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Objective To assess the ablative margin of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) using a three-dimensional (3D) reconstruction technique. Materials and methods We retrospectively analyzed 36 patients with stage I NSCLC lesions undergoing MWA and analyzed the relationship between minimal ablative margin and the local tumor progression (LTP) interval, the distant metastasis interval and disease-free survival (DFS). The minimal ablative margin was measured using the fusion of 3D computed tomography reconstruction technique. Results Univariate and multivariate analyses indicated that tumor size (hazard ratio [HR] = 1.91, P P = 0.01) and minimal ablative margin (HR = 0.13, P P P P P P Conclusions The minimal ablative margin is an independent factor of NSCLC relapse after MWA, and the fusion of 3D reconstruction technique can feasibly assess the minimal ablative margin.

// Jiafei Lu 1, 2, * , Yongmei Yin 3, * , Mulong Du 1, 2, * , Gaoxiang Ma 1, 2 , Yuqiu Ge 1, 2 , Qiang Zhang 1, 2 , Haiyan Chu 1, 2 , Na Tong 1, 2 , Meilin Wang 1, 2 , Jinrong Qiu 3, 4 , Zhengdong Zhang 1, 2 1 Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China 2 Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China 3 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 4 Department of Biological-Therapy, Eastern Hepatobiliary Surgery Hospital Affiliated to Second Military Medical University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Zhengdong Zhang, email: drzdzhang@gmail.com Jinrong Qiu, email: jrqiu@njmu.edu.cn Keywords: polymorphism, hOGG1 , gastric cancer, susceptibility Received: March 22, 2016 Accepted: August 24, 2016 Published: September 01, 2016 ABSTRACT Human 8-oxoguanine DNA glycosylase ( hOGG1 ) is known to play an important role in the prevention of carcinogenesis, including gastric cancer (GC). We performed a case-control study to investigate whether single nucleotide polymorphisms (SNPs) of hOGG1 are associated with GC risk in a Chinese population. Two potential functional tagSNPs (rs159153 and rs1052133) and a previously reported risk SNP (rs125701) were genotyped in 1,275 GC patients and 1,436 controls. We found that SNP rs125701 G > A was significantly associated with the increased GC risk [adjusted odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.05-1.79 in additive model]. Besides, the functional studies demonstrated that the minor A allele of rs125701 significantly reduced the transcriptional activity of hOGG1 promoter and enhanced the methylation level of CpG site of cg15357639. In conclusion, our results suggested that the SNP rs125701 in hOGG1 promoter was associated with the elevated GC risk, which could act as a new potential biomarker for GC susceptibility. Further functional verification of rs125701 in GC pathogenesis is warranted.

Genome-wide association studies (GWAS) of bladder cancer have identified a number of susceptibility loci in European populations but have yet to uncover the genetic determinants underlying bladder cancer incidence among other ethnicities. Therefore, we performed the first GWAS in a Chinese cohort comprising 3,406 cases of bladder cancer and 4,645 controls. We identified a new susceptibility locus for bladder cancer at 5q12.3, located in the intron of CWC27 (rs2042329), that was significantly associated with disease risk (OR = 1.40; P = 4.61 × 10−11). However, rs2042329 was not associated with bladder cancer risk in patients of European descent. The rs2042329 risk allele was also related to significantly increased expression levels of CWC27 mRNA and protein in bladder cancer tissues from Chinese patients. Additional functional analyses suggested that CWC27 played an oncogenic role in bladder cancer by inducing cell proliferation and suppressing apoptosis. In conclusion, the identification of a risk-associated locus at 5q12.3 provides new insights into the inherited susceptibility to bladder cancer in Chinese populations and may help to identify high-risk individuals. Cancer Res; 76(11); 3277–84. ©2016 AACR.

A polymorphism rs4938723 (T > C) within the promoter region of pri-miR-34b/c has been found to not only affect the expression of mature miR-34b/c but also contribute to the susceptibility to several cancer types. We designed a case-control study to evaluate the role of rs4938723 in childhood acute lymphoblastic leukemia (ALL). The rs4938723 CC genotype was significantly associated with reduced ALL risk (p = 0.003, ORadjusted = 0.51, 95% CI = 0.33-0.80 for CC vs. TT). Stratification analyses showed the differences were pronounced in older (> 6 years), male subjects, as well as in patients in low risk and T-ALL subtypes. The in vitro luciferase assays in Jurkat and K-562 cell lines showed that the transcription activity of miR-34b/c was increased when T allele transited to C allele (p

Genome-wide association studies have identified genes in the transforming growth factor-β (TGFβ) signaling pathway that are responsible for regulating carcinogenesis. We searched for single-nucleotide polymorphisms (SNPs) located within 3′-untranslated regions (3′-UTRs) that might affect the ability of miRNAs to bind genes in the TGFβ pathway for further analysis. We used TaqMan technology to genotype these SNPs in a population-based case–control study of 1147 colorectal cancer patients and 1203 matched controls in a Chinese population. The rs1590 variant of TGFBR1 exhibited a significant association with colorectal cancer risk. Compared with individuals carrying the rs1590 TT genotype, individuals carrying the GT/GG genotypes had a decreased risk of colorectal cancer [odd ratio (OR) = 0.82, 95% confidence interval (CI) = 0.68–0.97], which was more evident among older individuals with a family history of cancer. Luciferase assays confirmed that the rs1590 T allele altered the capacity of miR-532-5p to bind TGFBR1. Based on these findings, the rs1590 variant in the 3′-UTR of TGFBR1 may contribute to the susceptibility to colorectal cancer, predominantly by altering miR-532-5p binding.

