Fulan Hu

Does Physical Activity Reduce the Risk of Prostate Cancer? A Systematic Review and Meta-analysis

CONTEXT Numerous observational epidemiologic studies have evaluated the association between physical activity and prostate cancer (PCa); however, the existing results are inconsistent. OBJECTIVE To determine the association between physical activity and risk of PCa. EVIDENCE ACQUISITION A systematic search was performed using the Medline, Embase, and Web of Science databases through 15 May 2011 to identify all English-language articles that examined the effect of physical activity on the risk of PCa. This meta-analysis was conducted according to the guidelines for the meta-analysis of observational studies in epidemiology. EVIDENCE SYNTHESIS This meta-analysis consisted of 88,294 cases from 19 eligible cohort studies and 24 eligible case-control studies. When data from both types of studies were combined, total physical activity (TPA) was significantly associated with a decreased risk of PCa (pooled relative risk [RR]: 0.90; 95% confidence interval [CI], 0.84-0.95). The pooled RR for occupational physical activity (OPA) and recreational physical activity (RPA) were 0.81 (95% CI, 0.73-0.91) and 0.95 (95% CI, 0.89-1.00), respectively. Notably, for TPA, we observed a significant PCa risk reduction for individuals between 20 and 45 yr of age (RR: 0.93; 95% CI, 0.89-0.97) and between 45 and 65 yr of age (RR: 0.91; 95% CI, 0.86-0.97) who performed activities but not for individuals <20 yr of age or >65 yr of age. CONCLUSIONS There appears to be an inverse association between physical activity and PCa risk, albeit a small one. Given that increasing physical activity has numerous other health benefits, men should be encouraged to increase their physical activity in both occupational and recreational time to improve their overall health and potentially decrease their risk of PCa.

The relationship between body mass index and hip osteoarthritis: A systematic review and meta-analysis

OBJECTIVE Body mass index, a measure of relative weight, is increasingly recognized as an important risk factor for osteoarthritis, especially in weight bearing joints. The objective was to assess the association between body mass index and hip osteoarthritis susceptibility and investigate the difference between sex, study type and osteoarthritis definition. METHODS We did electronic searches of Medline, Embase and Cochrane library from the commencement to December 2009. A meta-analysis and meta-regression was executed to quantitatively assess the strength of associations between body mass index and hip osteoarthritis risk. Study-specific incremental estimates were standardized to determine the risk associated with a 5 kg/m(2) increase in body mass index. RESULTS Fourteen epidemiological studies were included. Our study showed that body mass index was significantly positive associated with hip osteoarthritis risk. A 5-unit increase in body mass index was related to an increased risk of hip osteoarthritis (RR: 1.11; 95%CI: 1.07, 1.16). The magnitudes of associations were similar in women as compared with men (women, RR: 1.10; 95%CI: 1.05, 1.15; men, RR: 1.08; 95%CI: 1.04, 1.12; p > 0.05). The summary estimates were 1.12 (95%CI: 1.02, 1.24) in case-control studies and 1.11 (95%CI: 1.06, 1.16) in cohort studies (p > 0.05). Body mass index was positively associated with hip osteoarthritis defined by radiography and/or clinical symptom (RR: 1.04; 95%CI: 1.00, 1.07) and clinical surgery (RR: 1.16; 95%CI: 1.11, 1.22) with no significant difference (p > 0.05). CONCLUSION Increased body mass index contributes to a positive effect on susceptibility to hip osteoarthritis. Associations between body mass index and hip osteoarthritis risk do not vary by sex, study design or osteoarthritis definition.

