Association between DAPK1 Promoter Methylation and Cervical Cancer: A Meta-Analysis

Background

Death-associated protein kinase1 (DAPK1) is an important tumor suppressor gene. DNA methylation can inactivate genes, which has often been observed in the carcinogenesis of cervical cancer. During the past several decades, many studies have explored the association between DAPK1 promoter methylation and cervical cancer. However, many studies were limited by the small samples size and the findings were inconsistent among them. Thus, we conducted a meta-analysis to assess the association between DAPK1 promoter methylation and cervical cancer.

Methods

We systematically searched eligible studies in the PubMed, Web of Science, EMBASE and CNKI databases. Using meta-regression, subgroup analysis and sensitivity analysis, we explored the potential sources of heterogeneity. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated by Meta-Analysis in R.

Results

A total of 15 studies from 2001 to 2012, comprising 818 tumor tissues samples and 671 normal tissues samples, were analyzed in this meta-analysis. The frequencies of DAPK1 promoter methylation ranged from 30.0% to 78.6% (median, 59.3%) in cervical cancer tissue and 0.0% to 46.7% (median, 7.8%) in normal cervical tissue. The pooled OR was 19.66 (95%CI = 8.72–44.31) with the random effects model, and heterogeneity was found through the sensitivity analysis. The I² = 60% (P = 0.002) decreased to I² = 29.2% (P = 0.144) when one heterogeneous study was excluded, and the pooled OR increased to 21.80 (95%CI = 13.44–35.36) with the fixed effects model.

Conclusion

The results suggested a strong association between DAPK1 promoter methylation and cervical cancer. This study also indicated that DAPK1 promoter methylation may be a biomarker during cervical carcinogenesis that might serve as an early indication of cervical cancer.     

Association between P16INK4a Promoter Methylation and Non-Small Cell Lung Cancer: A Meta-Analysis

Background

Aberrant methylation of CpG islands acquired in tumor cells in promoter regions plays an important role in carcinogenesis. Accumulated evidence demonstrates P^16INK4a gene promoter hypermethylation is involved in non-small cell lung carcinoma (NSCLC), indicating it may be a potential biomarker for this disease. The aim of this study is to evaluate the frequency of P^16INK4a gene promoter methylation between cancer tissue and autologous controls by summarizing published studies.

Methods

By searching Medline, EMBSE and CNKI databases, the open published studies about P^16INK4a gene promoter methylation and NSCLC were identified using a systematic search strategy. The pooled odds of P^16INK4A promoter methylation in lung cancer tissue versus autologous controls were calculated by meta-analysis method.

Results

Thirty-four studies, including 2 652 NSCLC patients with 5 175 samples were included in this meta-analysis. Generally, the frequency of P^16INK4A promoter methylation ranged from 17% to 80% (median 44%) in the lung cancer tissue and 0 to 80% (median 15%) in the autologous controls, which indicated the methylation frequency in cancer tissue was much higher than that in autologous samples. We also find a strong and significant correlation between tumor tissue and autologous controls of P^16INK4A promoter methylation frequency across studies (Correlation coefficient 0.71, 95% CI:0.51–0.83, P<0.0001). And the pooled odds ratio of P^16INK4A promoter methylation in cancer tissue was 3.45 (95% CI: 2.63–4.54) compared to controls under random-effect model.

Conclusion

Frequency of P^16INK4a promoter methylation in cancer tissue was much higher than that in autologous controls, indicating promoter methylation plays an important role in carcinogenesis of the NSCLC. Strong and significant correlation between tumor tissue and autologous samples of P^16INK4A promoter methylation demonstrated a promising biomarker for NSCLC.     