// Mulong Du 1, * , Weizhi Wang 2, * , Hua Jin 3, * , Qiaoyan Wang 1 , Yuqiu Ge 1 , Jiafei Lu 1 , Gaoxiang Ma 1 , Haiyan Chu 1, 4 , Na Tong 1, 4 , Haixia Zhu 3 , Meilin Wang 1, 4 , Fulin Qiang 3 , Zhengdong Zhang 1, 4 1 Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China 2 Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China 3 Core Laboratory, Nantong Tumor Hospital, Nantong, China 4 Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China * These authors have contributed equally to this work Correspondence to: Zhengdong Zhang, e-mail: drzdzhang@gmail.com Keywords: long noncoding RNA, HOTAIR, genetic variants, gastric cancer Received: May 12, 2015 Accepted: August 24, 2015 Published: September 04, 2015 ABSTRACT The HOX transcript antisense intergenic RNA ( HOTAIR ), a well-known long noncoding RNA, is involved in pathogenesis and progress of multiple tumors. Its ectopic expression and biological functions have been observed in gastric cancer. In this study, we conducted a two-stage case-control study to evaluate whether genetic variations of HOTAIR were associated with gastric cancer risk. We identified that a single nucleotide polymorphism (SNP) rs4759314 was significantly associated with the increased gastric cancer risk with an odds ratio (OR) of 1.39 [95% confidence interval (CI) = 1.13–1.71, P = 0.002] in the combined sets. Further functional experiments revealed the allele-specific effects on HOTAIR and HOXC11 expressions in gastric cancer tissues, of which HOTAIR and HOXC11 expressions of individuals carrying with AG genotype were much higher than those with AA genotype; similarly, the effects occurred in intronic promoter activities, of which the promoter activity of G allele was more pronounced than that of A allele. Interestingly, we identified a novel potential oncogene HOXC11 in gastric cancer pathogenesis with differential expression in gastric cancer tissues by association analysis with candidate gene strategy. These results suggest that SNP rs4759314 of HOTAIR acts as a potential biomarker for predicting gastric cancer, and the role of HOXC11 in gastric cancer etiology is warranted to further investigation.

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.

MicroRNAs are important regulators in numerous cellular processes, including cell differentiation, proliferation, and apoptosis. Recently, miR-143 was identified as a tumor suppressor in prostate cancer (PCa). To explore the mechanism of dysregulation and anti-tumor function of miR-143 in PCa, we first found a single-nucleotide polymorphism rs4705342T>C in the promoter region of miR-143 through bioinformatics tools and then performed a case–control study including 608 PCa patients and 709 controls. Results suggested that subjects with TC/CC genotypes had significantly decreased risk of PCa compared with those with TT genotype (adjusted OR 0.68, 95 % CI 0.55–0.85). Further functional assays showed that the risk-associated T allele increased the protein-binding affinity and reduced the activity of the promoter compared with C allele. In addition, restoration of miR-143 by mimics in PCa cells significantly inhibited cell proliferation and migration and down-regulated the expression level of kallikrein-related peptidase 2 (KLK2) mRNA and protein. The miR-143-KLK2 axis was also confirmed by luciferase reporter assay in vitro. In conclusion, our findings demonstrate that there is the significant association between the functional promoter variant rs4705342T>C in miR-143 and PCa risk and newly describe the miR-143-KLK2 interaction which provided another potential mechanism for miR-143 anti-tumor function.

Numerous studies have shown that elderly people are susceptible to high-level particles with aerodynamic diameter ≤ 2.5 μm (PM

Current procedures for diagnosis and biomarker examination of colorectal cancer (CRC) are invasive and unpleasant. There is a great need to identify sensitive and specific biomarkers for early diagnosis of CRC. Circulating microRNAs (miRNAs) are promising molecular markers for CRC prediction. We performed a comprehensive meta-analysis to integrate an evaluation index for diagnostic accuracy of circulating miRNAs in diagnosing CRC patients. Furthermore, we conducted an independent validation set of 49 CRC patients and 49 healthy controls. In our meta-analysis, we found that miR-21 yielded a pooled area under ROC curve (AUC) of 0.867 (sensitivity: 76%, specificity: 82%) in discriminating CRC from controls, and miR-92a yielded a summary AUC of 0.803 (sensitivity: 77%, specificity: 68%); miR-21 had a higher diagnostic efficiency than miR-92a. In the further validation, plasma miR-21 levels in CRC patients were significantly higher than levels observed in healthy subjects. A ROC curve analysis showed a consistent result. However, this phenotype was not present in miR-92a. Moreover, the expression trend of miR-21 in plasma samples was in line with that of tissue samples, along with the cellular level. Current evidences suggest that plasma miR-21 could be a reliable and non-invasive biomarker for CRC diagnosis. Studies with larger cohorts that include the diagnostic value of plasma miR-21 for CRC are warranted.

Background/Aims: FOXO3a is an essential tumor suppressor that regulates the mechanisms of tumorigenesis and leukemogenesis. FOXO3a polymorphisms have not been reported previously associated with an increased risk for childhood acute lymphoblastic leukemia (ALL). In this study, the rs4946936 polymorphism located in the 3'UTR of FOXO3a was selected to evaluate its relationship with a risk for ALL in Chinese children. Methods: Questionnaires, SNaPshot genotyping, real-time PCR, cell transfection and dual luciferase reporter assays were used in this study. Results: Parental alcohol consumption and whether the child’s house had been painted had significantly different distributions among the cases and controls. In addition, the C to T mutation was significantly associated with the risk for ALL. We determined that FOXO3a expression levels in patients with the CT or TT genotype were significantly higher than those of patients with the CC genotype. The T allele significantly increased the expression levels in luciferase assays and affected the binding affinity of miR-223 to the FOXO3a 3'UTR. Conclusion: Rs4946936 in FOXO3a was highly associated with an increased risk of childhood ALL in a Chinese population.