DNA Repair Gene XPD Polymorphisms and Cancer Risk: A Meta-analysis Based on 56 Case-Control Studies

Genetic variations in the XPD gene may increase cancer susceptibility by affecting the capacity for DNA repair. Several studies have investigated this possibility; however, the conclusions remain controversial. Therefore, we did a systematic review and executed a meta-analysis to explore the association. From 56 studies, a total of 61 comparisons included 25,932 cases and 27,733 controls concerning the Lys751Gln polymorphism; 35 comparisons included 16,781 cases and 18,879 controls in the case of Asp312Asn were reviewed. In this analysis, small associations of the XPD Lys751Gln polymorphism with cancer risk for esophageal cancer [for Lys/Gln versus Lys/Lys: odds ratio (OR), 1.34; 95% confidence interval (95% CI), 1.10-1.64; for Gln/Gln versus Lys/Lys: OR, 1.61; 95% CI, 1.16-2.25] and acute lymphoblastic leukemia (for Gln/Gln versus Lys/Lys: OR, 1.83; 95% CI, 1.21-2.75) are revealed. Overall, individuals with the Gln/Gln genotype have a small cancer risk compared with Lys/Lys genotype for the reviewed cancer in total (OR, 1.10; 95% CI, 1.03-1.16). Subtle but significant cancer risk was observed for the XPD Asp312Asn polymorphism in bladder cancer (for Asp/Asn versus Asp/Asp: OR, 1.24; 95% CI, 1.06-1.46). No significant associations were found for other cancers separately and all the reviewed cancer in total assessed for the Asp312Asn polymorphism. Our study suggests that XPD is a candidate gene for cancer susceptibility regardless of environmental factors. (Cancer Epidemiol Biomarkers Prev 2008;17(3):507–17)

MLH1 Promoter Methylation Frequency in Colorectal Cancer Patients and Related Clinicopathological and Molecular Features

Purpose To describe the frequency of MLH1 promoter methylation in colorectal cancer (CRC); to explore the associations between MLH1 promoter methylation and clinicopathological and molecular factors using a systematic review and meta-analysis. Methods A literature search of the PubMed and Embase databases was conducted to identify relevant articles published up to September 7, 2012 that described the frequency of MLH1 promoter methylation or its associations with clinicopathological and molecular factors in CRC. The pooled frequency, odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. Results The pooled frequency of MLH1 promoter methylation in unselected CRC was 20.3% (95% CI: 16.8–24.1%). They were 18.7% (95% CI: 14.7–23.6%) and 16.4% (95% CI: 11.9–22.0%) in sporadic and Lynch syndrome (LS) CRC, respectively. Significant associations were observed between MLH1 promoter methylation and gender (pooled OR = 1.641, 95% CI: 1.215–2.215; P = 0.001), tumor location (pooled OR = 3.804, 95% CI: 2.715–5.329; P<0.001), tumor differentiation (pooled OR = 2.131, 95% CI: 1.464–3.102; P<0.001), MSI (OR: 27.096, 95% CI: 13.717–53.526; P<0.001). Significant associations were also observed between MLH1 promoter methylation and MLH1 protein expression, BRAF mutation (OR = 14.919 (95% CI: 6.427–34.631; P<0.001) and 9.419 (95% CI: 2.613–33.953; P = 0.001), respectively). Conclusion The frequency of MLH1 promoter methylation in unselected CRC was 20.3%. They were 18.7% in sporadic CRC and 16.4% in LS CRC, respectively. MLH1 promoter methylation may be significantly associated with gender, tumor location, tumor differentiation, MSI, MLH1 protein expression, and BRAF mutation.

APC Polymorphisms and the Risk of Colorectal Neoplasia: A HuGE Review and Meta-Analysis

Adenomatous polyposis coli gene (APC) polymorphisms may influence the risk for colorectal neoplasia. However, results thus far have been inconclusive. We performed a systematic literature search of the Medline, Embase, Cochrane Collaboration, and HuGE databases and reviewed the references of pertinent articles through May 2012. Odds ratios with 95% confidence intervals were used to estimate the association between 3 APC polymorphisms (D1822V, E1317Q, and I1307K) and colorectal neoplasia. In total, 40 studies from 1997 to 2010 were included in this meta-analysis, and individuals with the D1822V variant homozygote VV genotype had a slight decrease in the risk for colorectal neoplasia compared with the wild-type homozygote DD genotype (pooled odds ratio = 0.87, 95% confidence interval: 0.77, 0.99). There was a small association between the APC E1317Q polymorphism and a risk for colorectal neoplasia (variant vs. wild-type: pooled odds ratio = 1.41, 95% confidence interval: 1.14, 1.76), particularly for colorectal adenomas (variant vs. wild-type: odds ratio = 2.89, 95% confidence interval: 1.83, 4.56). Compared with those who carried the wild-type I1307K, Ashkenazi Jews who carried the I1307K variant were at a significantly increased risk for colorectal neoplasia, with a pooled odds ratio of 2.17 (95% confidence interval: 1.64, 2.86). Our study suggests that APC is a candidate gene for colorectal neoplasia susceptibility.