The Association of RAS Association Domain Family Protein1A (RASSF1A) Methylation States and Bladder Cancer Risk: A Systematic Review and Meta-Analysis

RAS association domain family protein 1a (RASSF1A) is a putative tumor suppressor gene located on 3p21, has been regarded playing important roles in the regulation of different types of human tumors. Previous reports demonstrated that the frequency of RASSF1A methylation was significantly higher in patients group compared with controls, but the relationship between RASSF1A promoter methylation and pathological features or the tumor grade of bladder cancer remains controversial. Therefore, A meta-analysis of published studies investigating the effects of RASSF1A methylation status in bladder cancer occurrence and association with both pTNM (p, pathologic stage; T, tumor size; N, node status; M, metastatic status) and tumor grade in bladder cancer was performed in the study. A total of 10 eligible studies involving 543 cases and 217 controls were included in the pooled analyses. Under the fixed-effects model, the OR of RASSF1A methylation in bladder cancer patients, compared to non-cancer controls, was 8. 40 with 95%CI = 4. 96–14. 23. The pooled OR with the random-effects model of pTNM and tumor grade in RASSF1A methylated patients, compared to unmethylated patients, was 0. 75 (95%CI = 0. 28–1. 99) and 0. 39 (95%CI = 0. 14–1. 09). This study showed that RASSF1A methylation appears to be an independent prognostic factor for bladder cancer. The present findings also require confirmation through adequately designed prospective studies.     

RASSF1A Promoter Methylation Levels Positively Correlate with Estrogen Receptor Expression in Breast Cancer Patients

The aim of this study was to investigate the relationship between the promoter methylation in five cancer-associated genes and clinicopathologic features for identification of molecular markers of tumor metastatic potential and hormone therapy response efficiency in breast cancer. The methylation levels in paraffin-embedded tumor tissues, plasma, and blood cells from 151 sporadic breast cancer patients and blood samples of 50 controls were evaluated by quantitative multiplex methylation-specific polymerase chain reaction. DNA methylation of RAS-association domain family member 1 (RASSF1A), estrogen receptor 1 (ESR1), cadherin 1, type 1, E-cadherin (CDH1), TIMP metallopeptidase inhibitor 3 (TIMP3) and spleen tyrosine kinase (SYK) genes was detected in the tumors of 124, 19, 15, 15, and 6 patients with mean levels of 48.45%, 3.81%, 2.36%, 27.55%, and 10.81%, respectively. Plasma samples exhibited methylation in the same genes in 25, 10, 15, 17, and 3 patients with levels of 22.54%, 17.20%, 22.87%, 31.93%, and 27.42%, respectively. Cumulative methylation results confirmed different spectra in tumor and plasma samples. Simultaneous methylation in tumors and plasma were shown in less than 17% of patients. RASSF1A methylation levels in tumor samples statistically differ according to tumor size (P = .029), estrogen receptor (ER) and progesterone receptor (PR) status (P = .000 and P = .004), and immunohistochemical subtype (P = .000). Moreover, the positive correlation was found between RASSF1A methylation levels and percentage of cancer cells expressing ER and PR. The direct relationship between RASSF1A promoter methylation and expression of ER could aid the prognosis of hormonal therapy response.     

Association between P16INK4a Promoter Methylation and HNSCC: A Meta-Analysis of 21 Published Studies

Background

The p16^INK4a is an important tumor suppressor gene (TSG) and aberrant methylation of promoter is known to be a major inactivation mechanism of the tumor suppressor and tumor-related genes. Aberrant TSG methylation was considered an important epigenetic silencing mechanism in the progression of head and neck squamous cell carcinoma (HNSCC). However, some studies have reported differences in the methylation frequencies of P^16INK4a promoter between cancer and the corresponding control group. Therefore, we conducted a meta-analysis to better identify the association.

Methods

PubMed, Ovid, ISI Web of Science, and EMBASE were searched to identify eligible studies to evaluate the association of p16^INK4a promoter methylation and HNSCC. Odds ratio (ORs) and 95% confidence intervals (95%CI) were calculated to evaluate the strength of association between p16^INK4a promoter methylation and HNSCC.