Acute lymphoblastic leukemia (ALL) is a major cause of mortality and morbidity in childhood, and the causes of ALL are not completely understood. microRNAs (miRNAs) regulate various biological processes including organ development, cell growth regulation, cell differentiation, apoptosis, and tumorigenesis. We performed a case–control study with 570 childhood ALL cases and 673 cancer-free controls to investigate the association between hsa-miR-196a2 rs11614913 T > C polymorphism and ALL risk. The bioinformatics was used to estimate the potential target of hsa-miR-196a2. In the present study, the hsa-miR-196a2 variant TC heterozygote, and CC/TC genotypes were found to be associated with a significantly increased childhood ALL risk, compared with the TT wild-type homozygote (adjusted OR = 1.50, 95% CI = 1.15–1.95 for TC and OR = 1.40, 95% CI = 1.09–1.79 for CC/TC). Further, the difference was pronounced in younger (≤6) subjects or parental non-drinker. The significance of the increased risk is more obvious than the higher treatment branch. Additionally, we found that the rs11614913 TC genotype can increase B-phenotype ALL risk (OR = 1.37, 95% CI = 1.07–1.76). Finally, combination of three bioinformatics approaches revealed that HOXC8 may be the target gene of hsa-miR-196a2. Taken together, our finding suggested that hsa-miR-196a2 rs11614913 T > C may increase the risk of childhood ALL. Large studies with the function of hsa-miR-196a2 are needed in the further study.

It is well known that the tea extracts, mainly polyphenols as chemo-preventive elements, could act as cancer progression blockers. Although the association between tea consumption and colorectal cancer risk has been widely investigated, the results still remain inconsistent. We conducted a dose-response meta-analysis to evaluate their relationships by enrolling qualified 29 literatures. The summary odds ratio (OR) of colorectal cancer for the highest vs. lowest tea consumption was 0.93 with 0.87-1.00 of 95% confidence intervals (CIs) among all studies with modest heterogeneity (P = 0.001, I2 = 43.4%). Stratified analysis revealed that tea, especially green tea, had a protective effect among female and rectal cancer patients. Particularly, the dose-response analysis showed that there was a significant inverse association between an increment of 1 cup/day of tea consumption and colorectal cancer risk in the subgroup of the green tea drinking (OR = 0.98, 95% CI = 0.96-1.01, Pnonlinear = 0.003) and female (OR = 0.68, 95% CI = 0.56-0.81, Pnonlinear < 0.001). Our findings indicate that tea consumption has an inverse impact on colorectal cancer risk, which may have significant public health implications in the prevention of colorectal cancer and further similar researches.

Much evidence show that over-expression of epidermal growth factor receptor (EGFR) plays an important role in regulating carcinogenesis. Genetic variations in 3' untranslated region (3'UTR) of gene have been reported to affect gene expression by interfering with microRNAs (miRNAs), which are thought to function as either tumour suppressors or oncogenes by binding to their target mRNA. In this study, we investigated the association between the EGFR 3'UTR 774T>C polymorphism and bladder cancer risk. We used the TaqMan technology to genotype this genetic variant in a hospital-based case-control study of 908 bladder cancer patients and 1239 controls in a Chinese population. We found that the 774CC genotype was associated with a statistically significantly increased risk of bladder cancer [adjusted odds ratio = 1.29, 95% confidence interval = 1.05-1.58], compared with the 774TT/TC genotype, and this increased risk was more pronounced among subgroups of age > 65 years, non-smokers and patients' tumour invasive stage. Furthermore, luciferase assays in T24 cell showed that EGFR 3'UTR 774 T to C substitution could increase the expression of EGFR, which was consistent with the association study finding. Additionally, we also provide evidence that 774T>C polymorphism increasing EGFR expression was not regulated by hsa-miR-214 binding. These findings suggested that EGFR 3'UTR 774T>C polymorphism may contribute to susceptibility to bladder cancer.

This study aims to explore how microRNA-133a (miR-133a) affects cell apoptosis and radio-sensitivity by targeting EGFR via regulating MEK/ERK pathway in esophageal cancer (EC). A total of 358 EC patients were selected and assigned into the resistant and sensitive groups. Human EC KYSE 150 cell line was assigned into the blank, negative control (NC), miR-133a mimic, miR-133a inhibitors, si-EGFR, miR-133a inhibitors + si-EGFR groups after transfection. MiR-133a and EGFR mRNA expressions were detected by qRT-PCR and EGFR, MEK/ERK pathway-related protein expressions were detected by Western blotting. The radio-sensitivity and cell apoptosis were testified by clone formation and flow cytometry. MiR-133a was up-regulated but EGFR was down-regulated in the sensitive group than in the resistant group. Compared with the blank and NC groups, the miR-133a mimic and si-EGFR groups exhibited increased cell apoptosis rate but decreased EGFR, p-MEK1/2, and p-ERK1/2 protein expressions; while opposite trend was observed in the miR-133a inhibitors group. Compared with the miR-133a inhibitors group, the miR-133a inhibitors + si-EGFR group presented reduced cell survival rate, EGFR, p-MEK1/2, and p-ERK1/2 protein expressions but increased cell apoptosis rate. These results indicated that miR-133a could inhibit the MEK/ERK pathway to promote cell apoptosis and enhance radio-sensitivity by targeting EGFR in EC. J. Cell. Biochem. 118: 2625-2634, 2017. © 2017 Wiley Periodicals, Inc.

In our previous study, we demonstrated that four microRNAs (miRNAs) (miR-26a, miR-142-3p, miR-148a, and miR-195) that were downregulated in both plasma and tumor tissues were confirmed to be promising non-invasive diagnostic biomarkers for gastric cancer (GC).We used the quantitative reverse transcription polymerase chain reaction to assess the expression levels of the four miRNAs from paraffin-embedded surgical specimens of GC patients. Kaplan-Meier curves and log-rank test were applied to predict the correlation between miRNAs and cumulative overall survival (OS) of patients with GC. Besides, we performed in vitro assays including cell proliferation, migration, invasion and colony formation, and apoptosis.The median of miRNA expression in paraffin-embedded tissues were used as the cutoff value to classify patients into high or low expression groups. Down-regulation of miR-26a and miR-148a was significantly associated with shorter OS of GC patients either in the test set (miR-26a: P = 0.009; miR-148a: P = 0.005) or the validation set (miR-26a: P = 0.011; miR-148a: P = 0.024). When two sets were combined, Cox regression analysis demonstrated that both of miR-26a and miR-148a were independent prognostic factors for predicting OS of patients with GC (miR-26a: HR = 0.76, 95% CI = 0.61-0.94; miR-148a: HR = 0.73, 95% CI = 0.58-0.91). Furthermore, elevated expression of miR-26 significantly suppressed cell proliferation, migration, invasion and colony formation, and induced apoptosis of MGC-803 cells compared with negative control groups (P 0.05).These findings supported miR-26a and miR-148a could serve as potential prognostic biomarkers for GC.

