissues and cells, and BCLET transcript upregulation substantially inhibited tumor growth of both bladder cancer cells and xenograft models. Mechanistically, BCLET recognized and regulated AS of MSANTD2 to participate in bladder carcinogenesis, preferentially promoting the production of MSANTD2‐004. Conclusions: SNP rs558814 was associated with the expression of BCLET, which mainly increased the expression of MSANTD2‐004 through AS of MSANTD2. [ABSTRACT FROM AUTHOR]

Tobacco smoking is one of the most important environmental risk factors involving bladder tumorigenesis. However, smoking-related genes in bladder carcinogenesis and corresponding genetic effects on bladder cancer risk remain unclear. Weighted correlation network analysis (WGCNA) underlying transcriptome of bladder cancer tissues was applied to identify smoking-related genes. The logistic regression model was utilized to estimate genetic effects of single nucleotide polymorphisms (SNPs) in smoking-related genes on bladder cancer risk in the Chinese and European populations with a total of 6510 cases and 6569 controls, as well as the interaction with smoking status. Transcriptome of cells and tissues was used to profile the expression pattern of candidate genes and their genetic variants. Our results demonstrated that a total of 24 SNPs in 14 smoking-related genes were associated with the risk of bladder cancer, of which rs9348451 in CDKAL1 exhibited an interaction with smoking status (ORinteraction = 1.38, Pinteraction = 1.08 × 10−2) and tobacco smoking might combine with CDKAL1 rs9348451 to increase the risk of bladder cancer (Ptrend = 4.27 × 10−4). Moreover, rs9348451 was associated with CDKAL1 expression in bladder cancer, especially in smokers (P < 0.001). Besides, CDKAL1 was upregulated in bladder cancer compared to normal adjacent tissues, as well as upregulated via treatment of cigarette smoke extracts. This study highlights the important role of nurture and nature, as well as their interaction on tumorigenesis, which provides a new way to decipher the etiology of bladder cancer with smoking status. [ABSTRACT FROM AUTHOR]

Recently N6-Methyladenosine (m6A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m6A-switches. We systematically investigated the association between genetic variants in m6A-switches and bladder cancer risk. A two-stage case–control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m6A-switches with bladder cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder cancer risk. A series of experiments were adopted to explore the role of genetic variants of m6A-switches. We identified that rs5746136 (G > A) of SOD2 in m6A-switches was significantly associated with the reduced risk of bladder cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69–0.93, P = 3.6 × 10−3; validation stage: adjusted OR = 0.88, 95% CI 0.79–0.99, P = 3.0 × 10−2; combined analysis: adjusted OR = 0.85, 95% CI 0.78–0.93, P = 4.0 × 10−4). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m6A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder cancer cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m6A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m6A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk. [ABSTRACT FROM AUTHOR]

The Hippo pathway participates in development of numerous tumors through regulating tissue growth and cell fate. This study aimed to detect the association between the genetic variants in Hippo pathway genes and bladder cancer risk in a Chinese population. A case–control study of 580 cases and 1101 controls was performed to evaluate the association of single nucleotide polymorphisms (SNPs) in 39 candidate genes involved in the Hippo pathway with bladder cancer risk. A logistic regression model was used to assess the effects of SNPs on bladder cancer susceptibility. Candidate gene expression in human bladder cancer samples was detected using The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) datasets. We found that SNP rs755813 in WWC1 was significantly associated with a decreased risk of bladder cancer [odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.66–0.88, P = 3.63 × 10–4], which was more common in patients with low grade and non-muscle invasive tumors. Younger subjects (age ≤ 65) (OR = 0.70, 95% CI = 0.56–0.86), females (0.35, 0.23–0.52) and non-smokers (0.72, 0.58–0.88) showed a pronounced association between the rs755813 C allele and risk of bladder cancer by stratified analysis. The WWC1 was upregulated in bladder cancer tissues according to TCGA and GEO datasets. These findings indicated that genetic variant of WWC1 gene in Hippo signaling pathway contributes to the decreased risk of bladder cancer in the Chinese population and may have the protective effect against the development of bladder cancer. [ABSTRACT FROM AUTHOR]

The N6-methyladenosine (m6A) modification plays important regulatory roles in gene expression, cancer occurrence and metastasis. Herein, we aimed to explore the association between genetic variants in m6A modification genes and susceptibility to colorectal cancer. We used logistic regression models to investigate the associations between candidate single-nucleotide polymorphisms (SNPs) in 20 m6A modification genes and colorectal cancer risk. The false discovery rate (FDR) method was used for multiple comparisons. Dual luciferase assays and RNA m6A quantifications were applied to assess transcriptional activity and measure m6A levels, respectively. We found that SND1 rs118049207 was significantly associated with colorectal cancer risk in a Nanjing population (odds ratio (OR) = 1.69, 95% confidence interval (95% CI) = 1.31–2.18, P = 6.51 × 10−6). This finding was further replicated in an independent Beijing population (OR = 1.36, 95% CI = 1.04–1.79, P = 2.41 × 10−2) and in a combined analysis (OR = 1.52, 95% CI = 1.27–1.84, P = 8.75 × 10−6). Stratification and interaction analyses showed that SND1 rs118049207 multiplicatively interacted with the sex and drinking status of the patients to enhance their colorectal cancer risk (P = 1.56 × 10−3 and 1.41 × 10−2, respectively). Furthermore, rs118049207 served as an intronic enhancer on SND1 driven by DMRT3. SND1 mRNA expression was markedly increased in colorectal tumour tissues compared with adjacent normal tissues. The colorimetric m6A quantification strategy revealed that SND1 could alter m6A levels in colorectal cancer cell lines. Our findings indicated that genetic variants in m6A modification genes might be promising predictors of colorectal cancer risk. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44–2.21, P = 1.42 × 10–7, PFDR = 2.80 × 10–5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10–8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10–1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10–2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology. [ABSTRACT FROM AUTHOR]

