ATM gene polymorphisms are thought to influence the risk of cancer and radiation-induced pneumonitis (RP) risk in cancer patients treated with radiotherapy. However, the results of previous studies are inconsistent. We therefore conducted this comprehensive meta-analysis.Previous studies have suggested that DNA double-strand break (DSB) repair is an important protective pathway after damage. The ataxia telangiectasia mutated (ATM) gene plays an important role in the DNA DSB repair pathway. DNA damage is a major cytotoxic effect that can be caused by radiation, and the ability to repair DNA after damage varies among different tissues. Impaired DNA repair pathways are associated with high sensitivity to radiation exposure. Hence, ATM gene polymorphisms and both lung cancer and RP radiotherapy-treated lung cancer . The odds ratio (OR) and 95% confidence interval (CI) were used to investigate the strength of these relationships. Funnel plots and Begg’s and Egger’s tests were conducted to assess the publication bias. All analyses were performed in STATA 13.0 software.A systematic literature search was performed in the PubMed, Embase, China National Knowledge Internet (CNKI) and Wanfang databases to identify studies that investigated the association between the ATM gene, the rs189037 , rs664677  and rs664143  polymorphisms were significantly associated with lung cancer susceptibility . Additionally, the rs189037 variant was significantly associated with RP risk . No publication bias was found in the funnel plots, Begg’s tests or Egger’s tests.Ten eligible case-control studies (4731 cases and 5142 controls) on lung cancer susceptibility and four (192 cases and 772 controls) on RP risk were included. The results of the overall and subgroup analyses indicated that in the ATM rs189037, rs664677 and rs664143 gene polymorphisms are risk factors for lung cancer, while the ATM rs189037 variant was significantly associated with RP risk.The results indicate that the  Lung cancer is the most common cancer and the most common cause of death from cancer worldwide . AlthougRadiotherapy is an important treatment for cancers. However, 10% to 20% of cancer patients who undergo radiotherapy develop severe radiation-induced pneumonitis (RP), which influences their quality of life. Approximately half of patients with RP die –7. RP isATM plays an important role in the repair of DNA damage, especially DNA double-strand breaks (DSBs) [Nijmegen breakage syndrome 1 (NBS1), and the oncogenic protein murine double minute 2 (MDM2) [ATM may influence the structure and function of the protein, leading to defects in the activation of cell cycle checkpoints, DNA DSB repair, and cell apoptosis. Additionally, ATM gene mutations may alter the radiosensitivity of cells [The ataxia-telangiectasia mutated (ATM) gene is one such DNA repair gene. s (DSBs) , 14. DSBs (DSBs) . The ATMs (DSBs) . Once ans (DSBs) , 17. The2 (MDM2) , 19. Polof cells , 20, 21.of cells .ATM gene polymorphisms  may be associated with susceptibility to lung cancer [ATM gene polymorphisms and both susceptibility to lung cancer and the risk of RP in lung cancer patients treated with radiotherapy. To the best of our knowledge, the current study is the most comprehensive analysis of the relationship between susceptibility to lung cancer and ATM gene polymorphisms and the first meta-analysis to evaluate the association between RP risk and ATM gene mutations.Previous studies have shown that several g cancer –25, and g cancer , 27. HowATM gene polymorphisms and lung cancer as or RP in lung cancer patients treated with radiotherapy  using the following search terms: “ATM” and “cancer” or “lung cancer” or “Lung Neoplasms” and “polymorphism” or “variant”; “ATM” and “radiation pneumonia” or “radiation pneumonitis” and “polymorphism” or “variant”. The references listed in the resulting articles were also searched to identify additional relevant articles.We searched the PubMed, Embase, China National Knowledge Internet (CNKI) and Wanfang databases to identify studies that investigated the association between ATM polymorphisms and lung cancer susceptibility or RP risk, (2) data on genotype frequencies were available for both the cases and controls, (3) published in English or Chinese, and (4) the genotype distribution of the control group was in accordance with Hardy-Weinberg equilibrium. The following exclusion criteria were applied: (1) no control group, (2) duplication of a previous study, and (3) no usable data on genotype frequency.The following were the inclusion criteria for studies in our meta-analysis: (1) case-control studies focused on Two authors independently extracted the data from all eligible publications. The following information was extracted from each relevant study: the first author’s name, country of origin, publication year, ethnicity of the study individuals, cancer type, genotyping methods, sample size and genotype frequencies.ATM polymorphism and lung cancer or RP was measured by odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was evaluated by the chi-squared (x2) and I-squared (I2) test. If P > 0.10 and I2 < 50%, no heterogeneity was detected among the studies, and the OR was calculated by the fixed-effects model. Otherwise, the random-effects model was used. To evaluate ethnicity-specific effects, a subgroup analysis was performed by ethnicity group. The potential publication bias was assessed by funnel plots, Begg’s test and Egger’s test.All statistical analyses were performed by Stata 13.0. The strength of the association between an ATM gene rs373759 and susceptibility to lung cancer), and they were therefore not suitable for inclusion in this meta-analysis. Finally, 14 studies were included in our study  or other essential information. We extracted information from 16 studies. Two of these studies were excluded because no other studies referred to the same polymorphism  .For the ATM rs664677, five studies containing 2428 patients and 2439 controls were included. We found that the TT genotype was associated with a significantly higher risk of lung cancer , and no significant association was found for this genotype in other genetic models .For ATM rs664143, 1983 cases and 1981 controls from five studies were included. We found that the A allele was associated with an increased risk of lung cancer . No publication bias was detected in a funnel plot or Egger’s test (P = 0.303).For ATM rs609429 , we identified 1490 cases and 1501 controls in three studies. We failed to find any significant associations  .With regard for the association between the risk of RP and the In the present meta-analysis, we found that there were significant associations between lung cancer risk and rs189037, rs664677 and rs664143. Additionally, we found that the rs189037 A allele was significantly associated with the risk of RP. Significant heterogeneity was found in two of the genetic models used to evaluate the risk of RP. This may be because different diagnostic standards were used in different studies. Fortunately, the genetic models identified in our study that did produce significant associations results showed no significant heterogeneity. No significant publication bias was found in polymorphisms that were covered by at least five studies.ATM rs189037 is located in the 5’UTR of the promoter region of the ATM gene [ATM transcription, and different genotypes have different affinities for this transcription factor [ATM rs189037 increases the risk of oral [ATM rs664143 is located in the protein binding motifs that serve as binding sites for intronic splicing enhancers or repressors, suggesting the possibility that this site may be involved in the exon 61 splicing process and that it may cause inaccurate splicing [ATM gene plays a critical role in DNA damage repair and thereby affects the risk of lung cancer and RP. We performed this meta-analysis because the results of previous studies were inconclusive.ATM gene . This SN of oral  and brea of oral . Further of oral . ATM rs6splicing . The presplicing . Howeversplicing  or pancrsplicing . Other ssplicing , 47. DNAsplicing . Individsplicing . PreviouATM gene are included in this study. It is also the first meta-analysis to evaluate the association between ATM gene polymorphisms