Genome-wide association studies (GWASs) have identified multiple susceptibility loci for colorectal cancer, but much of heritability remains unexplained. To identify additional susceptibility loci for colorectal cancer, here we perform a GWAS in 1,023 cases and 1,306 controls and replicate the findings in seven independent samples from China, comprising 5,317 cases and 6,887 controls. We find a variant at 12p13.2 associated with colorectal cancer risk (rs2238126 in ETV6, P=2.67 × 10−10). We replicate this association in an additional 1,046 cases and 1,076 controls of European ancestry (P=0.034). The G allele of rs2238126 confers earlier age at onset of colorectal cancer (P=1.98 × 10−6) and reduces the binding affinity of transcriptional enhancer MAX. The mRNA level of ETV6 is significantly lower in colorectal tumours than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer., Genome-wide association studies have been performed to identify genetic variants that are associated with susceptibility to colorectal cancer. Here, the authors expand on these studies and identify a variant that regulates the expression of ETV6 and find that over-expression of ETV6 blocks cell proliferation in vitro.

Human oxoguanine glycosylase 1 (hOGG1) is a DNA repair enzyme, which plays important roles in the base excision repair (BER) pathway. Several studies reported a common polymorphism Ser326Cys (rs1052133) in hOGG1, which conferred the susceptibility of bladder cancer. We hypothesized that the polymorphism is associated with risk of bladder cancer in a Chinese population. In a case‐control study of 1050 histologically confirmed bladder cancer patients and 1404 age and sex matched healthy controls, we genotyped the hOGG1 Ser326Cys polymorphism using TaqMan technology and assessed its association with bladder cancer risk. We found that the hOGG1 Ser/Cys + Ser/Ser genotypes were associated with a significantly increased risk of bladder cancer (adjusted odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.01–1.41), compared with the Cys/Cys genotype. Furthermore, the increased risk was more pronounced among subjects over age 65 years (OR = 1.31, 95% CI = 1.04–1.66), male subjects (OR = 1.21, 95% CI = 1.00–1.47), ever smokers (OR = 1.29, 95% CI = 1.00–1.68) and heavy smokers (>20 pack‐years) (OR = 1.45, 95% CI = 1.03–2.04). No significant association was observed in the stratification of tumor grade and tumor stage for bladder cancer. In conclusion, our results suggest that hOGG1 Ser326Cys polymorphism may contribute to the susceptibility to bladder cancer in a Chinese population. (Cancer Sci 2012; 103: 1215–1220)

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.

Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC.

Nonsyndromic orofacial clefts (NSOC) are the most common developmental anomalies in human beings. Recently, a large-scale genome-wide association study identified two novel NSOC susceptibility loci: rs13041247 near MAFB and rs560426 near ABCA4. In the present study, we recruited 396 NSOC cases and 384 healthy controls to replicate their associations with risk of NSOC as well as their subgroups in a Chinese Han population. We found the overall genotype and allele frequencies of rs13041247, but not rs560426 were significantly different between cases and controls. Further logistic regression analysis showed rs13041247 CT, CC, and CT/CC were associated with decreased NSOC susceptibility, compared with rs13041247 TT wide-type homozygote. Moreover, the apparent protection against cleft lip with or without cleft palate (CL/P), cleft lip with cleft palate (CLP), and cleft lip only (CLO) was also identified in stratified analysis. However, none of any rs560426 genotypes or alleles was associated with risk of NSOC or their subgroups. Taken together, our findings confirmed the contribution of MAFB in the etiology of NSOC in a Chinese Han population. © 2011 Wiley-Liss, Inc.

Recently, a C>T polymorphism (rs1434536) in a miR-125b binding site in the 3′ untranslated region (3′UTR) of bone morphogenetic protein membrane receptor type IB gene (BMPR1B) has been found to contribute to cancer susceptibility. To investigate whether it plays an important role in the development of prostate cancer in southern Chinese Han population, we performed a case–control study. 247 prostate cancer and 278 control subjects were included in the cancer association study and dual-luciferase reporter assay was used to test the binding ability of miR-125b to BMPR1B-C or -T vectors. The effect of CT/TT genotype on prostate cancer risk was found to be significant for localized disease (OR = 1.60, 95% CI = 1.01–2.53, P = 0.044) and among subgroups of aged >70 years (OR = 1.90, 95% CI = 1.15–3.15, P = 0.015) compared with CC genotype. Moreover, C-allele gave a reduced luciferase activity relative to T-allele in dual-luciferase reporter assay. Our findings show that rs1434536 in the 3′UTR of BMPR1B gene affects the binding ability of miR-125b to BMPR1B mRNA and contributes to the genetic predisposition to localized prostate cancer and patients aged >70 years.