Genome‐wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk, but whether these SNPs have additive effects on the risk of CRC remains unclear. We performed a systematic analysis of GWAS‐identified SNPs using GWAS datasets from China (2,248 patients and 3,173 controls) and Europe (4,461 patients and 4,140 controls). We analyzed 58 independent variants from DNA samples from Chinese populations and found 19 SNPs that were significantly associated with CRC risk. We identified two genetic risk scores (GRSs) based on 58 and 19 SNPs, which were significantly associated with an increased risk of CRC. A decision curve analysis showed higher predictive power for the 58 SNPs. Using all the 58 SNPs to assess 5‐year absolute risk (AR), we found that, at a cutoff of 0.4% (two times the median AR) and 0.6% (three times the median AR), approximately 32.76 and 16.45% of Chinese individuals were grouped as high risk for developing CRC, respectively. Risk stratification analysis further indicated that the population in the top 30% risk group accounted for 46.71% of the CRC cases. In addition, the 58 SNPs could explain approximately 1.13% of the phenotypic variance in Chinese populations. Similar findings were found in European populations. Combinations of SNPs identified in GWASs may therefore be useful for identifying individuals at high risk for CRC. What's new? While multiple single nucleotide polymorphisms (SNPs) discovered through genome‐wide association studies (GWASs) have been associated with colorectal cancer (CRC) risk, their utility for evaluating CRC risk in individuals remains largely unexplored. In this case‐control study, risk stratification analysis using 58 GWAS‐identified SNPs from Chinese populations indicates that Chinese patients in the top 30% risk group account for more than 46% of CRC cases. Similar results were found using 75 GWAS‐identified SNPs in a European CRC cohort. The findings suggest that panels of GWAS‐identified SNPs can be used to identify individuals at high risk of CRC in general populations. [ABSTRACT FROM AUTHOR]

Background: Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values.Methods: This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts.Results: SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression.Conclusion: rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) within binding sites of microRNAs (miRNAs) could modify cancer susceptibility by changing the binding affinity of miRNAs on their target mRNA 3ʹ‐untranslated regions (UTRs). MicroRNA‐21 (miR‐21) is involved in the development of colorectal cancer. However, the relationship between SNPs within the binding sites of miR‐21 and colorectal cancer risk has not been widely investigated. A case‐control study including 1147 patients and 1203 controls was performed to evaluate the association of SNPs in miR‐21 binding sites and colorectal cancer risk. Dual‐luciferase reporter assays and functional assays were performed to evaluate the effects of miR‐21. The SNP rs6504593 C allele conferred an increased risk of colorectal cancer compared with the T allele in an additive model (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04‐1.36, P = 0.011). Dual‐luciferase reporter assays demonstrated that the rs6504593 T allele negatively post‐transcriptionally regulated IGF2BP1 by altering the binding affinity of miR‐21. Additionally, colorectal cancer cells transiently transfected with miR‐21 mimics promoted cell proliferation and suppressed apoptosis, whereas inhibition of miR‐21 decreased cell growth. These data suggest that the miR‐21 binding site SNP rs6504593 in the IGF2BP1 3ʹ‐UTR may alter IGF2BP1 expression and contribute to colorectal cancer risk. [ABSTRACT FROM AUTHOR]