and the risk of RP.Several limitations of the current analysis should be mentioned. First, we failed to conduct a subgroup analysis to evaluate the effects of other factors, such as gender, smoking status or histological subtypes, because insufficient data was available. Second, we included only articles published in either English or Chinese, resulting in potential publication bias, despite the fact that the Egger’s test and funnel plots showed that there was no publication bias. Despite these limitations, the likelihood of bias was minimized throughout the process because we used a detailed protocol that included study identification, data selection and the statistical analysis, and we controlled publication bias. Therefore, we believe that our results are reliable. Additionally, most polymorphisms and studies of the ATM rs189037 polymorphism is significantly associated with lung cancer and the risk of RP after radiotherapy. The ATM rs664677 and ATM rs664143 polymorphisms were significantly associated with lung cancer susceptibility, while rs609429 was not. More well-designed studies that include larger sample sizes should be performed in the future to further evaluate the association between the ATM gene and cancers.In conclusion, in this meta-analysis, we showed that the


TERT rs2736098 and cancer risk, but no consensus has been reached about the relationship. Here, we conducted this updated meta-analysis, aiming to comprehensively evaluate the role of TERT rs2736098 in cancer risk. We systematically searched potential relevant articles through PubMed, EMBASE, CNKI, and WanFang database before August 2017. A total of 33 studies with 18685 cases and 23820 controls were finally included in the current meta-analysis. We then adopted odds ratios (ORs) and 95% confidence intervals (CIs) to analyze the contributions of TERT rs2736098 to cancer risk. We found that the TERT rs2736098 polymorphism was associated with risk of cancer in overall analysis . Furthermore, in analysis stratified by cancer type, ethnicity, control source, quality score, and Hardy-Weinberg equilibrium (HWE) in controls, we found increased risk of cancer among lung cancer, bladder cancer, breast cancer, colorectal cancer, other cancers, Asians, hospital-based subgroup, score > 9 group, as well as controls agreement with HWE group. Despite some limitations, the current meta-analysis represented the largest and the most comprehensive investigations, with the strongest conclusion than ever before. To further explicit the association between TERT rs2736098 and cancer risk, more well-design case-control studies with larger sample size are warranted in the future.Increasing researches have been performed regarding the relationship between  Cancer is a substantial public health burden, with an estimate of 14.1 million new cancer cases and 8.2 million cancer-related deaths occurred globally [TERT gene is located on the short (p) arm of chromosome 5 at position 15.33 (5p15.33), and composes of 16 exons [TERT gene encodes the reverse transcriptase component of the telomerase, which is essential in maintaining the length of telomer [TERT mRNA is not expressed in most human somatic cells; however, aberrant expression of TERT mRNA and protein are associated with development of various cancers [Telomerase is an RNA-dependent DNA polymerase containing two essential components, catalytic subunit with the reverse transcriptase activity and an essential structural RNA component with a sequence complementary to the telomere sequence . TERT ge16 exons . TERT ge telomer . In addi telomer . Telomer telomer . Normall cancers , 12.TERT rs2736098 polymorphism and cancer risk, yet conflicting conclusions remain. Besides, the latest meta-analysis was performed a year ago, which updated to March 2015. Nearly 10 new case-control studies with larger sample size were published since then. Thus, it is of great value to updated the meta-analysis regarding the association of interest. The current meta-analysis was the most comprehensive to date, which undoubtedly will shed some light on the current uncertain claims.More and more epidemiological studies were accessible regarding the association between the A total of 144 potentially relevant publications were initially identified from the databases. After screening titles and abstracts, 106 publications were excluded because of their failure to reach inclusion criteria. The remaining 38 publications were further assessed through careful reading. We further excluded 8 publications based on the following reasons: 7 publications were meta-analyses –19, 1 waIn general, the current study contains 18685 cases and 23820 controls .In Begg's funnel plots, we could not detect any obvious asymmetrical shape Figure . MoreoveTERT rs2736098 in cancer risk. The obtained results suggested that there exists a significant relationship between TERT rs2736098 and cancer risk. To the best of our knowledge, this updated meta-analysis involves the largest samples and the most convincing conclusions.In this meta-analysis, we attempted to settle down the debate about the role of TERT gene rs2746098 polymorphism in the contributions to cancer risk. To obtain a clear association between TERT rs2736098 and cancer risk, several meta-analyses have been performed. The first meta-analysis was conducted by Zhang et al. [TERT rs2736098 polymorphism and overall cancer risk. However, after stratified by ethnicity, a significantly increased risk of cancers was shown Among Asians. In another meta-analysis with 12 studies including 10044 cases and 12480 controls. Wu et al. [Numerous studies have investigated the role of g et al.  in 2012,u et al.  found thu et al. . They foTERT rs2736098 polymorphism and cancer risk. In all, we found a significant relationship between TERT rs2736098 and cancer risk in the pooled analysis under all the five-genetic model, except for heterozygous model. Such findings were consistent with the results reported in the study of Wu et al. [TERT rs2736098 polymorphism from Asians but not among Europeans were more likely to exhibit an increased cancer risk, possibly because of the differences in genetic backgrounds among different populations. Our results suggested that genetic variants in TERT significantly increased the risk of lung cancer, bladder cancer, breast cancer, colorectal cancer and other cancer, but not HCC and SCCHN. These lines of evidence suggested that TERT rs2736098 polymorphism may have different effects in different cancer types. The possible reasons for discrepancies regarding cancer susceptibility may be ascribed to tumor specificity, differences in ethnicity, and variations in sample sizes included in each investigation.As several new studies have been updated since the latest meta-analysis, it is necessary for us to incorporate all the accessible studies to better elucidate the association between u et al.  and the u et al. . SubgrouTo improve the quality of the current meta-analysis, we adopted some measurements below. First, our meta-analysis was the first to search literatures from both English and Chinese, with the aim to strengthen the reliability of our conclusions. Second, we adopted sensitivity analysis and publication bias assay, and the results indicated that the conclusions are robust and no publication bias was detected.Yet, some limitations still exist and thus cautions are needed before interpreting the results obtained from the current meta-analysis. First, the number of included studies is far from enough to obtain a robust conclusion, especially for stratified analysis. Second, the validity of conclusion might be discount as significant between-study heterogeneity was observed in some comparisons. Third, we only calculated the crude ORs, but not the adjusted ORs, due to the lack of other important information like environmental factors, age, drinking status, and gene-environment interactions. Fourth, selection bias could not be avoided, as only the studies written in English or Chinese were extracted. Last, nearly all the eligible case-control studies included were conducted among Asians and Caucasians, other ethnicities such as Africans were not undertaken. Concerning genetic and geographical differences, additional studies are