Association of Topoisomerase II (TOP2A) and Dual-Specificity Phosphatase 6 (DUSP6) Single Nucleotide Polymorphisms with Radiation Treatment Response and Prognosis of Lung Cancer in Han Chinese.

BACKGROUND Mutations of DNA topoisomerase II (TOP2A) are associated with chemotherapy resistance, whereas dual-specificity phosphatase 6 (DUSP6) negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily to control cell proliferation. This study assessed TOP2A and DUSP6 single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) patients for association with chemoradiotherapy responses and prognosis. MATERIAL AND METHODS A total of 140 Chinese patients with histologically confirmed NSCLC were enrolled and subjected to genotyping of TOP2A rs471692 and DUSP6 rs2279574 using Taqman PCR. An independent sample t test was used to analyze differences in tumor regression after radiotherapy versus SNP risk factors. Kaplan-Meier curves analyzed overall survival, followed by the log-rank test and Cox proportional hazard models. RESULTS There were no significant associations of TOP2A rs471692 and DUSP6 rs2279574 polymorphisms or clinicopathological variables with response to chemoradiotherapy (p>0.05). Comparing overall survival of 87 patients with stage I-III NSCLC treated with radiotherapy or chemoradiotherapy to clinicopathological variables, the data showed that tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors (p=0.009, 0.043, 0.004, and 0.025, respectively). Tumor regression rate >0.34 was associated with patent survival versus tumor regression rate ≤0.34 (p=0.007). CONCLUSIONS TOP2A rs471692 and DUSP6 rs2279574 SNPs were not associated with chemoradiotherapy response, whereas tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors for these Chinese patients with NSCLC.

Dual Specificity Phosphatase 6 (DUSP6) Polymorphism Predicts Prognosis of Inoperable Non-Small Cell Lung Cancer after Chemoradiotherapy.

BACKGROUND: Dual-specificity phosphatase 6 (DUSP6) inactivates different target kinases to regulate cell proliferation and differentiation. Altered DUSP6 expressions or gene polymorphisms are associated with human cancer development including non-small cell lung cancer (NSCLC). DNA topoisomerase II alpha (TOP2A) regulates chromosome condensation and chromatid separation, and altered TOP2A expressions are associated with drug resistance development. This study assessed DUSP6 and TOP2A single nucleotide polymorphisms (SNPs) associated with NSCLC patient survival. METHODS: This study included 152 surgically resected NSCLC patients and 277 chemoradiotherapy treated inoperable cases. DNA samples from each patient were genotyped for DUSP6 and TOP2A SNPs. Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model were used to evaluate the association between these variants and NSCLC overall survival. RESULTS: DUSP6 rs2279574 A/A genotype was associated with significantly poor inoperable NSCLC patient overall survival (A/A vs. C/C, adjusted HR = 1.549, 95% CI = 1.019-2.355). Stratification analysis against clinical stage, histology, weight loss, and ECOG performance status revealed that the DUSP6 rs2279574 A/A variant homozygous genotype is associated with a decrease in survival of stage IV NSCLC patients compared to those with the C/C genotype (log-rank, p = 0.003). No association was found among histology, weight loss, and ECOG performance status. Moreover, there was no association of TOP2A SNPs between clinicopathological and survival data. CONCLUSIONS: Data obtained from the current study demonstrated that functional DUSP6 rs2279574 polymorphism was able to predict inoperable NSCLC patient survival after chemoradiotherapy.

Aberrant promoter methylation of the SFRP1 gene may contribute to colorectal carcinogenesis: a meta-analysis.

This meta-analysis of published cohort studies was conducted to evaluate whether promoter methylation of the secreted frizzled-related protein 1 (SFRP1) gene contributes to colorectal carcinogenesis. The Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) were searched without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated odds ratio (OR) and its 95 % confidence interval (95 % CI) to estimate the correlations between SFRP1 promoter methylation and colorectal carcinogenesis. In the present meta-analysis, 8 cohort studies with a total of 942 patients with colorectal cancer (CRC) were included. The pooled results revealed that the frequency of SFRP1 promoter methylation in cancer tissues were significantly higher than those of normal, adjacent, and benign tissues (cancer tissues vs. normal tissues: OR = 31.49, 95 % CI = 17.57 ~ 56.44, P < 0.001; cancer tissues vs. adjacent tissues: OR = 5.95, 95 % CI 3.12 ~ 10.00, P < 0.001; cancer tissues vs. benign tissues: OR = 3.01, 95 % CI 1.72 ~ 5.27, P < 0.001; respectively). Furthermore, ethnicity-stratified analysis indicated that SFRP1 promoter methylation was strongly correlated with colorectal carcinogenesis among both Asians and Caucasians (all P < 0.05). Our findings provide empirical evidence that SFRP1 promoter methylation may be correlated with the pathogenesis of CRC.

Relationships between genetic polymorphisms in inflammation-related factor gene and the pathogenesis of nasopharyngeal cancer.