Circadian clock genes influence biological processes and may be involved in tumorigenesis. We systematically evaluated genetic variants in the circadian clock pathway genes associated with colorectal cancer risk and survival. We evaluated the association of 119 single nucleotide polymorphisms (SNPs) in 27 circadian clock pathway genes with the risk of colorectal cancer in a case-control study (1150 cases and 1342 controls). The false discovery rate (FDR) method was applied to correct for multiple comparisons. Gene-based analysis was performed by the sequence kernel association test (SKAT). Cox proportional hazards regression was used to calculate the effects of SNPs on the overall survival of patients. We identified that compared to those with the G allele, individuals with the rs76436997 A allele in RORA had a significant 1.33-fold increased risk of colorectal cancer (P = 3.83 × 10− 4). Specifically, the GA/AA genotypes were related to an enhanced risk of colorectal cancer compared with that associated with the GG genotype, which was more common in patients with well and moderately differentiated tumors and Dukes A/B stages. The SNP rs76436997 significantly increased the overall survival time of colorectal cancer patients (P = 0.044). Furthermore, RNA-seq data showed that the mRNA levels of RORA were significantly lower in colorectal tumors than the paired normal tissues. Gene-based analysis revealed a significant association between RORA and colorectal cancer risk. These findings highlight the important roles of genetic variations in circadian clock pathway genes play in colorectal cancer risk and suggest that RORA is potentially related to colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Although studies have investigated the association of genetic variants and the abnormal expression of estrogen-related genes with colorectal cancer risk, the evidence remains inconsistent. We clarified the relationship of genetic variants in estrogen metabolic pathway genes with colorectal cancer risk and survival. A case-control study was performed to assess the association of single-nucleotide polymorphisms (SNPs) in ten candidate genes with colorectal cancer risk in a Chinese population. A logistic regression model and Cox regression model were used to calculate SNP effects on colorectal cancer susceptibility and survival, respectively. Expression quantitative trait loci (eQTL) analysis was conducted using the Genotype-Tissue Expression (GTEx) project dataset. The sequence kernel association test (SKAT) was used to perform gene-set analysis. Colorectal cancer risk and rs3760806 in SULT2B1 were significantly associated in both genders [male: OR = 1.38 (1.15-1.66); female: OR = 1.38 (1.13-1.68)]. Two SNPs in SULT1E1 were related to progression-free survival (PFS) [rs1238574: HR = 1.24 (1.02-1.50), P = 2.79 × 10−2; rs3822172: HR = 1.30 (1.07-1.57), P = 8.44 × 10−3] and overall survival (OS) [rs1238574: HR = 1.51 (1.16-1.97), P = 2.30 × 10−3; rs3822172: HR = 1.53 (1.67-2.00), P = 2.03 × 10−3]. Moreover, rs3760806 was an eQTL for SULT2B1 in colon samples (transverse: P = 3.6 × 10−3; sigmoid: P = 1.0 × 10−3). SULT2B1 expression was significantly higher in colorectal tumor tissues than in normal tissues in the Cancer Genome Atlas (TCGA) database (P < 1.0 × 10−4). Our results indicated that SNPs in estrogen metabolic pathway genes confer colorectal cancer susceptibility and survival. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs), endogenous small noncoding RNAs (ncRNAs), play crucial roles in cancer development. Many studies have demonstrated that miRNAs can serve as diagnostic and therapeutic biomarkers for malignancies. Additionally, single nucleotide polymorphisms (SNPs) located in miRNA functional regions have been reported to be involved in cancer susceptibility. In this study, we investigated the associations between SNPs located in miRNA functional regions and colorectal cancer (CRC) susceptibility. We systematically screened all candidate miRNAs and their SNPs and then evaluated the relationships between the SNPs and CRC susceptibility in a Han Chinese population including 878 patients with CRC and 884 controls. Genotyping was performed by TaqMan assay. After comprehensively screening the miRNAs and SNPs, we elected to evaluate the association between SNP rs2682818 in miR‐618 and CRC susceptibility. We found that the AA and AC/AA genotypes of rs2682818 were associated with a decreased risk of CRC compared with the CC genotype (odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37–0.79 for AA vs. CC in codominant model; OR = 0.82, 95% CI = 0.68–0.99 for AC/AA vs. CC in dominant model). However, we obtained no statically significant results in our subgroup analyses. SNP rs2682818 in miR‐618 has potential as a biomarker for individuals with high CRC susceptibility. Our findings need to be verified in studies including larger samples. Moreover, molecular functional studies of miR‐681 must be performed to confirm its relationship with CRC. [ABSTRACT FROM AUTHOR]

Summary: Although the genome-wide association study (GWAS) is a powerful method to identify disease-associated variants, it does not directly address the biological mechanisms underlying such genetic association signals. Here, we present PGA, a Perl- and Java-based program for post- GWAS analysis that predicts likely disease genes given a list of GWAS-reported variants. Designed with a command line interface, PGA incorporates genomic and eQTL data in identifying disease gene candidates and uses gene network and ontology data to score them based upon the strength of their relationship to the disease in question. [ABSTRACT FROM AUTHOR]

BACKGROUND PIWI-interacting RNAs (piRNAs), which are a novel type of identified small noncoding RNA (ncRNA), play a crucial role in germline development and carcinogenesis. METHODS By systematically screening all known piRNAs, the authors identified 7 common single nucleotide polymorphisms (SNPs) in 9 piRNAs. Associations between these selected SNPs and the risk of colorectal cancer (CRC) were detected in a case-control study. A quantitative real-time polymerase chain reaction assay was used to evaluate messenger RNA (mRNA) expression levels of piR-015551 and of the long ncRNA (lncRNA) LNC00964-3 in 88 pairs of tissue samples. RESULTS The assay revealed that reference SNP rs11776042 in piR-015551 was significantly associated with a decreased risk of CRC in an additive model ( P = .020). However, this protective effect was not significant after correction for multiple comparisons (test for the false discovery rate; P = .140). Furthermore, the authors observed that mRNA expression levels of LNC00964-3 (an lncRNA that included the piR-015551 sequence but not piR-015551) were significantly lower in CRC tissues than in corresponding normal tissues ( P = 1.5 × 10−5 for LNC00964-3; P = .899 for piR-015551). Correlation analysis revealed that piR-015551 expression was positively correlated with expression levels of LNC00964-3 (CRC tissues: r = 0.574, P = 5.13 × 10−9; normal tissues: r = 0.601, P = 5.76 × 10−10). Moreover, rs11776042 was not significantly correlated with mRNA expression levels of piR-015551 or LNC00964-3 (all P > .05). CONCLUSIONS The current findings reveal the possibility that piR-015551 may be generated from LNC00964-3, which may be involved in the development of CRC. Cancer 2015;121:2044-2052. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background and Aim Single nucleotide polymorphisms ( SNPs) located in long noncoding RNA CASC8 gene may influence the process of splicing and stability of messenger RNA conformation, resulting in the modification of its interacting partners. Genome-wide association studies have identified the SNP rs10505477 and SNP rs1562430 in CASC8 were associated with risk of the colorectal cancer ( CRC) and breast cancer, respectively. Methods In the present study, we genotyped the 940 surgically resected gastric cancer patients to explore the association between these two SNPs (e.g. rs10505477 and rs1562430) and survival of gastric cancer in a Chinese population. Results We found that the patients carrying rs10505477 GG genotype survived for a longer time than those with the GA and AA genotypes (log-rank P = 0.030). The similar result was also found in the dominant model ( GA/ AA vs GG, HR = 1.32, 95% CI = 1.08-1.63, log-rank P = 0.008). This risk effect was more pronounced among patients with tumor size ≤ 5 cm, diffuse-type gastric cancer, lymph node metastasis, no distant metastasis, and TNM stage III and IV. Furthermore, the area under the curve at five years was dramatically increased from 0.619 to 0.624 after adding the rs10505477 risk score to the traditional clinical risk score ( TNM stage and lymph node metastasis). However, there was no association be found between the rs1562430 and the survival of gastric cancer. Conclusion These findings suggested the SNP rs10505477 may contribute to the survival of gastric cancer and be a potential prognostic biomarker of gastric cancer. [ABSTRACT FROM AUTHOR]