needed to further confirm such conclusion from other ethnicities, especially Africans.TERT rs2736098 polymorphism is associated with cancer risk, from the perspective of the formed case-control studies. However, it is still needed for us to continue providing more new evidence based on large sample size, multi-center investigation case-control studies.To sum up, the current meta-analysis provides a powerful evidence that TERT or hTERT or rs2736098 or telomere reverse transcriptase”, and “cancer or neoplasm or tumor or carcinoma”. Then we further expanded the searching field to Chinese database China National Knowledge Infrastructure (CNKI) and Wanfang database using the same combination items in Chinese. The searching time was updated to August 2017. Moreover, we also included the eligible studies extracted from the references of retrieved articles. A single study would be treated as separate studies if two more ethnic subpopulations is included. Only the largest or the latest study was included if there exist two more articles with overlapping data. No language publication restrictions were set in this searching strategy. The designation and writing of this meta-analysis was under the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses.A comprehensive literature search was first conducted in English electronic database PubMed and EMBASE using the combination of the following items: “polymorphism or single nucleotide polymorphism or SNP or variant” and “In the current meta-analysis, only the studies met the following criteria were included: (1) studies published in English or Chinese; (2) unrelated case-control studies; (3) tested for the association of TERT rs2736098 polymorphism with cancer risk; (4) enough information to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Studies that failed to meet the above criteria were excluded in the final analysis.We arranged two authors (Tingyuan and Minjie) to screen the articles and extracted available data from all eligible studies, blindly. The data shown below were extracted: first author's surname, publication year, country, ethnicity, the source of controls, genotyping methods, quality score, and numbers of cases and controls with AA, AG and GG genotypes. Any discrepancy was resolved after full discussion.To strengthen the robustness of our meta-analysis, a quality assessment was performed to all the included studies through adopting the quality assessment criteria . In brie2 test to assess whether the SNP in the control was departure from HWE. The strength of the association between TERT rs2736098 polymorphism and overall cancers risk was measured by calculating crude ORs and their 95% CIs using all five genetic models: homozygous model (AA vs. GG), heterozygous model (AG vs. GG), recessive model (AA vs. AG + GG), dominant model (AA + AG vs. GG) and allele comparison (A vs. G). Stratification analyses were also performed by ethnicity, and source of control, quality score, and HWE in controls. Between-study heterogeneity was analyzed by the Cochran's Q test and quantified by I2 statistics. When homogeneity existed, the fixed model (Mantel-Haenszel method) was used to calculate the summary ORs and 95% CIs; otherwise, the random-effects model (the DerSimonian and Laird method) was utilized. Sensitivity analysis was done by individually removing studies one by one and reanalyzing the pooled risk estimates. Publication bias was further assessed using Begg's funnel plot and Egger's linear regression, with that asymmetric plot and a P value < 0.05 indicating the presence of publication bias. All statistical analysis was completed using STATA software . All the statistics were two-sided with significant findings set at a P value of < 0.05.We first adopted goodness-of-fit χ


Previous studies have investigated the role of miR-146a rs2910164 and miR-196a-2 rs11614913 polymorphisms in hepatocellular carcinoma (HCC) susceptibility, but the results are contradictory and few specifically studied hepatitis virus-related HCC. Therefore, we conducted a meta-analysis to evaluate the association between these two polymorphisms and hepatitis virus-related HCC risk. We performed a systematical search in EMBASE, PubMed, Web of Science, CNKI and Wanfang databases as of 25th November, 2016. Finally, we assessed 14 studies involving 3852 cases and 5275 controls. Our results suggest that rs2910164 has a significant association with increased hepatitis virus-related HCC risk in allelic, homozygous, heterozygous, and dominant models , particularly in Chinese and HBV-related HCC subgroups. Conversely, rs11614913 was associated with lower hepatitis virus-related HCC risk in the overall analysis under allelic , homozygous, dominant and recessive models. Subgroup analyses showed decreased risk in Chinese, HBV- and HCV-related HCC. In conclusion, miR-146a C>G (rs2910164) can increase HBV-related HCC risk while miR-196a-2 C>T (rs11614913) may decrease the risk of HBV- and HCV-related HCC, especially in the Chinese population. Further, large-scale studies including other races are required to confirm these findings. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, especially in less-developed countries. . It is wMicroRNAs (miRNA) are a class of small non-coding RNAs containing approximately 22 nucleotides. These endogenous molecules regulate gene expression via post-transcriptional repression. This regulation modulates diverse biological processes including proliferation, differentiation, and apoptosis, which are key steps in tumorigenesis , 5. MiRNA total of 392 potentially relevant studies were identified via a database search. Finally, 14 studies comprising 3852 hepatitis virus-related HCC patients and 5275 cancer-free controls were included. And Table versus (vs.) C , GG vs. CC  and CG+GG vs. CC . Additionally, this risk is more significant in the Chinese population. After omitting the study which did not conform to HWE, the results were found to be consistent with the overall analysis. Additionally, subgroup analyses showed a higher HBV-related HCC risk in the same 4 genetic models, whereas no significance was found in the HCV-related HCC subgroup. When stratifying data by source of control, rs2910164 was also observed to significantly increase hepatitis virus-related HCC risk based on hospital data, but there was no statistical significance based on population data.As presented in Table vs. C , TT vs. CC , TT vs. CT+CC . The results were similar in the overall population as well as particularly among the Chinese. However, further analysis of the studies which were in agreement with HWE showed no associations between rs11614913 and hepatitis virus-related HCC. Additionally, in subgroup analysis by source of control, decreased hepatitis virus-related HCC risk was observed based on hospital data, however, no significance was shown based on population data. Furthermore, in the stratified analysis according to etiology, rs11614913 was found to decrease both HBV- and HCV-related HCC risk in different genetic models.Conversely, miR-196a2 rs11614913 was associated with lower hepatitis virus-related HCC risk in overall analysis under T 2 in HCV-related HCC subgroup was reduced to zero. However, heterogeneity was still significant in other subgroups. We then used Galbraith plots to further investigate the heterogeneity and identified 3 three studies [2 values were <50% in heterozygous and recessive models in the overall populations and some subgroups (data not shown).No significant heterogeneity was observed for rs2910164 in all the genetic models analyzed. However, significant heterogeneity was detected for rs11614913 in each genetic model  as of 25th November, 2016. The search was performed using the following terms: “miR-146a OR microRNA-146a OR miR-196a-2 OR microRNA-196a-2” AND “polymorphisms OR variant OR SNP OR mutation” AND “hepatocellular carcinoma OR liver cell carcinoma OR liver cancer”. Additionally, references in retrieved articles were searched manually.The studies that complied with the following criteria were included: 1) original studies investigating the association of rs2910164 or rs11614913 and hepatitis virus-related HCC risk; 2) case-control design studies conducted in humans; 3) patients were pathologically