Can Vascular Endothelial Growth Factor and Microvessel Density Be Used as Prognostic Biomarkers for Colorectal Cancer? A Systematic Review and Meta-Analysis

Background. Vascular endothelial growth factor (VEGF) and microvessel density (MVD) are associated with greater incidence of metastases and decreased survival. Whether they can be used as prognostic indicators of colorectal cancer (CRC) is still controversial. Methods. The authors performed a meta-analysis using the results of a literature search of databases of PubMed and EMBASE, and the references of articles included in the analysis. Meta-analysis was performed using random effects model and hazard ratios (HRs) and 95% confidence intervals (CIs) as effect measures. Results. Twenty studies contributed to the analysis of VEGF, of which 16 were used for overall survival (OS) and 9 for disease-free survival (DFS). High VEGF levels has a relationship with unfavorable survival (OS: HR = 1.98, 95% CI: 1.30–3.02; DFS: HR = 2.10, 95% CI: 1.26–3.49) and a 4.22-fold increase in the rate of distant metastases. Analysis was performed on 18 studies for MVD; the results showed that patients with high MVD expression in tumors appeared to have poorer overall survival (HR = 1.39, 95% CI: 1.22–1.58) and were at a greater risk of having unfavorable clinical characteristics related to prognosis. Corresponding results were obtained from quantitative and/or qualitative analysis of clinicopathological. Conclusions. The meta-analysis demonstrates that VEGF and MVD can be used as prognostic biomarkers for CRC patients.

Bisphosphonate Use and the Risk of Breast Cancer: A Meta-Analysis of Published Literature

Bisphosphonates are widely used in clinical practice to prevent and treat osteoporosis and cancer-induced bone loss. Recently, analysis of results of several published observational studies found that women who used bisphosphonates had a significant reduction in the risk of breast cancer compared with nonusers. However, the findings were inconsistent. We systematically searched MEDLINE and EMBASE databases through June 1, 2011. The eligibility determination and the data extraction were conducted independently by 2 of the authors. A random-effect model was used to obtain the pooled estimates of effect. We identified 2 cohort studies and 2 case-control studies that were eligible for analysis, which involved 15,363 patients with breast cancer and 84,931 bisphosphonate users. The results of our meta-analysis revealed that women who received bisphosphonates have a 15% risk reduction of any breast cancer (pooled risk ratio [RR], 0.85 [95% confidence interval {CI}, 0.74-0.98]; P = .03) and a 32% risk reduction of invasive breast cancer (pooled RR, 0.68 [95% CI, 0.59-0.80]; P < .001) compared with nonusers. In addition, there was a significant dose-response relationship between the duration of bisphosphonate use and breast cancer risk. A significantly protective effect of bisphosphonates was observed in patients who used bisphosphonates for more than 1 year before the diagnosis of breast cancer compared with nonusers. The bisphosphonate users had a risk reduction of breast cancer by 8% (pooled RR, 0.92 [95% CI, 0.87-0.96]; P = .001) for each additional year of the duration of bisphosphonate use. The use of bisphosphonates may have a beneficial effect on breast cancer risk.

CpG island methylator phenotype and prognosis of colorectal cancer in Northeast China.