Angiogenesis is fundamentally important to the pathogenesis of clear cell renal cell carcinoma (ccRCC). We investigated the association between variations of genes related to angiogenesis and the risk of ccRCC. In a case–control study of 859 ccRCC patients and 1004 cancer-free subjects, we genotyped 24 potentially functional single nucleotide polymorphisms (SNPs) in seven angiogenesis-related genes (HIF1A, EPAS1, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) using the TaqMan or Snapshot method. Unconditional logistic regression, adjusted for potential confounding factors, was used to assess the risk associations. The functionality of selected SNPs was assessed by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and luciferase reporter gene assays. We found two SNPs (VEGFA rs2010963 and VEGFR3 rs448012) that were significantly associated with increased risk of ccRCC, after adjusting for multiple comparisons [rs2010963 CC/GC cf. GG: false discovery rate (FDR) = 0.048, odds ratio (OR) = 1.36, 95% confidence interval (95% CI) = 1.12–1.66; rs448012 CC/GC cf. GG: FDR = 0.048, OR = 1.38, 95% CI =1.13–1.69]. Real-time quantitative PCR revealed that the variant genotypes of rs2010963, but not rs448012, were associated with increased gene expression in normal tissues of ccRCC patients (CC/GC cf. GG: P = 0.036). The luciferase reporter assay showed that the rs2010963 C allele significantly increased luciferase activity over that of the rs2010963 G allele. Our results indicate that VEGFA rs2010963 and VEGFR3 rs448012 are associated with risk of ccRCC. Furthermore, rs2010963 is a functional SNP that may affect ccRCC susceptibility by modulating endogenous VEGFA expression. [ABSTRACT FROM PUBLISHER]

Objectives: Genome-wide association studies (GWAS) have demonstrated that the single nucleotide polymorphism (SNP) MAP3K1 rs889312 is a genetic susceptibility marker significantly associated with a risk of hormone-related tumors such as breast cancer. Considering steroid hormone-mediated signaling pathways have an important role in the progression of gastric cancer, we hypothesized that MAP3K1 rs889312 may be associated with survival outcomes in gastric cancer. The purpose of this study was to test this hypothesis. Methods: We genotyped MAP3K1 rs889312 using TaqMan in 884 gastric cancer patients who received subtotal or total gastrectomy. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between MAP3K1 rs889312 genotypes and survival outcomes of gastric cancer. Results: Our findings reveal that the rs889312 heterozygous AC genotype was significantly associated with an increased rate of mortality among patients with diffuse-type gastric cancer (log-rank P = 0.028 for AC versus AA/CC, hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 1.03–1.69), compared to those carrying the homozygous variant genotypes (AA/CC). Additionally, univariate and multivariate Cox regression analysis demonstrate that rs889312 polymorphism was an independent risk factor for poor survival in these patients. Conclusions: In conclusion, we demonstrate that MAP3K1 rs889312 is closely correlated with outcome among diffuse-type gastric cancer. This raises the possibility for rs889312 polymorphisms to be used as an independent indicator for predicting the prognosis of diffuse-type gastric cancer within the Chinese population. [ABSTRACT FROM AUTHOR]

Members of the miR-34 family have been shown to be transcriptional targets of the tumour suppressor gene P53. Aberration expression of miR-34 impairs p53-mediated cell cycle arrest and apoptosis. A single nucleotide polymorphism T > C (rs4938723) located within the CpG island in the promoter region of pri-miR-34b/c may affect its expression and has been suggested to influence cancer risk. In this study, we genotyped rs4938723 using the TaqMan method to explore the relationship between this polymorphism and the risk of renal cell cancer (RCC) in a case-control study of 710 RCC patients and 760 control subjects. We found that individuals carrying the CC genotype had a significantly increased RCC risk compared with those with TT or TT/TC genotypes [odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.06–2.21 for CC vs. TT and OR = 1.48, 95% CI = 1.05–2.10 for CC vs. TT/TC). Furthermore, the increased risk was more evident in the subgroups of older subjects (OR = 1.80, 95% CI = 1.08–3.01), males (OR = 1.64, 95% CI = 1.08–2.51), smokers (OR = 2.07, 95% CI = 1.16–3.69) and drinkers (OR = 1.94, 95% CI = 1.01–3.73), although no interaction between rs4938723 and these characteristics was observed. Twenty-seven normal tissues adjacent to tumour were used to evaluate the association between the expression level of miR-34b/c and the polymorphism, which revealed higher expression levels of miR-34b/c in normal renal tissues with TT+TC genotypes than in those with CC genotypes (P < 0.01). Furthermore, a luciferase gene assay in 293-T cells showed that the luciferase activities with rs4938723 T allele are higher than that with C allele (P < 0.05). These results suggest that the miR-34b/c rs4938723 C allele may increase susceptibility to RCC by decreasing the activity of pri-miR-34b/c promoter. [ABSTRACT FROM AUTHOR]