diagnosed, with cancer-free individuals used as controls; 4) availability of full text, with detailed data of the allele and genotype distributions. Studies without a control group, repeated publications, reviews, and conference abstracts were excluded. If two or more studies showed an overlapping study population, only the most comprehensive study was included. The details of included and excluded articles were shown in Fig. P value of Hardy-Weinberg equilibriums (HWE) in controls were collected. Any discrepancy was discussed between authors to reach a consensus.Based on the criteria listed above, 2 authors independently reviewed the literature. The quality of each included article was assessed by Newcastle-Ottawa Quality Assessment Scale for case-control studies. For each eligible study, the raw data and information including: first author, publication year, country of origin, ethnicity, genotype methods, source of control, numbers of cases and controls, frequencies of allele and genotypes, and vs. A), homozygote (BB vs. AA), heterozygote (AB vs. AA), dominant model (BB+AB vs. AA), and recessive model (BB vs. AA+AB). The combined ORs were determined by Z test and P<0.05 was judged as statistically significant. Heterogeneity between studies was detected using I2 test and Q statistic, while significance was considered at I2>50%. A random-effects model was applied to analyze the pooled ORs if I2≥50%. Otherwise, a fixed-effects model was implemented. We carried out subgroup analyses to investigate the specific effects of ethnicity, source of control and etiology. Additionally, we assessed publication bias using Egger's test and Begg's funnel plot (significant bias was considered if P<0.05). We also performed a sensitivity analysis to assess the consistency and stability of our meta-analysis by removing each study in turn. All statistical analyses were accomplished with the software Review Manager 5.3 .and STATA .Odds ratios (OR) with corresponding 95% confidence intervals (CI) for miR-146a and miR-196a-2 polymorphisms were calculated in each study under 5 different genetic models: allele comparison (B


Autism spectrum disorder (ASD) is a common severe pervasive neurodevelopmental disorder of undetermined etiology. Environmental exposures, especially pregnancy complications, have been increasingly recognized as a potential risk factor for ASD. Our aim was to (1) systematically evaluate the association between hypertensive disorders of pregnancy (HDP) and the risk of ASD in offspring, (2) specifically draw a subgroup analysis of disease severity in patients with HDP to achieve more sufficient evidence on this issue.A total of 21 studies were identified with more than 6.5 million participants, including 31,027 ASD probands. A comparative meta-analysis established that offspring born premature to HDP were significantly associated with ASD than matched controls . Subgroup analysis of clinical classification include: (1) gestational hypertension, (2) pre-eclampsia, (3) chronic hypertension complicating pregnancy (CHP). The offspring of mothers with pre-eclampsia and CHP have slightly higher risk  of ASD than those of mothers with gestational hypertension (OR = 1.37). In consistence with most previous researches, higher ASD prevalence was observed in male than female (OR = 1.38), indicating a potential role for gender in the pathophysiology of ASD.We conducted a systematic literature search on PubMed, EMBASE, Web of Science, PsycINFO database and China National Knowledge Infrastructure up to Jun. 2017. Statistical analysis was performed using Stata 10.0.This meta-analysis implies a possible link between HDP and the risk of ASD in offspring. However, further investigation should be conducted to confirm this conclusion, and intensive prenatal surveillance and early prediction for ASD is needed. Autism spectrum disorders (ASD) is a neurodevelopmental syndrome characterized by various degrees of social impairment, deficits in language and communication, and repetitive patterns of behavior , 2, but Hypertensive disorders of pregnancy (HDP) is a complex multisystem disorder, encompassing (1) gestational hypertension, (2) chronic hypertension complicating pregnancy (CHP), (3) pre-eclampsia and eclampsia , which cAlthough a number of clinical studies –38 have This meta-analysis was conducted following the guidance provided in the Cochrane Handbook and was reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines .We performed a systematic electronic search in all available literature until Jun. 2017 on PubMed, EMBASE, Web of Science, PsycINFO database and China National Knowledge Infrastructure. We searched with the terms: “preeclampsia”, “HDP”, “hypertensive disorders of pregnancy”, “hypertensive disorders in pregnancy”, “hypertensive disorders complicating pregnancy”, “pregnancy hypertension”, “PIH”, “pregnancy induced hypertension”, “gestational hypertension”, “gravid hypertension”, “gravidic hypertension”, “ASD”, “autism spectrum disorder”, “autism”, “autistic disorder”, “pervasive development disorders”, “children”, “childhood”, “infantile”. Searches were limited to human articles published in the English or Chinese. Two investigators inspected the titles and abstracts of citations and obtained the full texts. The search strategies are summarized in Figure Studies were eligible if they: (i) were case–control studies, prospective studies, or RCTs; (ii) evaluated the association between HDP and ASD in offspring; (iii) presented relative risk (RR) or odds ratio (OR) estimates with 95% confidence intervals (CI) or necessary data for determination. Studies were excluded if they were (a) review articles, case reports, experimental studies, conference abstracts, animal studies or letters; (b) unpublished data; (c) lacked essential data for the pooled calculation. Two reviewers independently evaluated titles and abstracts of the identified articles and subsequently excluded those that were irrelevant.A pair of investigators independently carried out the data extraction. Disagreements were resolved by discussion, with input from other investigators. Data extracted from each study included: the first author’s last name, year of publication, study location, study design, characteristics of study population , number of ASD participants with or without HDP, effect sizes of the associations, covariates adjusted for in the analysis; diagnostic criteria of HDP and scoring of Newcastle-Ottawa Quality Assessment Scale (NOS).Quality evaluation of each included study was performed utilizing the Newcastle–Ottawa Scale (NOS) . The ass2 method [P value for chi-squared test was less than 0.10 or I2 was more than 50%, there was obvious heterogeneity among those included studies, and random-effect model was used to pool data. If there was no obvious heterogeneity among those included studies, a fixed-effect model was used to pool data. Subgroup analyses were stratified by clinical classification of HDP, maternal age, perinatal complications (preterm birth and premature rupture of membranes), maternal education, geographic area and gender of participants. Sensitivity analysis was performed by omitting one study by turns to test the changes of pooled ORs. Potential risk of publication bias was estimated by inspection of funnel plot. Publication bias was also assessed by Egger’s test [Stata version 12  was used for statistical analyses. Pooled odds ratios (OR) with 95% confidence intervals (CIs) between HDP and ASD were used to estimate effect sizes. The heterogeneity was assessed using both chi-squared test and I2 method . When P r’s test .Detailed search procedures are summarized in Figure All 21 eligible studies were assessed for quality according to the NOS. The quality of them varied from 5 to 8, with a mean of 6.57 .After summarizing estimates from all available studies, there was a significant association between HDP and incidence of ASD  , maternal education, geographic area and gender of participants. Results of subgroup meta-analyses are summarized in Table p = 0.441) and Egger’s test (p = 0.806) all suggested that there was not a possibility of publication biases that would influence the stability of the results.Sensitivity analysis performed by omitting one study by turns