Purpose. To investigate the association between CpG island methylator phenotype (CIMP) and the overall survival of sporadic colorectal cancer (CRC) in Northeast China. Methods. 282 sporadic CRC patients were recruited in this study. We selected MLH1, MGMT, p16, APC, MINT1, MINT31, and RUNX3 as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM). Proportional hazards-regression models were fitted with computing hazard ratios (HR) and the corresponding 95% confidence intervals (95% CI). Results. 12.77% (36/282) of patients were CIMP-0, 74.1% (209/282) of patients were CIMP-L, and 13.12% (37/282) of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association between APC gene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05–2.46; P = 0.03). CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19–7.89; P = 0.02) and CIMP-L (HR = 1.97; 95% CI: 1.11–3.48; P = 0.02), respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0), CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02–5.24; P = 0.04). Conclusion. CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.

Novel DNA Variants and Mutation Frequencies of hMLH1 and hMSH2 Genes in Colorectal Cancer in the Northeast China Population

Research on hMLH1 and hMSH2 mutations tend to focus on Lynch syndrome (LS) and LS-like colorectal cancer (CRC). No studies to date have assessed the role of hMLH1 and hMSH2 genes in mass sporadic CRC (without preselection by MSI or early age of onset). We aimed to identify novel hMLH1 and hMSH2 DNA variants, to determine the mutation frequencies and sites in both sporadic and LS CRC and their relationships with clinicopathological characteristics of CRC in Northeast of China. 452 sporadic and 21 LS CRC patients were screened for germline and somatic mutations in hMLH1 and hMSH2 genes with PCR–SSCP sequencing. We identified 11 hMLH1 and seven hMSH2 DNA variants in our study cohort. Six of them were novel: four in hMLH1 gene (IVS8-16 A>T, c.644 GAT>GTT, c.1529 CAG>CGG and c.1831 ATT>TTT) and two in hMSH2 gene (−39 C>T, insertion AACAACA at c.1127 and deletion AAG at c.1129). In sporadic CRC, germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 15.59% and 17.54%, respectively (p = 0.52). Germline mutations present in hMLH1 and hMSH2 genes were 5.28% and 10.78%, respectively (p<0.01). Somatic mutations in hMLH1 and hMSH2 genes were 6.73% and 11.70%, respectively (p = 0.02). In LS CRC, both germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 28.57%. The most prevalent germline mutation site in hMSH2 gene was c.1168 CTT>TTT (3.90%), a polymorphism. Somatic mutation frequency of hMLH1/hMSH2 gene was significantly different in proximal, distal colon and rectal cancer (p = 0.03). Our findings elucidate the mutation spectrum and frequency of hMLH1 and hMSH2 genes in sporadic and LS CRC, and their relationships with clinicopathological characteristics of CRC.

Meta-analysis of MSH6 gene mutation frequency in colorectal and endometrial cancers.

Studies on mutations and mutation frequencies of the MSH6 gene, which mainly focus on new types of mutations in small samples, have been published ever since the first report of MSH6 mutation in two atypical hereditary non-polyposis colorectal cancer patients. However, the results remain inconsistent. Therefore, a systematic review was conducted and a meta-analysis was undertaken to determine the frequency of MSH6 mutation in colorectal and endometrial cancers. From 27 studies, 180 cases with MSH6 mutation in a total of 3196 cases were detected. In colorectal and endometrial cancers the MSH6 mutation frequency is 7.2 and 9.6%, respectively. MSH6 mutation frequency was 10.4% in hereditary non-polyposis colorectal cancer patients, 7.1% in atypical hereditary non-polyposis colorectal cancer patients, and 5.9% in sporadic patients. The frequency of MSH6 mutation in high microsatellite instability (MSI-H) was 11.6% and in low microsatellite instability (MSI-L) cases was (13.3%), which were higher than in microsatellite stability (MSS) cases (1.7%). The mean age of the earliest onset of colorectal and endometrial cancers in MSH6 mutation carriers was 51.2 and 56.5 yr, respectively. Data suggest that the frequency of MSH6 mutation is higher in hereditary non-polyposis colorectal cancer patients than in atypical hereditary non-polyposis colorectal cancer and sporadic patients. MSH6 mutation frequency was also higher in endometrial than colorectal cancers. The mean age of earliest onset of endometrial cancer (56.5 yr) is older than for colorectal cancer (51.2 yr) in carriers of MSH6 mutation. Our results provide evidence for clinical genetic testing and counseling.