Results

A total of twenty-one studies with 1155 cases and 1017 controls were included in the meta-analysis. The frequencies of p16^INK4a promoter methylation in the cancer group were significantly higher than those in the control group (cancer group: median: 46.67%, range = 7.84%-95.12%; control group: median: 18.37%, range = 0–83.33%; respectively). The pooled odds ratio was 3.37 (95%CI = 2.32–4.90) in the cancer group versus the corresponding control group under the random-effects model.

Conclusion

This meta-analysis of 21 published studies identified that aberrant methylation of p16^INK4a promoter was found to be significantly associated with HNSCC.     

DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis

Objective

The Death-Associated Protein Kinase 1 (DAPK1) gene has been frequently investigated in cervical cancer (CC). The aim of the present study was to carry out a systematic review and a meta-analysis in order to evaluate DAPK1 promoter methylation as an epigenetic marker for CC risk.

Methods

A systematic literature search was carried out. The Cochrane software package Review Manager 5.2 was used. The fixed-effects or random-effects models, according to heterogeneity across studies, were used to calculate odds ratios (ORs) and 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by histological type, assays used to evaluate DAPK1 promoter methylation, and control sample source.

Results

A total of 20 papers, published between 2001 and 2014, on 1929 samples, were included in the meta-analysis. DAPK1 promoter methylation was associated with an increased CC risk based on the random effects model (OR: 21.20; 95%CI = 11.14–40.35). Omitting the most heterogeneous study, the between study heterogeneity decreased and the association increased (OR: 24.13; 95% CI = 15.83–36.78). The association was also confirmed in all the subgroups analyses.

Conclusions

A significant strong association between DAPK1 promoter methylation and CC was shown and confirmed independently by histological tumor type, method used to evaluate methylation and source of control samples. Methylation markers may have value in early detection of CC precursor lesions, provide added reassurances of safety for women who are candidates for less frequent screens, and predict outcomes of women infected with human papilloma virus.     

Association among Dietary Flavonoids,Flavonoid Subclasses and Ovarian Cancer Risk: A Meta-Analysis

Background

Previous studies have indicated that intake of dietary flavonoids or flavonoid subclasses is associated with the ovarian cancer risk, but presented controversial results. Therefore, we conducted a meta-analysis to derive a more precise estimation of these associations.

Methods

We performed a search in PubMed, Google Scholar and ISI Web of Science from their inception to April 25, 2015 to select studies on the association among dietary flavonoids, flavonoid subclasses and ovarian cancer risk. The information was extracted by two independent authors. We assessed the heterogeneity, sensitivity, publication bias and quality of the articles. A random-effects model was used to calculate the pooled risk estimates.

Results

Five cohort studies and seven case-control studies were included in the final meta-analysis. We observed that intake of dietary flavonoids can decrease ovarian cancer risk, which was demonstrated by pooled RR (RR = 0.82, 95% CI = 0.68–0.98). In a subgroup analysis by flavonoid subtypes, the ovarian cancer risk was also decreased for isoflavones (RR = 0.67, 95% CI = 0.50–0.92) and flavonols (RR = 0.68, 95% CI = 0.58–0.80). While there was no compelling evidence that consumption of flavones (RR = 0.86, 95% CI = 0.71–1.03) could decrease ovarian cancer risk, which revealed part sources of heterogeneity. The sensitivity analysis indicated stable results, and no publication bias was observed based on the results of Funnel plot analysis and Egger’s test (p = 0.26).

Conclusions

This meta-analysis suggested that consumption of dietary flavonoids and subtypes (isoflavones, flavonols) has a protective effect against ovarian cancer with a reduced risk of ovarian cancer except for flavones consumption. Nevertheless, further investigations on a larger population covering more flavonoid subclasses are warranted.     