Our study aims to discuss the association between inflammation-related factors such as single nucleotide polymorphisms (SNPs) with susceptibility and recurrence in nasopharyngeal carcinoma. We used Taqman real-time polymerase chain reaction (PCR) to characterize the genetic variation of five SNPs in 194 nasopharyngeal carcinoma patients and 231 healthy subjects. All statistical analysis is performed with statistical product and service solutions v13.0; odds ratio (OR) value and 95 % confidence interval (CI) were calculated. There is no relationship between TGFß1 -869 T/C, IL-6 -634C/G, TGFß1 -509C/T, IL1 -511C/T and nasopharyngeal carcinoma susceptibility. Both single factor and multiple factors analysis showed that IL1a -889 T/T genotype is significantly associated with nasopharyngeal carcinoma in decreasing the risk of nasopharyngeal carcinoma. A highly significant association was found between IL1a -889 T/T genotype and protective genotype as defined by various pathological types. This is more obvious in the protective genotype of the non-keratin-type squamous carcinoma undifferentiated type. We also discovered that genotype G/G and C/G + G/G of IL6 -634 gene are associated with reduced recurrence of nasopharyngeal carcinoma. IL1a -889 gene polymorphism and susceptibility is related to nasopharyngeal carcinoma and can potentially decrease the risk of nasopharyngeal carcinoma in the Han Chinese population in north China. IL1-889 TT genotype is protective genotype for nasopharyngeal carcinoma. We have provided evidence that the GG genotype of the IL6 -634 gene is associated with recurrent risk of nasopharyngeal carcinoma. The G allele is the protective gene of nasopharyngeal carcinoma recurrence.

Genetic polymorphisms in the CYP1A1 and CYP1B1 genes and susceptibility to bladder cancer: a meta-analysis.

The current meta-analysis of case-control studies was conducted to evaluated the relationships of genetic polymorphisms in the CYP1A1 and CYP1B1 genes with the susceptibility to bladder cancer, aiming at determine whether these polymorphisms may contribute to the pathogenesis of bladder cancer. Related articles were determined via searching the following electronic databases without any language restrictions: PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases for relevant articles published before November 1st, 2013. STATA 12.0 software was also selected to deal with statistical data. The relationships were evaluated using the pooled odds ratios (ORs) and their 95% confidence intervals (CI). Eleven case-control studies with a total of 2,609 bladder cancer patients and 2,634 healthy subjects met the inclusion criteria. The results of our meta-analysis demonstrated that CYP1A1 genetic polymorphisms were associated with increased risks of bladder cancer (allele model: RR = 1.18, 95% CI 1.07-1.30, P = 0.001; dominant model: RR = 1.15, 95% CI 1.05-1.27, P = 0.003; respectively), especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. A subgroup analysis by ethnicity was conducted to investigate its effect on susceptibility to bladder cancer. The subgroup analysis results revealed positive significant correlations between CYP1A1 genetic polymorphisms and bladder cancer risk among Asians (allele model: RR = 1.26, 95% CI 1.10-1.44, P = 0.001; dominant model: RR = 1.22, 95% CI 1.08-1.38, P = 0.001), but not among Caucasians (all P < 0.05). Nevertheless, we observed no significant correlations between CYP1B1 genetic polymorphisms and bladder cancer risk (all P > 0.05). Our meta-analysis indicates that CYP1A1 genetic polymorphisms may be involved in the pathogenesis of bladder cancer, especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. However, CYP1B1 genetic polymorphisms may not be important determinants of bladder cancer susceptibility.

Dual-specificity phosphatase 6 genetic variants associated with risk of lung squamous cell carcinoma in Han Chinese.

BACKGROUND: Nonsmall cell lung cancer (NSCLC) mainly contains adenocarcinoma (AC) and squamous cell carcinoma (SqCC). This study investigated single nucleotide polymorphism (SNP) of topoisomerase II alpha (TOP2A) and dual-specificity phosphatase 6 (DUSP6) in a hospital-based case and control cohort of individuals for association with risk of different histological subtypes of NSCLC. MATERIALS AND METHODS: A total of 454 (237 SqCC and 217 AC) NSCLC patients, and 454 healthy controls were recruited for analysis of TOP2A rs471692 and DUSP6 rs2279574 genotypes using the TaqMan polymerase chain reaction technique. RESULTS: TOP2A rs471692 and DUSP6 rs2279574 SNPs were in complete linkage disequilibrium; however, frequency of DUSP6 rs2279574 genotype was significantly different between the case and control, that is, DUSP6 rs2279574a/A and A/C genotypes might contribute to an increased risk of lung squamous carcinoma compared with the C/C genotype. Moreover, DUSP6 rs2279574 AA genotype was also significantly associated with advanced stages of lung cancer. In contrast, frequency of the TOP2A rs471692 genotype had no association between cases and controls (P = 0.906). Genotype frequency of DUSP6 rs2279574 was 11.9% for C/C, 43.6% for C/A, and 44.5% for A/A in the case versus 16.7% C/C, 43.4% C/A, and 39.9% A/A in the control population (χ2 = 3.136, P= 0.077 by Hardy-Weinberg equilibrium test [HWE]). The genotype frequency of TOP2A rs471692 was 50.0% for C/C, 41.6% for C/T, and 8.4% for T/T in the case versus 50.2% C/C, 43.0% C/T, and 6.8% T/T in the control populations (χ2 = 0.023, P= 0.879 by HWE test). CONCLUSION: Individuals are carrying DUSP6 rs2279574 AA and AC genotypes associated with an increased risk in developing lung squamous carcinoma in Han Chinese and with advanced NSCLC stages.