OBJECTIVES To identify predictors for repeat biopsies in Chinese men with increasing prostate-specific antigen (PSA) levels or other risk factors for prostate cancer. METHODS The study included 129 patients who underwent transrectal sonography-guided repeat biopsies. Potential predictors, including age, body mass index, symptoms, digital rectal examination (DRE), total PSA, free PSA, free/total PSA ratio, prostate volume, PSA density, PSA velocity, PSA doubling time, and volume/biopsy ratio, were subjected to univariate analysis. Multivariate stepwise logistic regression was performed to identify major independent predictors for repeat biopsies, and a scoring system for predicting cancer was devised. A receiver operating characteristic (ROC) curve was constructed to test the sensitivity and specificity of the scoring system. RESULTS Thirty-four patients (26.36%) had cancer. On univariate analysis, the DRE (P = .002), total PSA (P = .020), free/total PSA ratio (P < .001), prostate volume (P < .001), PSA density (P = .003), and volume/biopsy ratio (P < .001) were significant predictors of cancer. On multivariate analysis, the DRE, total PSA, free/total PSA ratio, and volume/biopsy ratio were independently significant predictors, with odds ratios and 95% confidence intervals of 4.61 (1.62-13.07), 1.02 (1.00-1.04), 0.87 (0.78-0.96), and 0.56 (0.43-0.79). Using ROC analysis, we determined a cutoff value of 2.5 for the scores, at which the sensitivity and specificity of the scoring system for predicting positive repeat biopsy results were 76.50% and 74.70%, with an area under the curve of 0.816 (P < .001). Patients with scores of 3 to 5 had higher cancer detection rates than those with scores of 0 to 2 (52.00% versus 10.13%; P < .001). CONCLUSIONS Key predictors may exist to help formulate a scoring system to identify Chinese men who need repeat prostate biopsies. More studies are required to learn its applicability to broader populations.

Interleukin-6 (IL-6) is a multifunctional cytokine involved in different physiologic and pathophysiologic processes and plays important roles in the etiology of cancer. The -174G>C polymorphism of the IL-6 gene influences IL-6 transcription and has been implicated in cancer risk. However, published data have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 29,377 cancer cases and 37,739 controls from 50 published case-control studies was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between -174G>C polymorphism and cancer risk. Overall meta-analysis indicated that no association was found between -174G>C genotypes and cancer risk. However, the positive association was found in bladder cancer (OR=4.33, 95% CI: 1.93-9.71 for CC vs. GC, OR=2.81, 95% CI: 1.39-5.68 for CC vs. GG, and OR=2.19, 95% CI: 1.32-3.64 for CC vs. GG/GC), and among Asians (OR=2.08, 95% CI: 1.07-4.06 for CC vs. GG, and OR=2.20, 95% CI: 1.02-4.74 for CC vs. GG/GC) and Africans (OR=1.61, 95% CI: 1.07-2.42 for GC vs. GG). This meta-analysis showed the evidence that the -174G>C of the IL-6 gene was a low-penetrance susceptibility gene for bladder cancer. Further larger, preferably prospective studies are needed to confirm this relationship.

CCND1 plays a key role in cell cycle progression and may cause methotrexate (MTX) resistance, as well as its cytotoxicity. CCND1 870A variant allele is associated with altered transcripts of this gene. We hypothesized that this polymorphism may contribute to the elimination rate and hepatotoxicity of MTX in childhood acute lymphoblastic leukemia (ALL). We genotyped the CCND1 G870A polymorphism in 125 childhood ALL patients treated with HDMTX. We found no notable associations between G870A polymorphism and the risk of delayed MTX elimination. However, this polymorphism was significantly associated with an increased risk of MTX hepatotoxicity [adjusted odds ratio (OR) = 4.44, 95% confidence interval (CI) = 1.35-14.63 for AG versus GG and adjusted OR = 6.39, 95% CI = 1.82-22.43 for AA versus GG]. Our results indicated that the CCND1 G870A polymorphism may be involved in the hepatotoxicity of MTX and act as a biological marker.

The first genome-wide association study (GWAS) for bladder cancer has identified a susceptibility locus at 3q28 in the European ancestry. However, the causal variant at 3q28 remains unknown. We conducted a three-stage fine mapping study to identify potential causal variants in the region. A total of 41 single nucleotide polymorphisms (SNPs) across 120 kb at 3q28 were tested for association with bladder cancer risk among 3,094 bladder cancer cases and 3,738 controls. Resequencing and functional assays were further evaluated. The SNP rs35592567 in the 3'-UTR of TP63 was consistently associated with bladder cancer risk in all three stages. In the combined analysis, the T allele of rs35592567 was significantly associated with a decreased risk for bladder cancer (OR = 0.82, 95% CI = 0.75-0.90, P = 9.797 × 10(-6) in the additive model). Biochemical assays revealed that the T allele reduced the post-transcriptional levels of TP63 mediated by interfering binding efficiency of miR-140-5p. In addition, overexpression of miR-140-5p inhibited bladder cancer cell proliferation and attenuated cell migration, invasion and G1 cell-cycle arrest. Together, these results suggest that rs35592567 in TP63 may be a novel causal variant contributing to the susceptibility to bladder cancer, which provides additional insight into the pathogenesis of bladder carcinogenesis.

MicroRNAs (miRNAs) have been demonstrated playing important roles in the procession of prostate cancer cells transformation from androgen-dependence to androgen-independence.We conducted the miRNA microarray and realtime PCR analyses in both androgen-dependent (ADPC) and androgen-independent prostate cancer (AIPC) tissues. We also explored the role of hsa-miR-146a-5p (miR-146a) in MSKCC prostate cancer clinical database. Moreover, the impact of miR-146a on prostate cancer cells apoptosis were detected by Hoechst staining and fluorescence-activated cell sorter (FACS). Its target is predicted by DIANA LAB online database and the result was assumed by western blotting and luciferase assay.We demonstrated that miR-146a was down-regulated in AIPC tissues and cell lines compared to that in the ADPC tissues. In MSKCC data re-analyses, we found that miR-146a was underexpressed in metastatic prostate cancer tissues and those with Gleason score8, moreover, low level of miR-146a represented a high biochemical relapse rate after radical prostatectomy. In the functional analyses, we transfected miR-146a mimics into CPRC cell lines and found miR-146a induced cells apoptosis. In mechanic analyses, we found that miR-146a inhibited the basal level of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) expression by targeting its 3'UTR and an inverse correlation of expression between miR-146a and ROCK1 was observed. Moreover, caspase 3 activity was stimulated by miR-146a overexpression.miR-146a has a critical role in the process of AIPC prostate cancer cells apoptosis through regulation of ROCK/Caspase 3 pathway. Targeting this pathway may be a promising therapeutic strategy for future personalized anti-cancer treatment.