showed all the pooled ORs were statistically significant Figure . In addiCurrently, accumulating studies were performed to evaluate the relationship between pregnant complications and child neurodevelopmental disorders based on populations. A previous meta-analysis  conducteThere is increasing evidence that maternal immune activation (MIA) is associated with a wide array of neurologic and psychiatric disorders , 45. It A meta-analysis  performeThe strength of our meta-analysis, firstly, lies in its large sample size and comprehensive subgroup analysis, which allows a detailed examination of this association by stratifying the data according to clinical classification of HDP, maternal age, perinatal complications , maternal education, geographic area and gender of participants. Secondly, this study provides clinical evidence for the association between HDP and ASD in offspring, indicating that HDP may confer vulnerability to the fetal neurodevelopment. More clinical investigations are necessary to deeply investigate the mechanism, in the hope of illustrating the etiology of ASD and generating new therapies. Thirdly, the results from our sensitivity analyses suggest that our main results were credible to inclusion of studies and were not driven by a single study. There was insufficient statistical evidence of publication bias based on Egger’s test. However, this meta-analysis also has some inherent limitations warranting discussion. First, blood pressure grade of HDP and drug treatment have been seldom mentioned in the included studies. Hence, the between-study heterogeneity of blood pressure or treatment strategy could be potential confounders precluding rigorous evaluation. Second, the pooled estimates were originated from 12 case-control, 7 retrospective cohort and only 2 prospective studies. The NOS scores of included studies range from 5 to 8, with a mean of 6.57, indicating moderate quality according to NOS scale . There is a compelling need for larger-size, multi-center and higher-quality prospective studies with unified criteria to obtain more persuasive conclusions. Finally, our meta-analysis is not suitable for worldwide generalizability due to the geographic restriction of the selected studies, which were mostly comprised of participants from America or Europe. Future clinical investigations performed in other regions are highly needed.In summary, the present comprehensive meta-analysis suggests that intrauterine exposure to hypertensive disorders during pregnancy might be a risk factor for ASD in offspring. Identifying the infants most at risk for ASD is crucial to allow for preventative interventions from birth . One int


Non-syndromic cleft lip with or without palate (NSCL/P) is a common congenital malformation worldwide, with complex etiology. It has been proposed that interaction of genes and environmental factors play a role in the predisposition to this disease.The aim of this study was to examine the association between AXIN2 (axis inhibition protein 2) rs7224837, BMP4 (bone morphogenetic protein 4) rs17563, and IRF6 (interferon regulatory factor 6) rs861019 and 2235371 polymorphisms and NSCL/P in an Iranian population.This case-control study was carried out on 132 unrelated NSCL/P patients and 156 healthy subjects. The variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The findings suggest that BMP4 rs17563 polymorphism significantly decreased the risk of NSCL/P in codominant , dominant , recessive , overdominant , and allele  inheritance models. Our findings did not support an association between AXIN2 rs7224837 and IRF6 rs861019 polymorphism and risk/protection of NSCL/P. The IRF6 2235371 variant was not polymorphic in our population.The results indicate that the BMP4 rs17563 variant is likely to confer a protective effect against the occurrence of NSCL/P in a sample of the southeast Iranian population. The AXIN2 (axis inhibition protein 2) acts as a tumor suppressor gene in numerous cancers mapped at human chromosome 17q23-q24th embryonic day, demonstrating that the BMP signal pathway is critical for cell proliferation and fusion of oral and maxillofacial construction. The rs17563 (538T/C) functional polymorphism of the BMP4 gene is shown to be associated with risk of NSCL/P development Bone morphogenetic proteins (BMPs) are secreted signaling molecules that belong to the transforming growth factor-b (TGF-b) superfamily of growth factors. The bone morphogenetic protein 4 (BMP4) gene is located at chromosome 14q22-23, contains four exons, and encodes the BMP4 protein,,The interferon regulatory factor 6 (IRF6) gene is located on chromosome 1q32.2. It has been shown that variants of the IRF6 gene increased the risk of NSCL/P as well as tooth agenesisGenetic risk factors for NSCL/P may be attributed to ethnic and environmental differences among various populations. Accordingly, repeating previously described genetic associations in different populations is required to define the associations of the genetic risk in each population. Therefore, this study aimed to evaluate the possible association among AXIN2 rs7224837, BMP4 rs17563, and IRF6 rs861019 and 2235371 polymorphisms and NSCL/P risk in a sample of the southeast Iranian population.-A total of 288 subjects, including 132 NSCL/P and 156 healthy subjects, were recruited for this case-control study. The criteria for participants with NSCL/P and healthy individuals were previously describedGenotyping of AXIN2, BMP4 and IRF6 variants was carried out using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The primers sequences and amplicon sizes are shown in All statistical analyses were performed using the SPSS 22.0 software. The associations between alleles or genotypes and NS-CL/P were assessed by computing the odds ratio (OR) and 95% confidence intervals (95%CI) from unconditional logistic regression analyses. P-values less than 0.05 were considered statistically significant.This study consisted of 132 NSCL/P  and 156 healthy individuals . Of the 132 patients, 52 had CL, 44 had CL with CP (CLP), and 36 had CP. There were no statistically significant differences between the groups regarding sex and age . Genotypic and allelic frequencies of AXIN2, BMP4 and IRF6 polymorphisms are shown in The findings revealed that BMP4 rs17563 polymorphism significantly decreased the risk of NSCL/P in codominant , dominant , recessive , and overdominant  inheritance models. The T allele significantly decreased the risk of NSCL/P , compared to the C allele.Our findings did not support an association between AXIN2 rs7224837 and IRF6 rs861019 polymorphisms and risk/protection of CL/P in any inheritance model tested . In addiWe also analyzed gene-gene interaction . In compWe also stratified the patients into cleft lip (CL), cleft lip with cleft palate (CLP), and cleft palate (CP) and assessed the impact of the polymorphisms and the risk of the disease by comparing with the controls . The finThe documentation of risk factors according to ethnicity and geographic origin is important for understanding the major causes of NSCL/P.-We have previously shown an association between FGF1 rs34010, CDH1 rs16260, MSX1 rs12532 and DHFR 19-bp insertion/deletion polymorphisms and NSCL/P in a sample of the southeast Iranian populationLetra, et al.Mijiti, et al.,Several previous studies have shown that BMP4 can be implicated in the development of CL/P. A meta-analysis performed by Hu, et al.,,,,,,The association of IRF6 rs2235371 polymorphism and NSCL/P has been extensively investigated, but the findings are still controversialThe inconsistent results may arise from different ethnic origins, environmental differences, and the complex genetic etiology of the NSCL/P disease.One of the limitations of this study is its relatively small sample sizes. Another limitation is that we evaluated limited variants of the AXIN2, BMP4, and IRF6. Other genetic variants of these genes should also be evaluated.In conclusion, we performed an association study of AXIN2, BMP4 and IRF6 gene SNPs with NSCL/P in an Iranian population and the findings proposed that BMP4 rs17563 polymorphism is associated with reduced risk against NSCL/P. Future studies with larger samples from different ethnicities are needed to confirm our findings.