Endogenous and exogenous factors can induce DNA damage, leading to increased risk of cancer. Nucleotide excision repair (NER) is considered as the most versatile DNA repair pathway to deal with a variety of different DNA lesions. ERCC1 and ERCC2 are the two important proteins in NER pathway. In this study, we investigated the association of three functional single nucleotide polymorphisms (SNPs) (ERCC1 rs11615, ERCC2 rs13181 and ERCC2 rs1799793) with the clinical outcome of 940 gastric cancer patients in a Chinese population. Multiplex SNaPshot technology was used to genotype these three SNPs. Our results revealed that individuals with ERCC2 rs13181TG/GG genotypes had a decreased risk of death compared with those with TT genotype [log-rank P = 0.008; adjusted hazard ratio = 0.68, 95% confidence interval = 0.51–0.91] and this protective effect was more pronounced among the subgroups of patients with tumour size ≤ 5cm (0.59, 0.39–0.89), non-cardia gastric tumour (0.69, 0.48–0.98), no lymph node metastasis (0.55, 0.32–0.96), no distant metastasis (0.70, 0.52–0.95) and chemotherapy (0.39, 0.21–0.72). We conclude that ERCC2 rs13181 polymorphism could play different roles in the overall survival of gastric cancer. Further larger studies should be conducted to validate our findings. [ABSTRACT FROM PUBLISHER]

Purpose: Several studies have examined the prognostic value of the TP53 Arg72Pro polymorphism (rs1042522) and/or MDM2 SNP309 (rs2279744) in multiple tumors. Our aim was to determine whether these two genetic variants were correlated with clinical outcome of gastric cancer. Methods: We genotyped the two SNPs, TP53 codon 72 polymorphism and MDM2 SNP309, in 940 gastric cancer patients with complete follow-up information and analyzed the correlation between the SNPs and gastric cancer survival. Results: The two SNPs were not significantly associated with gastric cancer survival. However, the TP53 codon 72 polymorphism had a prominent correlation with clinical outcome of patients receiving 5-fluorouracil (5-Fu)-based postoperative chemotherapy [Arg/Arg + Arg/Pro vs. Pro/Pro, adjusted hazard ratio (HR) = 1.63, 95 % confidence interval (CI) = 1.08-2.44]. Moreover, the unfavorable effect of Arg allele on survival outcome was more predominant for subgroups of older (age >60 years), male, intestinal histology type, advanced stage ( T3/ T4), and none metastasis of lymph node ( N0) or distant ( M0) (adjusted HR = 2.34, 95 % CI = 1.24-4.44 for age >60 years; 1.72, 1.10-2.69 for male; 2.30, 1.10-4.80 for intestinal; 1.62, 1.01-2.59 for T3/ T4; 3.42, 1.26-9.24 for N0; and 1.62, 1.06-2.47 for M0). Among multiple chemotherapy regimens, the association was only significant in the subgroup of 5-Fu/calcium folinate plus oxaliplatin (FOLFOX) chemotherapy regimen (adjusted HR = 4.47, 95 % CI = 1.21-16.55). Conclusions: Our findings showed that TP53 codon 72 polymorphism was associated with survival of gastric cancer patients treated with 5-Fu-based postoperative chemotherapy. The codon 72 polymorphism may be a potential prognostic factor. [ABSTRACT FROM AUTHOR]