Evidence has shown that miR-146a is involved in carcinogenesis and a common G/C variant (rs2910164) in the pre-miR-146a gene has been found to be associated with various cancers. We investigated the potential prognostic role of miR-146a polymorphism in prostate cancer after radical prostatectomy. Seventy-two southern Chinese with prostate cancer undergoing radical prostatectomy were included in this study. miR-146a polymorphism was analyzed by PCR-RFLP. Its prognostic role in biochemical recurrence was assessed using Kaplan-Meier analysis and Cox regression model. We did not find a significant association between miR-146a polymorphism and prostrate-specific antigen failure in the Chinese population [HR (95%CI): 0.83 (0.30-2.32) for CC vs GG/GC]. However, high Gleason score (over 8) was associated with increased biochemical recurrence and poorer PSA-free survival. This study was limited by the length of follow-up. Future studies with longer follow-up would allow evaluation of more direct metrics, such as disease-specific survival, metastasis-free survival, and overall survival.

Long non-coding RNA HOX transcript antisenseRNA (HOTAIR) has been widely identified to participate in tumour pathogenesis, acting as a promoter in colorectal cancer carcinogenesis. However, the association between genetic variants in HOTAIR and cancer risk has not yet been reported. In the present study, we performed a two-stage case-control study to investigate the association between HOTAIR tagSNPs and the risk of colorectal cancer. We found that individuals with rs7958904 CC genotype had a significantly decreased risk of colorectal cancer in both Stage 1 and 2, compared with those carrying GG genotype [odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.51-0.97 in Stage 1; OR = 0.58, 95% CI = 0.37-0.91 in Stage 2; OR = 0.67, 95% CI = 0.51-0.87 in combined stage]. The subsequently stratified analyses showed that the protective effect of rs7958904 was more pronounced in several subgroups. In summary, our study showed that genetic variants in HOTAIR were associated with risk of colorectal cancer and rs7958904 may act as a potential biomarker for predicting the risk of colorectal cancer.

The importance of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene for the prediction of the response to fluorouracil-based adjuvant chemotherapy in gastric cancer patients remains unclear. The aim of this study is to assess the predictive value of several polymorphisms of the MTHFR gene for clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population.Three hundred and sixty-two Chinese patients with gastric cancer were treated with fluorouracil-based adjuvant chemotherapy. DNA samples were isolated from peripheral blood collected before treatment. The three single nucleotide polymorphisms (SNPs) (rs1801131, rs1801133, rs2274976) genotypes of the MTHFR gene were determined by matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).The average response rate for chemotherapy was 46.7%. Homozygous genotypes rs2274976G/G (χ(2) = 22.7, P0.01) and rs1801131A/A (χ(2) = 14.3, P = 0.008) were over-represented in responsive patients. Carriers of the rs2274976A allele genotypes (G/A and A/A) and of the rs1801131C allele genotypes (A/C and C/C) were prevalent in nonresponsive patients. In the haplotype association analysis, there was a significant difference in global haplotype distribution between the groups (χ(2) = 20.69, P = 0.000 124).These results suggest that polymorphisms of the MTHFR gene may be used as predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of MTHFR gene as clinical markers for predicting the response to fluorouracil-based therapy in gastric cancer patients is warranted.

PIWI-interacting RNAs (piRNAs), which are a novel type of identified small noncoding RNA (ncRNA), play a crucial role in germline development and carcinogenesis.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.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).The current findings reveal the possibility that piR-015551 may be generated from LNC00964-3, which may be involved in the development of CRC.

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.

The human murine double minute 2 (MDM2) is known as an oncoprotein through inhibiting P53 transcriptional activity and mediating P53 ubiquitination. Therefore, the amplification of MDM2 may attenuate the P53 pathway and promote tumorigenesis. The SNP309 T>G polymorphism (rs2279744), which is located in the intronic promoter of MDM2 gene, was reported to contribute to the increased level of MDM2 protein. In this hospital-based case-control study, which consisted of 573 cases and 588 controls, we evaluated the association between MDM2 SNP309 and the risk of colorectal cancer (CRC) in a Chinese population by using the TaqMan method to genotype the polymorphism. We found that the MDM2 SNP309 polymorphism was significantly associated with CRC risk. In addition, in our meta-analysis, we found a significant association between MDM2 SNP309 and CRC risk among Asians, which was consistent with our results. In conclusion, we demonstrated that the MDM2 SNP309 polymorphism increased the susceptibility of CRC in Asian populations.

Acute lymphoblastic leukemia (ALL) is a clonal hematologic disease, and is the most common cause of childhood malignancy. Recently, a new locus was identified at 10p12.31-12.2 through a genome-wide association study (GWAS) that included racially and ethnically diverse populations. We conducted a replication study with 570 cases of ALL and 673 cancer-free controls to validated the association of this locus with ALL susceptibility in a Chinese population. The results of our study confirmed that the 10p12.31-12.2 locus was linked to childhood ALL susceptibility in the Chinese population. Interestingly, we also found that the single nucleotide polymorphisms (SNPs) in this locus had a larger effect on susceptibility to high-risk ALL than on susceptibility to low-risk ALL.

MicroRNAs (miRNAs) are a class of short non-coding, single-stranded RNAs, which perform posttranscriptional 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 versus TT/TC, adjusted odds ratio = 0.65, 95% confidence interval (CI) = 0.52-0.83] and with survival of RCC in dominant model (TC/CC versus TT, adjusted hazard ratio = 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.