P = 0.03, I2 = 66%), especially in Asian population . miR-146a G>C rs2910164 was a protective factor of urological cancers , especially for bladder cancer. miR-499 A>G rs3746444 was correlated with an increased risk of urological cancers, specifically in Asian population. In conclusion, our meta-analysis suggests that polymorphisms in microRNAs, miR-196a2, C>T rs11614913, miR-146a G>C rs2910164 and miR-499 A>G rs3746444, may be associated with the development of urological cancers and the risks mainly exist in Asian populations.Accumulating evidence has demonstrated that some single nucleotide polymorphisms (SNPs) existing in miRNAs correlate with the susceptibility to urological cancers. However, a clear consensus still not reached due to the limited statistical power in individual study. Thus, we concluded a meta-analysis to systematically evaluate the association between microRNA SNPs and urological cancer risk. Eligible studies were collected from PubMed, Embase, Web of Science, and CNKI databases. Pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to assess the strength of the relationships between three SNPs  and the risk of urological cancers. In addition, the stability of our analysis was evaluated by publication bias, sensitivity and heterogeneity analysis. Overall, a total of 17,019 subjects from 14 studies were included in this meta-analysis. We found that CT  was a risk factor for renal cell carcinoma (CT vs. CC: OR = 1.72, 95%CI = 1.05–2.80,  Urological cancers, which consist of prostate cancer (PCa), bladder cancer (BC), and renal cell cancer (RCC) are common malignancies with increasing incidence and mortality worldwide  are a group of small non-coding RNAs with ~22 nucleotides in length that play key roles in vital biological processes such as cell differentiation, metabolism, intracellular signaling, immunity, and cell movement Bartel, . Over thRecently, SNPs in miRNAs (miR-SNPs) have been confirmed to be associated with urological cancer risks in different studies  case-control design; (2) research on the association between polymorphisms in microRNAs and risk of urological cancer; (3) sufficient published genotype frequencies data to estimate the odds ratio (OR) and 95% confidence interval (CI). The exclusion criteria included: (1) the genotype frequencies data was unavailable; (2) animal model research; (3) review articles, case reports, meta-analysis; (4) overlapping publications (the studies with more subjects or recently published were included).There were two independent researchers (Ji and Luo) to extract the data from all included studies for analysis, including first author, year of publication, country, ethnicity (classified as either Asian or non-Asian), source of controls, number of different genotypes, Hardy-Weinberg equilibrium (HWE) for controls, genotyping method and cancer type. The third reviewer (Wang) joined the discussion if some discrepancies existed.The quality scoring criteria was modified from previous literatures and the score ranged from 0 point to 9 points Table . Two indI2 test were used to access the heterogeneity between different studies  was used. In contrast, ORs were calculated by the random effects model  with corresponding 95% confidence intervals (CIs) were served as effect size. For the miR-196a2 C>T (rs11614913) polymorphism, the allelic (T vs. C), heterozygous (CT vs. CC), homozygous (TT vs. CC), dominant (CT+TT vs. CC) and recessive (TT vs. CC+CT) genetic models were used to obtain pooled ORs. These models were also applied to assess the miR-146a G>C (rs2910164), and miR-499 A>G (rs3746444) polymorphisms. The subgroup analysis was performed according to cancer type, ethnicity, source of controls and HWE status of controls. The Cochran's Q statistic and Higgins, . HeterogIn the beginning, a total of 589 relevant publications was identified after a systematic literature search using our search strategy Figure . 571 of P = 0.03 I2 = 66%). However, miR-196a2 rs11614913 C>T showed no significant correlation with risks in prostate cancer and bladder cancer. In ethnicity subgroup analysis, significantly increased cancer risks were observed in Asian populations for allele genetic model . For subgroup analysis based on source of controls and HWE status of controls, no significant association was found. Sensitivity analysis showed that none of the studies leaded to change the global ORs, indicating the robustness and stable of the results in this meta-analysis. Begg's funnel plot and Egger's test showed that no obvious publication bias existed in the eligible literatures .There were 11 eligible studies with 2,511 cases and 2,992 controls that focused on the association of miR-196a2 rs11614913 C>T and urological cancer risks. Overall, no significant association was revealed in the pooled results under any genetic model statistically. Table P < 0.01, I2 = 0%; GC vs. GG: OR = 0.81, 95%CI = 0.73–0.90, P < 0.01, I2 = 0%; CC vs. GG: OR = 0.73, 95%CI = 0.63–0.85, P < 0.01, I2 = 0%; CC+GC vs. GG: OR = 0.80, 95%CI = 0.72–0.88, P < 0.01, I2 = 0%; CC vs. GC+GG: OR = 0.87, 95%CI = 0.77–0.98, P = 0.02, I2 = 0%, Figure P < 0.01, I2 = 0%; GC vs. GG: OR = 0.78, 95%CI = 0.68–0.89, P < 0.01, I2 = 0%; CC vs. GG: OR = 0.72, 95%CI = 0.59–0.87, P < 0.01, I2 = 0%; CC+GC vs. GG: OR = 0.77, 95%CI = 0.68–0.88, P < 0.01, I2 = 5%, Figure P < 0.01, I2 = 0%; GC vs. GG: OR = 0.76, 95%CI = 0.66–0.86, P < 0.01, I2 = 0%; CC vs. GG: OR = 0.69, 95%CI = 0.59–0.82, P < 0.01, I2 = 0%; CC+GC vs. GG: OR = 0.74, 95%CI = 0.65–0.83, P < 0.01, I2 = 0%; CC vs. GC+GG: OR = 0.85, 95%CI = 0.75–0.97, P = 0.01, I2 = 0%, Figure P = 0.08; GC vs. GG: P = 0.59; CC vs. GG: P = 0.07; CC+GC vs. GG: P = 0.54; CC vs. GC+GG: P = 0.18; Figure A total of 11 eligible studies, consisting of 3,943 cases and 4,321 controls focused on miR-146a rs2910164 G>C. The overall OR with its 95% CI revealed a significantly reduced risk of urological cancers in all the five genetic models . The pooled ORs did not display any change with sensitivity analysis. Publication bias was not conducted because of the small number of studies (<10) focused on miR-499 rs3746444 A>G polymorphism.For miR-499 rs3746444 A>G polymorphism, seven studies that focused on the association of miR-499 rs3746444 A> G polymorphism and urological cancer risk involving 1,473 cases and 1,779 controls were pooled into the meta-analysis. Significant association was found in two genetic models  which were considered to have certain correlation to cancer risk by pooled results from 29 eligible case-control studies including 7,927 cases and 9,092 controls. The results demonstrated