The Correlation of MGMT Promoter Methylation and Clinicopathological Features in Gastric Cancer: A Systematic Review and Meta-Analysis

The silencing of the tumor suppressor gene O-6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation commonly occurs in human cancers. The relationship between MGMT promoter methylation and gastric cancer (GC) remains inconsistent. This study aimed to evaluate the potential value of MGMT promoter methylation in GC patients. Electronic databases were searched to identify eligible studies. The pooled odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were used to evaluate the effects of MGMT methylation on GC risk and clinicopathological characteristics. In total, 31 eligible studies including 2988 GC patients and 2189 nonmalignant controls were involved in meta-analysis. In the pooled analysis, MGMT promoter methylation was significantly associated with GC risk (OR = 3.34, P < 0.001) and substantial heterogeneity (P < 0.001). Meta-regression and subgroup analyses based on the testing method, sample material and ethnicity failed to explain the sources of heterogeneity. Interestingly, MGMT methylation showed a trend associated with gender, and methylation is lower in males compared with females (OR = 0.76, 95% CI = 0.56–1.03). We did not find a significant association in relation to tumor types, clinical stage, age status or H. pylori status in cancer (all P > 0.1). MGMT promoter methylation may be correlated with the prognosis of GCs in disease free survival (DFS) or overall survival (OS) for univariate analysis. MGMT promoter methylation may play a crucial role in the carcinogenesis and prognosis of GC. MGMT methylation was not correlated with tumor types, clinical stage, age status, H. pylori status. However, the result of the association of MGMT methylation and gender should be considered with caution.     

The Association between Leptin Level and Breast Cancer: A Meta-Analysis

Background

Contradictory results have been reported regarding the association between leptin level and breast cancer. Therefore, a meta-analysis was performed to investigate this issue.

Methods

Published literature from PubMed and the Chinese National Knowledge Infrastructure (CNKI) Database was retrieved. This study was performed based on different cases and control groups. The combined effect () with 95% confidence interval (CI) was calculated using fixed-effects or random-effects model analysis.

Results

Overall, the mean serum leptin level of case groups was significantly higher than that of control groups. A) For 9 studies comparing breast cancer cases and healthy controls the combined effect was 0.58 with 95% CI (0.48, 0.68). B) For 4 studies comparing premenopausal breast cancer cases and healthy controls the was 0.32 (0.12, 0.52). C) For 5 studies comparing postmenopausal cases and healthy controls the was 0.65 (0.46, 0.84). D) For 4 studies comparing breast cancer cases and breast benign controls the was 0.38 (0.17, 0.59). E) For 2 studies comparing premenopausal breast cancer cases and breast benign controls the was 0.33 (-0.25, 0.91). F) For 6 studies comparing postmenopausal breast cancer cases and breast benign controls the was 0.39 (0.19, 0.60). G) For 4 studies comparing lymph node metastasis positive cases and negative controls the was 0.72 (0.45, 1.00). H) For 3 studies comparing breast benign cases and healthy controls the was 0.71 (0.41, 1.01).

Conclusion

This meta-analysis suggests that leptin level plays a role in breast cancer and has potential for development as a diagnostic tool.     

Association between CYP1A2 and CYP1B1 Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis

Background

The previous published data on the association between CYP1A2*F (rs762551), CYP1B1 Leu432Val (rs1056836), Asn453Ser (rs180040), and Arg48Gly (rs10012) polymorphisms and colorectal cancer risk remained controversial.

Methodology/Principal Findings

The purpose of this study is to evaluate the role of CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly genotypes in colorectal cancer susceptibility. We performed a meta-analysis on all the eligible studies that provided 5,817 cases and 6,544 controls for CYP1A2*F (from 13 studies), 9219 cases and 10406 controls for CYP1B1 Leu432Val (from 12 studies), 6840 cases and 7761 controls for CYP1B1 Asn453Ser (from 8 studies), and 4302 cases and 4791 controls for CYP1B1Arg48Gly (from 6 studies). Overall, no significant association was found between CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly and colorectal cancer risk when all the eligible studies were pooled into the meta-analysis. And in the subgroup by ethnicity and source of controls, no evidence of significant association was observed in any subgroup analysis.