Background: As an imperative part of PI3K/Akt/mTOR pathway, mammalian target of rapamycin (mTOR) has been demonstrated to increase in gastric cancer cells and tumors. Our research explored the relationship between single nucleotide polymorphism (SNP) rs2295080 in mTOR promoter region and the risk of gastric cancer (GC). Methods: Seven hundred and fifty-three (753) gastric adenocarcinoma patients and 854 matched healthy subjects were recruited in the cancer association study and 60 tissues were used to test the expression of mTOR. Unconditional logistic regression was selected to evaluate the association between the rs2295080 T>G polymorphism and GC risk. We then examined the functionality of this promoter genetic variant by luciferase assay and EMSA. Results: Individuals with G allele had a 23% decreased risk of GC, comparing with those carrying T allele (adjusted OR = 0.77, 95% CI = 0.65–0.92). This protective effect of G allele stood out better in male group. Meanwhile, GC patients carrying TG/GG genotype also displayed a decreased mRNA level of mTOR (P = 0.004). In luciferase assay, T allele tended to enhance the transcriptional activity of mTOR with an approximate 0.5-fold over G allele. Furthermore, EMSA tests explained that different alleles of rs2295080 displayed different affinities to some transcriptional factor. Conclusion: The mTOR promoter polymorphism rs2295080 was significantly associated with GC risk. This SNP, which effectively influenced the expression of mTOR, may be a new biomarker of early diagnosis of gastric cancer and a suitable indicator of utilizing mTOR inhibitor for treatment of GC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Excessive reactive oxygen species (ROS) accumulation is a common phenomenon in carcinogenesis. However, the rationale behind ROS involvement in gastric cancer is unclear. In this study, the authors investigated the clinical significance of the single nucleotide polymorphisms (SNPs) of 2 ROS metabolic process-related genes: superoxide dismutase 2 ( SOD2) and glutathione S-transferase π ( GSTP1). METHODS: In total of 929 patients with gastric cancer who had definitive clinicopathologic and follow-up data were collected. SOD2 reference SNP 4880 (rs4880) and GSTP1 rs1695 genotyping were examined in DNA samples extracted from paraffin-embedded tumor tissue. Association of the 2 SNPs with each clinicopathologic feature was analyzed using the Pearson chi-square test and the independent Student t test. Gastric cancer-specific overall survival was analyzed using Kaplan-Meier curves and log-rank tests. Multivariate Cox regression analyses of these SNPs also were performed. RESULTS: The SOD2 rs4880 CT + CC genotypes were significantly associated with a high level of lymph node metastasis ( P = .023), whereas the GSTP1 rs1695 GA + GG genotypes were significantly associated with larger tumor size (>5 cm long; P = .048). Kaplan-Meier and Cox regression data indicated that the SOD2 rs4880 CT + CC genotypes alone (hazard ratio, 1.299; 95% confidence interval, 1.053-1.603; P = .015) and the GSTP1 rs1695 GA + GG combined genotypes (hazard ratio, 1.496; 95% CI, 1.078-2.074; P = .016) were independent predictors for overall survival. CONCLUSIONS: The current data, based on a large cohort (n = 929) of Chinese patients with gastric cancer, suggested that the presence of SOD2 rs4880 and GSTP1 rs1695 genotypes may contribute to cancer progression as well as tumor aggressiveness. The components of ROS metabolism pathways may be potential therapeutic targets for this aggressive malignancy. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Neonatal listeriosis is a rare but severe disease manifesting as septicemia and central nervous system (CNS) infections with a high fatality rate of around 20 to 30%. Whole genome sequencing (WGS) is a promising technique for pathogen identification and infection source tracing with its high resolution.Case Presentation: A case of neonatal sepsis with listeriosis was reported with positive blood culture for Listeria monocytogenes. The case was investigated to confirm the vertical transmission of the infection and identify the potential food source of the maternal L. monocytogenes infection using WGS. L. monocytogenes was isolated from the neonate's blood sample the day after caesarean delivery and from the mother's genital and pudenda swab samples 5 days and 13 days after caesarean delivery. WGS showed that the isolate from the neonate was identical to the genome type of the isolates from the mother, with only one of the 4 isolates from the mother differing by one single nucleotide polymorphism (SNP). By WGS, one L. monocytogenes isolate from a ready-to-eat (RTE) meat sample in the patients' community market shared the same sequence type but was ruled out as the cause of infection, with 57 SNP differences to the strain causing the maternal-neonatal infection. The food isolate also carried a novel plasmid pLM1686 that harbored heavy metal resistance genes. After caesarean section, the mother was treated with a third generation cephalosporin which L. monocytogenes is naturally resistant to, which may explain why genital and pudenda swabs were still culture-positive for L. monocytogenes 13 days after delivery.Conclusions: Genital swab culture for L. monocytogenes had been informative in the diagnosis of maternal listeriosis in this case. The high resolution of WGS confirmed the maternal-neonatal transmission of L. monocytogenes infection and ruled out the L. monocytogenes contaminated RTE meat from the local market as the direct source of the mother's infection. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a class of short non-coding, single stranded RNAs, which perform post-transcriptional regulatory functions as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) genes are currently being identified for contributing to cancer risk, prognosis and survival. We investigated whether genetic variations of miRNAs were associated with the risk and prognosis of renal cell carcinoma (RCC). We genotyped four common miRNA SNPs (i.e., miR-146a rs2910164, miR-149 rs2292832, miR-196a2 rs11614913, and miR-499 rs3746444) to assess their associations with RCC risk in a two-stage case-control study (355 cases and 362 controls in discovery set, meanwhile 647 cases and 660 controls in validation set), as well as RCC survival in 311 patients. We found that the miR-196a2 SNP rs11614913 was associated with RCC susceptibility in recessive model (CC vs. TT/TC, adjusted OR = 0.65, 95% CI = 0.52-0.83) and with survival of RCC in dominant model (TC/CC vs. TT, adjusted HR = 0.40, 95% CI = 0.18-0.89). Meanwhile, the rs11614913 CC genotype was associated with the significantly decreased expression of miR-196a-5p in 26 renal cancer tissues (P = 0.018). Moreover, luciferase reporter assays revealed the potential effect of rs11614913 SNP on the binding of miR-196a-3p to its targets. These results suggested that the miR-196a2 rs11614913 may contribute to the genetic susceptibility and prognosis for RCC, which may act as a biomarker for RCC occurrence and prognosis. [ABSTRACT FROM PUBLISHER]