Background Global miRNA expression profile has been widely used to characterize human cancers. It is well established that genetic variants in miRNAs can modulate miRNA biogenesis and disease risk. Methods Genome-wide miRNA microarray was employed for assessment of miRNA expression profile of gastric adenocarcinoma (GAC). The variants of significantly dysregulated miRNA were genotyped in test (715 cases and 804 controls) and validation (940 cases and 1050 controls) subject sets. Results MiRNA microarray revealed that 12 miRNAs including miR-107 significantly dysregulated in GAC tissues. The sequencing of the promoter of miR-107 identified 3 SNPs (rs11185777, rs78591545, and rs2296616) with minor allele frequency (MAF) > 5%. Analyzing their association with GAC risk and prognosis revealed that the C allele of rs2296616 (T > C) was significantly associated with the decreased risk of GAC among the test, validation and combined sets (TC/CC vs . TT, adjusted OR = 0.39, 95% CI = 0.31–0.49 for the combined set). However, the C allele was related to an unfavorable prognosis of Cardia GAC (CGAC) (adjusted HR = 1.49, 95% CI = 1.01–2.20). In vivo evidence showed that the individuals with the rs2296616C allele had lower miR-107 expression compared with the homozygous T allele carriers. Conclusion miR-107 is dysregulated in GAC pathogenesis and the SNP rs2296616 may play a role in the process.

The FAS, FAS ligand (FASL), and CASP8 are key regulators for apoptosis and their deregulations play an important role in carcinogenesis. However, the effects of promoter polymorphisms of the FAS, and FASL, and CASP8 genes on the survival of gastric cancer are unknown. In this study, we investigated the association of four polymorphisms (FAS -1377GA, -670AG, FASL -844CT, and CASP8 -652 6N insdel) with the clinical outcome of 940 gastric cancer patients in a Chinese population. The correlation between genotype and survival outcomes was assessed by the Kaplan-Meier method, Cox proportional hazards models and the log-rank test. Our results revealed that individuals with CASP8 -652 6N ins/del+del/del genotypes had a decreased risk of death compared with those with ins/ins genotype (log-rank P=0.005; hazard ratio=0.75, 95% confidence interval=0.62-0.92). The protective effect of the del allele was further confirmed in subgroups of patients with tumor size ≤ 5 cm (0.66, 0.50-0.86) and T2 depth invasion (0.59, 0.37-0.94), but no significant association was observed in the subgroups of lymph node metastasis (0.67, 0.47-0.97), and distance metastasis (0.73, 0.60-0.90). Our findings suggest that, if validated in different independent populations, the CASP8 -652 6N insdel polymorphism may serve as a promising genetic marker for gastric cancer prognosis.

This paper studies the effects of Lobelia chinensis on colon precancerous lesions and on colonic epithelial proliferation and apoptosis in DMH-induced rats. After two weeks of feeding, 50 Wistar rats were randomly divided into five groups, namely the normal group, model group, Lobelia chinensis low-dose group, medium-dose group and high-dose group. Lobelia chinensis was made into ACF model, and administered to experimental groups for 10 consecutive weeks. Control group was given equivalent amount of normal saline. After feeding for 10 weeks, the rats in each group were sacrificed and the changes in colonic ACF number of rats in experimental groups were observed, and the inhibition rates were calculated. The results showed that among the rats fed for 24 h and 48 h, the number of apoptotic cells in colonic crypts of rats in DMH group did not differ significantly from the control group, while the difference was obvious between the control group and Lobelia chinensis treatment groups. The medium and high doses, that is, 0.45 g/kg and 1.35 g/kg can significantly inhibit ACF formation (P

Recent genome-wide association studies have identified 14 genetic variants associated with bladder cancer in Caucasians. The effects of these risk variants and their cumulative effects in Asian populations are unknown. We genotyped these newly identified variants in a case-control study of 1,050 patients diagnosed with bladder cancer and 1,404 controls in the Chinese population. Odds rations (ORs) and 95% confidence intervals (CIs) were computed by logistic regression, and cumulative effect of risk alleles were evaluated. Overall, seven of the 14 variants were significantly associated with bladder cancer risk (p = 9.763 × 10(-3) for rs9642880 at 8q24.21, p = 3.004 × 10(-3) for rs2294008 at 8q24.3, p = 0.012 for rs798766 at 4p16.3, p = 0.034 for rs1495741 at 8p22, p = 2.306 × 10(-4) for GSTM1, p = 8.507 × 10(-8) for rs17674580 at 18q12.3, p = 7.179 × 10(-4) for rs10936599 at 3q26.2) and the odds ratios (ORs) ranged from 1.13 to 1.65. Moreover, there were a significant increased risk for bladder cancer positively correlated numbers of risk alleles and smoking status (Ptrend = 7.060 × 10(-16) ). However, no allelic interaction effects on bladder cancer risk were observed between cumulative effects of variants and clinical characteristics. These findings suggest that seven bladder cancer risk-associated variants (rs9642880, rs2294008, rs798766, rs1495741, GSTM1 null, rs17674580 and rs10936599) may be used, collectively, to effectively measure inherited risk for bladder cancer.

The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1β, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1β generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.

The purpose of this study was to assess the prognostic value of 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) in therapy for non-small cell lung cancer (NSCLC) and to further analyze the possible risk factors contributing to overall survival (OS) and progression-free survival (PFS). We retrospectively analyzed fifty patients between June 2007 and June 2010 with NSCLC who underwent positron emission tomography/computed tomography. We examined the correlation of the maximum standardized uptake value (SUVmax) in FDG-PET of the primary tumor with other possible factors. The FDG uptake in the primary tumor was also compared for the different Union for International Cancer Control (UICC) staging groups and further correlation was analyzed. We divided the patients into two groups by the receiver operating characteristic curve of SUVmax: SUVmax

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 ≤ 5 cm (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.

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 ≤ 5 cm (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.

PURPOSE: miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk. EXPERIMENTAL DESIGN: We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs. RESULTS: We found that rs10719T>C polymorphism located in 3' untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein. CONCLUSIONS: Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3'UTR.