Conclusions/Significance

In summary, this meta-analysis indicates that CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly polymorphisms do not support an association with colorectal cancer, and further studies are needed to investigate the association. In addition, our work also points out the importance of new studies for CYP1A2*F polymorphism in Asians, because high heterogeneity was found (dominant model: I ² = 81.3%; heterozygote model: I ² = 79.0).     

Association between TGFBR1 Polymorphisms and Cancer Risk: A Meta-Analysis of 35 Case-Control Studies

Background

Numerous epidemiological studies have evaluated the association between TGFBR1 polymorphisms and the risk of cancer, however, the results remain inconclusive. To derive a more precise estimation of the relation, we conducted a comprehensive meta-analysis of all available case-control studies relating the TGFBR1*6A and IVS7+24G>A polymorphisms of the TGFBR1 gene to the risk of cancer.

Methods

Eligible studies were identified by search of electronic databases. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were applied to assess the associations between TGFBR1*6A and IVS7+24G>A polymorphisms and cancer risk.

Results

A total of 35 studies were identified, 32 with 19,767 cases and 18,516 controls for TGFBR1*6A polymorphism and 12 with 4,195 cases and 4,383 controls for IVS7+24G>A polymorphism. For TGFBR1*6A, significantly elevated cancer risk was found in all genetic models (dominant OR = 1.11, 95% CI = 1.04∼1.18; recessive: OR = 1.36, 95% CI = 1.11∼1.66; additive: OR = 1.13, 95% CI = 1.05∼1.20). In subgroup analysis based on cancer type, increased cancer risk was found in ovarian and breast cancer. For IVS7+24G>A, significant correlation with overall cancer risk (dominant: OR = 1.39, 95% CI = 1.15∼1.67; recessive: OR = 2.23, 95% CI = 1.26∼3.92; additive: OR = 1.43, 95% CI = 1.14∼1.80) was found, especially in Asian population. In the subgroup analysis stratified by cancer type, significant association was found in breast and colorectal cancer.

Conclusions

Our investigations demonstrate that TGFBR1*6A and IVS7+24G>A polymorphisms of TGFBR1 are associated with the susceptibility of cancer, and further functional research should be performed to explain the inconsistent results in different ethnicities and cancer types.     

RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma,Cirrhotic and Non-Cirrhotic Liver,and Correlation with Liver Cancer in Brazilian Patients

Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Most cases of HCC are associated with cirrhosis related to chronic hepatitis B virus or hepatitis C virus infections. Hypermethylation of promoter regions is the main epigenetic mechanism of gene silencing and has been involved in HCC development. The aim of this study was to determine whether aberrant methylation of RASSF1A and DOK1 gene promoters is associated with the progression of liver disease in Brazilian patients. Methylation levels were measured by pyrosequencing in 41 (20 HCC, 9 cirrhotic, and 12 non-cirrhotic) liver tissue samples. Mean rates of methylation in RASSF1A and DOK1 were 16.2% and 12.0% in non-cirrhotic, 26.1% and 19.6% in cirrhotic, and 59.1% and 56.0% in HCC tissues, respectively, showing a gradual increase according to the progression of the disease, with significantly higher levels in tumor tissues. In addition, hypermethylation of RASSF1A and DOK1 was found in the vast majority (88%) of the HCC cases. Interestingly, DOK1 methylation levels in HCC samples were significantly higher in the group of younger (<40 years) patients, and higher in moderately differentiated than in poorly differentiated tumors (p < 0.05). Our results reinforce the hypothesis that hypermethylation of RASSF1A and DOK1 contributes to hepatocarcinogenesis and is associated to clinicopathological characteristics. RASSF1A and DOK1 promoter hypermethylation may be a valuable biomarker for early diagnosis of HCC and a potential molecular target for epigenetic-based therapy.     