that miR-146a rs2910164 G>C was a significantly reduced urological cancer risk, especially for bladder cancer, which is in agreement with the work conducted by Ma et al. . It has To our knowledge, it was the first quantitative study focused on the association between microRNA polymorphisms and urological cancer risk specially to date. The strengths our study are listed as follows: first, most of the genotype distributions in controls were consistent with HWE. Second, the relationship was analyzed by using five kinds of genetic models, and the results were statistically significant. Third, the methodological issues for meta-analysis, such as Egger's test, Begg's funnel plots and subgroup analysis were performed to ensure the stability of the results.However, we also pay attention to the limitations in our meta-analysis. Firstly, the small sample size of studies included was still inadequate, so that the statistical power was reduced. Secondly, the effects of combination genetic and environmental factors could not be taken into account because accurate individual information was not available. Thirdly, there might exist publication bias because of the inclusion of published articles only. Finally, the diversity of genotyping methods could partly bring about the change of analyzed results.In conclusion, the data of our meta-analysis indicate that the miR-146a rs2910164 C allele is a protective gene mutation for urological cancer, especially for bladder cancer in Asian. miR-499 rs3746444 polymorphisms may contribute to increased susceptibility of urological cancer. However, miR-196a2 rs11614913 only serve as a risk factor for renal cell carcinoma in particular in Asian populations. Further multi-centric investigation still need to confirm the relationship of these polymorphisms in microRNAs and urological cancer susceptibility.FW, C-HY, and YW conceived the study. YW, JJ, CL, and C-QY searched the databases and extracted the data. YW, HH, and HC analyzed the data. YW wrote the draft of the paper. FW and C-HY reviewed the manuscript. All the authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Migraine is a recurrent headache disease related to genetic variants. The brain-derived neurotrophic factor (BDNF) gene rs6265  and rs2049046 polymorphism has been found to be associated with migraine. However, their roles in this disorder are not well established. Then we conduct this meta-analysis to address this issue.PubMed, Web of Science and Cochrane databases were systematically searched to identify all relevant studies. Odds ratio (OR) with corresponding 95% confidence interval (CI) was used to estimate the strength of association between BDNF gene rs6265 and rs2049046 polymorphism and migraine.p = 0.03), recessive model  and additive model , respectively. We also found significant association between rs2049046(A/T) polymorphism and migraine in allele model , recessive model  and additive model , respectively.Four studies with 1598 cases and 1585 controls, fulfilling the inclusion criteria were included in our meta-analysis. Overall data showed significant association between rs6265 polymorphism and migraine in allele model (OR = 0.86, 95%CI: 0.76–0.99, Our meta-analysis suggested that BDNF rs6265 and rs2049046 polymorphism were associated with common migraine in Caucasian population. Further studies are awaited to update this finding in Asian population and other types of migraine. PrevThe Val66Met (rs6265) polymorphism is the most common and studied variant of BDNF gene. It can disrupt the release of mature BNDF and contribute to migraine. Meanwhile, the rs2049046 polymorphism was also found to be associated with migraine. It may influence the transcription of BDNF gene to induce migraine .The association between BDNF gene variant and migraine attracts more and more attention in recent years. However, their roles among the disorder sufferers are still not well established –12. ThenThe literature search was performed in October 2016 without restriction of language, region and publication type. PubMed, Web of Science and Cochrane databases were systematically searched to identify all relevant studies. The following terms and their combinations were searched in title and/or abstract: BDNF, brain-derived neurotrophic factor, polymorphism, migraine and headache. The reference lists of included studies and review articles were manually searched to find relevant studies. The search was conducted independently by two of the authors (Cai and Shi). If the same group of participants was studied for more than one times, the latest publication was included.Studies investigating the association between BNDF polymorphism and migraine were evaluated. The following inclusion criteria were applied to select eligible studies: (1) independent case–control study evaluated the association between BDNF polymorphism and migraine; (2) BDNF rs6265 (G/A) polymorphism and/or rs2049046 (A/T) polymorphism were evaluated; (3) migraine diagnosis should met the International Headache Society (IHS) criteria; (4) Hardy-Weinberg equilibrium (HWE) must be performed; (5) genotype data of cases and controls must be available. Exclusion criteria were as follows: (1) no controls; (2) reviews, comments and animal studies.Data from included studies was extracted and summarized independently by two of the authors (Cai and Shi). Any disagreement was resolved by discussion and reexamination. The following information was extracted prospectively: first author, publish year, country, ethnicity, age, sex, number of cases and controls, frequency of available genotype, genotype method and Hardy-Weinberg equilibrium (HWE) evidence in controls.The quality of included studies was evaluated independently through the Newcastle-Ottawa scale (NOS) by two of the authors (Cai and Shi). NOS is composed of eight assessment items for quality appraisal, with score ranging from 0–9 . Accordi2 test [p < 0.1 in Q test or I2 > 50%. If there was heterogeneity among studies, random-effects model (DerSimonian Laird method) was applied to calculate the summary OR, otherwise, the fixed-effects model (Mantel-Haenszel method) was used [p < 0.05 was considered significant.The strength of the association between BDNF genetic polymorphism and migraine was calculated using odds ratio (OR), with corresponding 95% confidence interval (CI). BDNF rs6265 (G/A) polymorphism and rs2049046 (A/T) polymorphism were evaluated separately in the allele model, dominant model, recessive model and additive model. Heterogeneity among studies was examined through Chi squared-based Q-test and I2 test , 15. Thewas used . The