PI3K/Akt/mTOR pathway is involved in tumor initiation and progression, including gastric cancer (GC). However, the single nucleotide polymorphisms (SNPs) in this pathway and underlying molecular mechanism remain largely unexplored. A case-control study of 1275 GC patients and 1436 controls was performed to explore the associations of potentially functional SNPs in PI3K/Akt/mTOR pathway genes with the risk of GC. In the logistic regression analyses, one SNP rs7536272 out of the four candidate SNPs showed a significant association with GC risk (additive model: OR = 1.16, 95% CI = 1.03–1.30; co-dominant model: AG vs. AA, OR = 1.30, 95% CI = 1.11–1.53; dominant model: AG/GG vs. AA, OR = 1.28, 95% CI = 1.10–1.49).The luciferase assay indicated that rs7536272 G allele significantly enhanced the transcriptional activity, compared with A allele. Further expression quantitative trait loci (eQTL) analysis showed that GC patients with rs7536272 AG/GG genotypes had remarkably higher PIK3R3 levels than those with AA genotype, suggesting that rs7536272 polymorphism influenced the expression of PIK3R3 . Additionally, we observed that GC patients with high expression of PIK3R3 had significant poorer outcome than those with low expression (HR = 1.29, 95% CI = 1.09–1.53). Our result demonstrated that SNP rs7536272, a functional risk variant located in the promoter region of PIK3R3 , showed association with increased transcriptional activity and upregulation of PIK3R3 expression, thus involved in GC development. [ABSTRACT FROM AUTHOR]

Background The HOX transcript antisense intergenic RNA ( HOTAIR ) is a well-known long noncoding RNA (lncRNA) that plays a critical role in biological processes in most cancers. However, the function of HOTAIR in bladder cancer remains largely unknown. In this study, we hypothesize that tag single nucleotide polymorphisms (tagSNPs) in HOTAIR are associated with bladder cancer (BCa) risk. Methods We performed a hospital-based case-control study of 1050 cases and 1407 controls to investigate the associations between tagSNPs and the risk of BCa in a Chinese population. Results We found that individuals with the rs874945 AG/AA genotype had a significantly increased risk of BCa compared with those carrying the GG genotype, with an odds ratio (OR) of 1.23 [95% confidence interval (CI) = 1.04–1.46, P  = 0.014]. The subsequently stratified analyses showed that the increased risk was more pronounced in subgroups of older subjects (age > 60 years), never smokers and subjects without pack-years of smoking. Interactive analysis showed that there was no interaction effect between smoking status and rs874945. Conclusion Our study showed that rs874945 in HOTAIR was associated with BCa risk in a Chinese population. [ABSTRACT FROM AUTHOR]

Objective We explored the association between single nucleotide polymorphisms (SNPs) rs207454 and rs494852 located in xanthine dehydrogenase ( XDH ) and gastric cancer (GC) survival. Methods A total of 940 patients with gastric cancer were enrolled and genotyped using TaqMan allelic discrimination method. The Kaplan–Meier test and log-rank examine were used to assess the effect of genetic variation. Results Patients carrying rs207454 CC genotype had a longer survival time than those with the AA genotype ( P  = 0.042). The similar association was detected in the recessive model ( P  = 0.017). We conducted expression quantitative trait loci (eQTL) analysis and found that gastric cancer patients carrying rs207454 CC genotype had significant lower XDH levels than those with AA/AC genotype, suggesting that rs207454 polymorphism effected the expression of XDH . Additionally, the Kaplan-Meier curves showed that gastric cancer patients with high expression of XDH had remarkably poor survival outcome than those with low expression (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.29–1.82). Conclusions Genetic variants in XDH were associated with the survival of gastric cancer and may act as prognostic markers for individual suffered from gastric cancer. [ABSTRACT FROM AUTHOR]

Tumor tissues were potential resources in cancer susceptibility studies. To assess the genotyping concordance between tumor tissues and peripheral blood, we conducted this study in a large sample size and genome-wide scale. Genome-wide genotypes of human colon adenocarcinoma (COAD) retrieved from The Cancer Genome Atlas (TCGA) was analyzed. A total of 387 pairs of matched fresh frozen tumor tissues and peripheral blood samples passed the quality control processes. High concordant rate (94.85% with no-calls and 97.89% without no-calls) was found between tumor tissues and peripheral blood. The discordant rate raised with the increase of heterozygote rate, and the tendency was statistically significant. The total missing rate was 3.10%. We also verified 14 susceptibility SNPs and the average genotyping concordant rate was 97.42%. These findings suggest that majority of SNPs could be accurately genotyped using DNA isolated from tumor tissues. [ABSTRACT FROM AUTHOR]

Exposure to particulate matter 2.5 (PM 2.5 ) may result in DNA damage. Histone variant H2AX phosphorylation plays a central role in the response to damaged chromatin. In the current study, we investigated whether H2AX gene polymorphisms account for PM 2.5 -modulated DNA damage levels. A total of 307 healthy urban residents were collected from three cities in southern, central, and northern China, Zhuhai, Wuhan, and Tianjin, respectively. The dust mass concentrations of PM 2.5 were detected by Gilian 5000 pumps, and the DNA damage levels were measured using comet assay. Seven potentially functional single nucleotide polymorphisms (SNPs) of H2AX gene were selected and genotyped by Illumina Infinium ® BeadChip. We found that three SNPs (rs10790283 G > A, rs604714 C > A and rs7759 A > G) were significantly associated with DNA damage levels (adjusted P = 0.002, 0.018 and 0.027, respectively). Significant interactions ( P < 0.05) were observed between certain genetic polymorphisms and PM 2.5 -modulated DNA damage levels. These results suggested that genetic variations of H2AX might be associated with the DNA damage levels in urban residents with different exposure to PM 2.5 . Further studies with large sample size in independent populations merit validating these findings. [ABSTRACT FROM AUTHOR]