Association between the XRCC1 Polymorphisms and Thyroid Cancer Risk: A Meta-Analysis from Case-Control Studies

Background

The previous published data on the association between the X-ray repair cross-conplementation group 1 (XRCC1) polymorphisms and thyroid cancer risk remained controversial. Hence, we performed a meta-analysis on all available studies that provided 1729 cases and 3774 controls (from 11 studies) for XRCC1 Arg399Gln, 1040 cases and 2487 controls for Arg194Trp (from 7 studies), and 1432 cases and 3356 controls for Arg280His (from 8 studies).

Methodology/Principal Findings

PubMed, CNKI, and EMBASE database were searched to identify relevant studies. Overall, no significant association was found between XRCC1 Arg399Gln (recessive model: OR = 0.95, 95% CI = 0.77–1.15; dominant model: OR = 0.89, 95% CI = 0.75–1.05; homozygote model: OR = 0.92, 95% CI = 0.69–1.23; Heterozygote model: OR = 0.91, 95% CI = 0.80–1.03; additive model: OR = 0.93, 95% CI = 0.81–1.07), Arg194Trp (recessive model: OR = 1.41, 95% CI = 0.62–3.23; dominant model: OR = 1.01, 95% CI = 0.77–1.34; homozygote model: OR = 1.42, 95% CI = 0.55–3.67; Heterozygote model: OR = 1.03, 95% CI = 0.85–1.26; additive model: OR = 1.08, 95% CI = 0.81–1.42), and Arg280His (recessive model: OR = 1.08, 95% CI = 0.56–2.10; dominant model: OR = 1.01, 95% CI = 0.84–1.22; homozygote model: OR = 1.00, 95% CI = 0.51–1.96; Heterozygote model: OR = 1.04, 95% CI = 0.75–1.42; additive model: OR = 1.03, 95% CI = 0.86–1.23) and thyroid cancer risk when all the eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significant association was still not found in these three genetic polymorphisms.

Conclusions/Significance

In summary, this meta-analysis indicates that XRCC1 Arg399Gln, Arg280His, and Arg194Trp are not associated with thyroid cancer.     

Association of Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms with Cancer: A Meta-Analysis

Background

Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and cancer risk report conflicting results. To derive a more precise estimation of the relationship between MTHFD1 polymorphisms and cancer risk, the present meta-analysis was carried out.

Methodology/Principal Findings

A comprehensive search was conducted to determine all the eligible studies about MTHFD1 polymorphisms and cancer risk. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between the MTHFD1 polymorphisms and cancer risk. We investigated by meta-analysis the effects of 2 polymorphisms in MTHFD1: G1958A (17 studies, 12348 cases, 44132 controls) and G401A (20 studies, 8446 cases, 14020 controls). The overall results indicated no major influence of these 2 polymorphisms on cancer risk. For G1958A, a decreased cancer risk was found in acute lymphoblastic leukemia (ALL)/Asians (the dominant: OR = 0.74, 95% CI = 0.58–0.94, P = 0.01; allelic: OR = 0.80, 95% CI = 0.65–0.99, P = 0.04) and other cancers (recessive: OR = 0.80, 95% CI = 0.66–0.96, P = 0.02). For G401A, the data showed that MTHFD1 G401A polymorphism was associated with a decreased colon cancer risk under dominant model (OR = 0.89, 95% CI = 0.80–0.99, P = 0.04).

Conclusions

The results suggest that MTHFD1 G1958A polymorphism might be associated with a decreased risk of ALL and other cancers. Meanwhile, the MTHFD1 G401A might play a protective role in the development of colon cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk: A Meta-Analysis

Background

The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer.