Diagnostic performance of serum macrophage inhibitory cytokine-1 in pancreatic cancer: a meta-analysis and meta-regression analysis.

Many existing studies have demonstrated that the macrophage inhibitory cytokine-1 (MIC-1) might be a powerful diagnostic biomarker in patients with pancreatic cancer; but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the diagnostic performance of serum MIC-1 in pancreatic cancer. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases from their inception through August 1st, 2013. Meta-analysis was performed using Meta-Disc version 1.4 and STATA version 12.0 software. Crude standardized mean difference (SMD) and their 95% confidence intervals (CI) were estimated. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Ten case-control studies were included in this meta-analysis with a total of 1235 pancreatic cancer patients and 730 healthy subjects. Our meta-analysis results revealed that serum MIC-1 levels in pancreatic patients were higher than those of healthy subjects (SMD=1.38, 95% CI=1.15-1.62, p<0.001). The area under the SROC curve was 0.92 (SE=0.020); the pooled sensitivity was 0.79 (95% CI=0.77-0.82); and the pooled specificity was 0.86 (95% CI=0.84-0.88). The pooled positive LR was 6.20 (95% CI=1.24-30.91); the pooled DOR was 35.73 (95% CI=18.52-68.93). In conclusion, the present meta-analysis suggests that serum MIC-1 may be a useful diagnostic biomarker with high sensitivity and specificity for identifying pancreatic cancer.

Relationships between p16 gene promoter methylation and clinicopathologic features of colorectal cancer: a meta-analysis of 27 cohort studies.

Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14-2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37-4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63-4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57-2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03-3.85, p=0.041; location: OR=2.49, 95% CI: 1.95-3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.

PARP-1 rs3219073 polymorphism may contribute to susceptibility to lung cancer.

OBJECTIVE: To investigate the relationship between the PARP-1 rs3219073 C>G polymorphism and susceptibility to lung cancer in Chinese people. METHODS: In accordance with the case-control study principle, 645 of the patients had histologically recognized primary lung cancer, among them 240 had squamous carcinoma, 217 had adenocarcinoma, and 188 had small-cell lung cancer. The control group consisted of 643 healthy subjects who had received a physical examination. Extracts of peripheral blood were taken from all subjects, and genomic DNA was extracted by the phenol-chloroform method. RESULTS: After adjusting for age and smoking status, the results show significant association between genetic variations in the rs3219073 C/C genotype and an increased risk of lung cancer (p=0.045, odds ratio [OR]=0.625). After combining C/G, G/G is still statistically significant (p=0.042, OR=0.637). Hierarchical analysis found that the number of subjects with a G/G genotype in the adenocarcinoma group is lower than in the control group (p=0.015, OR=0.543). After combining C/G, G/G is still statistically significant (p=0.027, OR=0.595). After correcting for age and smoking status, the group with C/G genotype and the group with G/G genotype both appear to have a reduced risk for lung cancer compared with the control group (p=0.045, OR=0.566; p=0.013, OR=0.489). The combination of C/G and G/G displays a more statistically significant difference (p=0.018, OR=0.528). CONCLUSIONS: The study found that PARP-1 rs3219073 C>G polymorphism is indeed associated with lung cancer susceptibility. The carriers of G alleles may have reduced risk of lung cancer, especially adenocarcinoma.

[Mechanisms of subspecies differentiation in a filial generation of rice indica-japonica hybridization under different ecological conditions].

Indica-japonica hybridization is one of the most important breeding methods in China, whereas identifying subspecies differentiation mechanisms is the key in indica-japonica hybridization breeding. By using InDels (Insert/Deletion) and ILPs (Intron Length Polymorphism), an analysis was made on the F6 populations derived from the hybridization of indica-japonica (Qishanzhan/Akihikari) planted in Liaoning and Guangdong provinces and generated by bulk harvesting (BM), single-seed descent methods (SSD), and pedigree method (PM). No segregation distortion was observed for the BM and SSD populations. The frequency distribution of japonica kinship percentage (Dj) was concentrated in 40%-60%. The PM populations in the two provinces presented indica-deviated distribution (30%-55%), with significant difference between Guangdong (38%) and Liaoning (42%). In addition, there was a significant positive correlation between the Dj and the kinship of functional gene regions in the BM and SSD populations. However, part of the positive correlation was broken in the PM populations that showed a regular distribution in the genotype patterns of indica and japonica loci. The above results demonstrated that artificial selection could be the main factor affecting the population differentiation in indica-japonica hybridization, and, with the synergistic effect of natural selection, induced the phenomenon of segregation distortion. There existed a close relationship between the differentiation of subspecies and the important agronomic traits, which could be the main reason why indica-japonica hybridiation breeding could not achieve the expected effect of combining the two subspecies advantages.