PURPOSE Recently, genetic polymorphism (rs3803662C>T) in TOX3 was reported to induce the risk of breast cancer. In this study, we hypothesized that rs3803662 could influence gastric cancer survival outcomes. METHODS With multiplex SNaPshot method, we genotyped TOX3 rs3803662 in 880 gastric patients with surgical resection. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, Cox regression analysis models and the log-rank test. RESULTS There was no association in the analyses of rs3803662 and survival of gastric cancer. However, the stratified analysis by histology showed that rs3803662 CT/TT genotype was associated with a significantly better survival for diffuse-type gastric cancer (log-rank p = 0.030, hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.46-0.96), than the CC genotype. In addition, this favorable effect was especially obvious among gastric cancer patients with tumor size >5 cm, T3 and T4 depth of invasion, lymph node metastasis, no drinking, no distant metastasis, no chemotherapy and gastric cardia cancer. CONCLUSIONS TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer.

Recent genome-wide association studies (GWAS) that focus on childhood acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15 years 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 (P0.0001). 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.

BACKGROUND: MicroRNAs (miRNAs) are a class of small non-coding RNAs to regulate cell differentiation, proliferation, development, and apoptosis. The single nucleotide polymorphism (SNP) rs895819 is located at the terminal loop of pre-miR-27a. Here, we aimed to investigate whether SNP rs895819 was associated with the development of renal cell cancer (RCC) in a Chinese population. METHODS: In this case-control study, we recruited 594 RCC patients and 600 cancer-free controls with frequency matched by age and sex. We genotyped this polymorphism using the TaqMan assay and assessed the effect of this polymorphism on RCC survival. Logistic regression model was used to assess the genetic effects on the development of RCC and interactions between rs895819 polymorphism and risk factors. RESULTS: Compared with AA homozygote, individuals carrying AG/GG genotypes had a statistically significant reduced susceptibility to RCC (adjusted OR = 0.71, 95% CI = 0.56-0.90). Furthermore, AG/GG genotypes were associated with reduced RCC susceptibility in localized clinical stage (adjusted OR = 0.71, 95% CI = 0.55-0.91), and similar effects were observed in well differentiated and poorly differentiated RCC (adjusted OR = 0.71, 95% CI = 0.55-0.93 for well differentiated, adjusted OR = 0.51, 95% CI = 0.28-0.93 for poorly differentiated). We also observed that rs895819 had multiplicative interactions with age and hypertension. However, the polymorphism did not influence the survival of RCC. CONCLUSION: Our results suggest that the pre-miR-27a rs895819 polymorphism can predict RCC risk in a Chinese population. Larger population-based prospective studies should be used to validate our findings.

Recently, genome-wide association studies (GWAS) have identified several susceptibility loci for childhood acute lymphoblastic leukemia (ALL) in populations of European descent; only a few loci could be confirmed in Asian populations because of those populations' genetic heterogeneity. To identify genetic factors associated with childhood ALL risk in the Chinese population, we performed a three-stage GWAS of 1184 childhood ALL cases and 3219 non-ALL controls. The combined analysis identified a new locus (rs1121404 in WWOX) at 16q23.1 associated with childhood ALL susceptibility (odds ratio (OR) = 1.38, P = 5.29 × 10-10), especially in the subtype of B-ALL (OR = 1.39, P = 2.47 × 10-9). The functional studies subsequently revealed that the expression of WWOX in ALL bone marrow was significantly lower than that in normal bone marrow. The G allele of rs1121404 displayed significantly decreased levels of mRNA expression of WWOX These results suggest that WWOX plays an important role in the development of childhood ALL and provide new insights into the etiology of childhood ALL.

Background In the past decades, a good deal of studies has provided the possibility of the circulating microRNAs (miRNAs) as noninvasive biomarkers for cancer diagnosis. The aim of our study was to detect the levels of circulating miRNAs in tissues and plasmas of gastric cancer (GC) patients and evaluate their diagnostic value. Methods Tissue samples were collected from 85 GC patients. Plasma samples were collected from 285 GC patients and 285 matched controls. Differentially expressed miRNAs were filtered with by Agilent Human miRNA Microarray and TaqMan low density array (TLDA) with pooled samples, followed by the quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation. Receiver operating characteristic (ROC) curves were structured to evaluate the diagnostic accuracy of the miRNAs. The plasma level of miR-26a in GC patients of different clinical stages was compared. Results Four miRNAs (miR-26a, miR-142-3p, miR-148a, and miR-195) revealed coincidentally decreased levels in tissue and plasma of the GC patients compared with controls, and ROC curves were constructed to demonstrate that miR-26a had a highest area under the ROC curve (AUC) of 0.882. Furthermore, miR-26a was stably detected in the plasma of GC patients with different clinical characteristics. Conclusion Plasma miR-26a may provide a novel and stable marker of gastric cancer.

MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that involved in a wide range of biological processes including differentiation, proliferation, and apoptosis. A polymorphism G>C (rs2910164) is located in the stem region opposite to the mature miR-146a sequence. In our study, we investigated whether rs2910164 is associated with the risk of colorectal cancer (CRC) in a Chinese population. We genotyped the rs2910164 polymorphism using TaqMan method and evaluated the association with CRC risk in a case–control study, including 1,147 CRC patients and 1,203 cancer-free controls. Logistic regression models were used to assess the genetic effects on the development of CRC. Overall, we found that rs2910164 was significantly associated with the reduced CRC risk [GC/CC versus GG: adjusted odds ratio (OR) = 0.78, 95 % confidence intervals (CIs) = 0.66–0.93]. In the stratification analysis, this decreased risk was also pronounced among non-smokers (0.75, 0.61–0.93), non-drinkers (0.77, 0.63–0.94), and no family history of cancer (0.79, 0.65–0.95). Furthermore, GC/CC genotypes were associated with reduced CRC susceptibility in intermediate differentiated CRC (0.75, 0.62–0.90), and similar effect was observed in patients with the advanced stage tumor (Dukes C and D) (0.76, 0.61–0.93). In conclusion, our results suggest that miR-146a rs2910164 may contribute to the susceptibility to CRC in a Chinese population. Further larger population-based prospective and functional studies are needed to validate our findings.