Methodology/Principal Findings

A systematic literature search was conducted to identify all prospective case-control studies and case-control studies on circulating IGFs and IGFBPs levels. Six nested case-control studies (1 043 case subjects and 11 472 control participants) and eight case-control studies (401 case subjects and 343 control participants) were included in this meta-analysis. Pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted OR with 95% CIs for highest vs. lowest levels to assess the association of circulating IGF-1 and IGFBP-3 concentrations and lung cancer. Standard mean difference (SMD) was also calculated to indicate the difference of the circulating IGF-1 and IGFBP-3 concentrations between the lung cancer case group and the control group. Of the nested case-control studies, ORs for the highest vs. lowest levels of IGF-1 and IGFBP-3 were 1.047 (95% CI: [0.802,1.367], P = 0.736) and 0.960 (95%CI: [0.591,1.559], P = 0.868) respectively; and SMDs were −0.079 (95%CI:[ −0.169, 0.011], P = 0.086) and −0.097 (95%CI:[ −0.264,0.071], P = 0.258) for IGF-1 and IGFBP-3 respectively. As to the case-control studies, SMDs were 0.568 (95%CI:[ −0.035, 1.171], P = 0.065) and −0.780 (95%CI:[ −1.358, −0.201], P = 0.008) for IGF-1 and IGFBP-3 respectively.

Conclusions/Significance

Inverse association was shown between IGFBP-3 and lung cancer in the case-control studies,and the circulating level of IGFBP-3 underwent a decline during tumorogenesis and development of lung cancer, which suggested IGFBP-3 a promising candidate for the biomarker of lung cancer.     

CDH1 基因启动子甲基化与宫颈癌临床病理类型的关系

目的:探讨分析CDH1基因启动子甲基化与宫颈癌临床病理类型的关系。方法:选取2012年5月~2015年7月我院105例宫颈癌患者为宫颈癌组,同时选取60例正常宫颈组织为正常组,以甲基化特异性聚合酶链反应(MSP)检测CDH1基因启动子Cp G岛甲基化状态及高危型HPV DNA状态,分析CDH1基因甲基化状态与高危型HPV DNA状态及临床病理参数的关系。结果:宫颈癌组CDH1基因启动子甲基化阳性率为56.19%,明显高于正常组的6.67%,具有统计学差异(P0.05);宫颈癌组的高危型HPV DNA阳性率为84.76%,明显高于正常组的20.00%,具有统计学差异(P0.05);高危型HPV DNA与CDH1基因启动子甲基化的一致性分析结果具有统计学意义(P0.05);CDH1基因启动子甲基化率与患者的WHO组织分化程度分级、FIGO分期、组织病理学分型、肿瘤大小有关,差异有统计学意义(P0.05)。结论:宫颈癌CDH1基因启动子甲基化与WHO组织分化程度分级、FIGO分期、组织病理学分型、肿瘤大小具有关联,并与高危型HPV DNA阳性具有一致性,可以作为宫颈癌诊断和预后评估的参考指标。     

Relationships between p14ARF Gene Methylation and Clinicopathological Features of Colorectal Cancer: A Meta-Analysis

We conducted a meta-analysis to explore the relationships between p14^ARF gene methylation and clinicopathological features of colorectal cancer (CRC). Databases, including Pubmed, Embase and Cochrane Library, were searched and, finally, a total of 18 eligible researches encompassing 1988 CRC patients were selected. Combined odds ratios (ORs) with 95% confidence intervals (95% CIs) were evaluated under a fixed effects model for absence of heterogeneity. Significant associations were observed between p14^ARF gene methylation and tumor location (OR = 2.35, 95% CI: 1.55–3.55, P = 0.001), microsatellite instability (MSI) status (OR = 3.28, 95% CI: 2.12–5.07, P<0.0001). However, there were no significant associations between p14^ARF gene methylation and tumor stage, tumor differentiation. We concluded that p14^ARF gene methylation may be significantly associated with tumor location, and MSI status of CRC.     