Recent genome-wide association study (GWAS) on esophageal squamous-cell carcinoma (ESCC) among Chinese population has identified two novel single nucleotide polymorphisms (SNPs) rs11066280 and rs2074356 on C12orf51 gene. We hypothesized that SNPs rs11066280 and rs2074356 could influence gastric cancer survival outcomes. We genotyped the SNPs rs11066280 and rs2074356 in 940 patients with surgically resected gastric cancer. Analyses of genotype association with survival outcomes were assessed by the Kaplan-Meier method, Cox proportional hazards models and the log-rank test. There was no significant association between rs11066280 and survival of gastric cancer. However, in the stratification analysis of histology, we found that the rs11066280 TA/AA genotypes were associated with a poor survival of intestinal-type gastric cancer (log-rank P = 0.041, hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.02–1.93), Moreover, this hazardous effect was more prominent among patients with tumor size > 5 cm, no distant metastasis, chemotherapy and drinking. No significant association was observed between rs2074356 and the survival of gastric cancer. C12orf5 rs11066280 could be useful marker of survival assessment and individualized clinical therapy for gastric cancer, particularly among the intestinal-type gastric cancer. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) in the 3′-untranslated regions (UTRs) targeted by putative mircoRNAs (miRNAs) could influence the susceptibility of cancer. Recently, miR-29c has been reported to be down-regulated in gastric cancer (GC) and serve as a tumor suppressor that regulated tumor progression. The present study was aimed at investigating whether the miR-29c binding site SNPs within the 3′-UTRs of target genes affected the gastric cancer risk. Using bioinformatics tools, we chose three SNPs ( IGHMBP2 rs3750980, LAMTOR3 rs11944405 and WWOX rs2288035) located in miR-29c binding sites. We genotyped these three SNPs to assess their associations with GC risk in a case-control study comprising 753 GC cases and 950 controls. Among these three SNPs, we found a significantly decreased risk of GC associated with the LAMTOR3 rs11944405 T > C polymorphism [TC vs. TT, adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.63–0.99; TC/CC vs. TT, adjusted OR = 0.81, 95% CI = 0.65–1.00]. The significant association was also presented in the subgroup analysis by age (≤ 65), sex (female), depth of invasion (T3/T4), lymph node metastasis (N1-3), distant metastasis (M0) and TNM stage (III/IV). However, no significant association was detected for IGHMBP2 rs3750980 and WWOX rs2288035. Our results suggested that the LAMTOR3 rs11944405 polymorphism may be a potential biomarker for genetic susceptibility to GC. [ABSTRACT FROM AUTHOR]

Abstract: A recent genome-wide association study (GWAS) on esophageal squamous-cell carcinoma (ESCC) among Chinese people has discovered a novel single nucleotide polymorphism (SNP) rs10484761 on 6p21.1 region. We hypothesized that SNP rs10484761 T/C is associated with survival of gastric cancer. We genotyped SNP rs10484761 in 940 gastric cancer patients treated with surgical resection. Kaplan–Meier survival analysis, log-rank test, and Cox proportional hazard models were used to evaluate the association between the SNP rs10484761 and gastric cancer survival. In the dominant model, those who carry TC/CC genotypes had a significant shorter survival time (log-rank P =0.005), especially in the subgroups of aged male patients, cardia intestinal tumor (HR=1.41, 95% CI=1.08–1.84 for cardia cancer and HR=1.64, 95% CI=1.14–2.37 for intestinal-type), tumor size≤5cm (HR=1.41, 95% CI=0.56–0.99), T1 depth invasion (HR=2.34, 95% CI=1.20–4.56), lymph node metastasis (HR=1.51, 95% CI=1.19–1.96), no distant metastasis (HR=1.33, 95% CI=1.05–1.68), TNM stage III+IV (HR=1.50, 95% CI=1.13–1.98), and with chemotherapy (HR=1.53, 95% CI=1.17–1.99). The results indicated that SNP rs10484761 was associated with prognosis of gastric cancer, suggesting that this genetic variant may serve as a potential marker to predict the survival of gastric cancer in Chinese population. [Copyright &y& Elsevier]

Highlights: [•] Hsa-miR-196a2 rs11614913 T>C was associated with the significantly increase the risk of childhood ALL. [•] Difference was pronounced in the younger (≤6) subjects and parental non-drinker. [•] Hsa-miR-196a2 rs11614913 TC genotype can increase the risk of B-phenotype ALL and the high-risk ALL. [•] This is the first report on hsa-miR-196a2 polymorphism and Chinese childhood ALL risk. [Copyright &y& Elsevier]

Abstract: Recent genome-wide association studies (GWAS) that focus on childhood acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15years old, have found evidence that single nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2) and CEBPE (14q11.2) are strongly related to the risk of childhood ALL. These polymorphisms may lead to abnormal expression and dysfunction of the corresponding transcription factors and are likely to increase the risk of ALL. To validate the relationship between these SNPs and the risk of childhood ALL in Chinese population, we conducted a case–control study of 570 ALL cases and 673 controls. We determined that the SNP rs10821936 in ARID5B was statistically significantly associated with the risk of childhood ALL (P <0.0001). The results were also significant for the subgroup analysis of high-risk, medium-risk and low-risk ALL as well as B-lineage ALL. Statistically significant differences were not found in the SNPs for IKZF1 and CEBPE. In conclusion, ARID5B rs10821936 could serve as a potential biomarker for assessing the risk of childhood ALL in Chinese children. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]