Association between Tooth Loss and Gastric Cancer: A Meta-Analysis of Observational Studies

Observational studies showed that tooth loss is associated with gastric cancer, but the findings are inconsistent. In this study, a meta-analysis was conducted to evaluate the relationship between tooth loss and gastric cancer. Relevant studies were screened in PubMed and Embase databases, and nine observational studies were considered eligible for the analysis. The combined relative risks for the highest versus the lowest categories of tooth loss were 1.86 (95% CI: 1.08–3.21) and 1.31 (95% CI: 1.12–1.53) in case control and cohort studies, respectively. However, unstable results were observed in the stratified and sensitivity analysis. The current evidence, based solely on four case-control studies and five cohort studies, suggested that tooth loss is a potential marker of gastric cancer. However, we can not concluded at this time that tooth loss may be a risk factor for gastric cancer due to significant heterogeneity among studies and mixed results between case-control studies and cohort studies. Additional large-scale and high-quality prospective studies are required to evaluate the association between tooth loss and risk of gastric cancer.     

Association between Dairy Intake and Gastric Cancer: A Meta-Analysis of Observational Studies

Purpose

Observational studies have given inconsistent findings on the relationship between intake of dairy products and gastric cancer. We therefore conducted a systematic review with a meta-analysis of observational studies to summarize available evidence on this point.

Methods

We searched the electronic literature databases of PubMed (Medline), EMBASE and the Chinese Biomedical Literature Database up until August 30, 2013. All studies were limited to the English language. Random-effects models were used to pool study results between dairy products consumption and the risk of gastric cancer. We also performed subgroup, publication bias and sensitivity analysis.

Results

Eight prospective studies and 18 case-control studies were included in our analysis, with a total number of 7272 gastric cancer cases and 223,355 controls. Pooled relative risks of all studies showed no significant association between dairy intake and gastric cancer (odds ratio [OR]: 1.09, 95% confidence interval [CI]: 0.96–1.25). When study design was separately analyzed, population-based case-control studies showed a positive association between dairy intake and gastric cancer risk (OR: 1.36; 95% CI: 1.07–1.74), whereas no associations were shown by hospital-based case-control studies (OR: 0.86, 95% CI: 0.72–1.02) or cohort studies (OR = 1.01, 95% CI = 0.91–1.13).

Conclusions

The meta-analysis shows that no clear association apparently exists between consumption of dairy products and gastric cancer risk. Further well-designed cohort and intervention studies should be conducted to verify this lack of association.     

Methylation of the Promoter Region of the RASSF1A Candidate Tumor Suppressor Gene in Primary Epithelial Tumors

The methylation of the promoter CpG island of the RASSF1A tumor suppressor gene in primary tumors of 172 Muscovites with renal cell carcinoma (RCC), breast cancer (BC), or ovarian epithelial tumors (OET) was assayed by means of methylation-specific PCR (MSP) and PCR-based methylation-sensitive restriction enzyme analysis (MSRA). The MSP, MSRA, and previous bisulfite sequencing data correlated significantly with each other (P 10^–6 for Spearman's rank correlation coefficients). By MSP and MSRA, the respective methylation frequencies of the RASSF1A promoter were 86% (25/29) and 94% (50/53) in RCC, 64% (18/28) and 78% (32/41) in BC, and 59% (17/29) and 73% (33/45) in OET. Methylation-sensitive restriction enzymes (HpaII, HhaI, Bsh1236I, AciI) increased the analysis sensitivity and made it possible to establish the methylation status for 18 CpG dinucleotides of the RASSF1A promoter region. With the MSRA data, the density of methylation of the CpG island was estimated at 72% in RCC, 63% in BC, and 58% in OET (the product of the number of CpG dinucleotides and the number of specimens with RASSF1A methylation was taken as 100%). Methylation of the RASSF1A promoter region was observed in 11–35% of the DNA specimens from the histologically normal tissue adjacent to the tumor but not in the peripheral blood DNA of 15 healthy subjects. The RASSF1A methylation frequency showed no significant correlation with the stage, grade, and metastatic potential of the tumor. On the other hand, epigenetic modification of RASSF1A was considerably more frequent than hemizygous or homozygous deletions from the RASSF1A region. These results testify that methylation of the RASSF1A promoter region takes place early in carcinogenesis and is a major mechanism inactivating RASSF1A in epithelial tumors.