Z-tOne-way sensitivity analysis was performed to evaluate the influence of a single study on the overall result. Begg’s test and Egger’s test were applied to assess publication bias , 18. AllA total of 89 studies were identified through searching in PubMed, Web of Science and Cochrane databases. Four studies with 1598 cases and 1585 controls fulfilling the predefined inclusion criteria were included in the current meta-analysis  polymorphism and migraine were shown in Tables p = 0.03), recessive model  and additive model . The association was not significant in dominant model  or additive model   polymorphism and migraine were in Tables p = 0.02), recessive model  and additive model . No significant association was revealed in dominant model  (Table The data indicated significant association between rs2049046 (A/T) polymorphism and migraine in allele model .In the sensitivity analysis, there was no change of statistical significance in our analysis when any single study was omitted. Both Begg’s test and Egger’s test indicated that there was no publication bias in our meta-analysis  and rs2049046 (A/T) polymorphism were associated with migraine in Caucasian population.BDNF, which is associated with the pathogenesis of migraine, shares a wide distribution in central nervous system, such as hippocampus, amygdala, and hypothalamus. It can modulate synaptic plasticity, neurogenesis, neural growth and differentiation . This moThe rs6265 polymorphism is a G to A single nucleotide polymorphism (SNP) of BDNF gene at nucleotide 196. It is located in the 5’ pro-protein region of BDNF, resulting in the replacement of the Val66 in the pro-BDNF sequence with a Met. Previous eQTL (expression quantitative trait locus) study has confirmed the association between BDNF Val66Met variant and mRNA level in whole peripheral blood in European . SubjectThe rs2049046 polymorphism is located at 5’ end of the BDNF gene, upstream to a region that contains obesity-associated SNPs . It may The studies included were all moderate-high quality, providing a reliable basis for the current analysis. No relative case–control studies were excluded from our analysis. No evidence of public bias was detected in our meta-analysis and the heterogeneity between different studies was insignificant. However, the number of studies included in our meta-analysis was limited. Meanwhile, all the cases were from Caucasian population, and the G allele frequency of BDNF gene rs6265 polymorphism was found to be different between Caucasian (80%) and Asian (56%) population, making our results be unappropriated for Asian countries . Future −7), leading to the lack of statistical power of BDNF gene. As a candidate-gene association study, our hypothesis arose from the positive association between BDNF and migraine revealed in previous clinical researches. This connection strengthened the reliability of our results. Up to now, with large sample sizes used to analysis, only a small number of susceptible genes has been found to be associated with migraine [So far, several Genome-Wide Association Studies (GWAS) have been perform to evaluate the susceptibility loci of migraine –37. Howemigraine . Thus caIn conclusion, our meta-analysis suggested that BDNF rs6265 and rs2049046 polymorphism were associated with common migraine in Caucasian population. And it requires further studies to evaluate the association of BDNF rs6265 and rs2049046 polymorphism with migraine in Asian population and other types of migraine.


Therefore, we performed this meta-analysis to obtain a more precise estimation between MDM2 SNP285 polymorphism and risk of cancer. A systematic literature search was performed using the PubMed, Embase, and Chinese Biomedical (CBM) databases. Ultimately, 16 published studies comprising 14,573 cases and 9,115 controls were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of associations. Overall, MDM2 SNP285 polymorphism was significantly associated with a decreased overall cancer risk with the heterozygous model , and reduced ORs were observed with other genetic models  but not reaching statistical significance. Stratification analysis indicated a decreased risk for ovarian cancer, Caucasians, and studies with relatively large sample size. Despite some limitations, this meta-analysis indicated that the MDM2 SNP285 polymorphism was associated with a decreased cancer risk, which warrants further validation in large and well-designed studies. The Elev protein , 10, whi protein . Therefo MDM2 intronic promoter (P2): SNP309 (rs2279744 T>G) [ MDM2 promoter in comparison with the SNP285G allele [ MDM2 SNP285 in different types of cancers [ MDM2 SNP285 polymorphism and cancer risk.Two functional SNPs have been discovered which are located in the744 T>G)  and SNP2744 T>G)  located 744 T>G) . In contG allele . AlthougG allele , there a cancers –22. One MDM2 or mouse double minute 2”, “variant or polymorphism or variation”, and “cancer or carcinoma or tumor or neoplasm” . We also checked all references of relevant reviews and eligible articles for additional studies. Only the latest or the largest study would be included in the current meta-analysis if studies were carried out with the same or overlapped subjects.We systematically searched all relevant articles from PubMed, Embase, and Chinese Biomedical (CBM) databases using the search terms: “ MDM2 SNP285 polymorphism and cancer risk; (b) case-control design; (c) written in English or Chinese; (d) providing sufficient data to calculate odds ratios (ORs) with corresponding 95% confidence intervals (CIs).Studies included in the meta-analysis had to meet the following criteria: (a) evaluating the association betweenThe following exclusion criteria were used: (a) case-only studies or case reports; (b) conference abstracts, reviews, or meta-analysis; (c) duplicate publications; and (d) no available data reported.Two authors (Ping Wang and Meilin Wang) independently extracted data from all the publications according to the inclusion and exclusion criteria. Disagreements were resolved through discussion until a consensus was reached. The following information was extracted from each study: first author's surname, year of publication, country of origin, ethnicity, cancer type, control source, total number of cases and controls, genotype methods, and numbers of cases and controls with the GG, GC, and CC genotypes. Ethnic backgrounds were categorized as Caucasians, Africans, or Mixed which contained more than one ethnic group. MDM2 polymorphism and cancer risk. The pooled ORs were estimated for MDM2 SNP285 polymorphism under the dominant model (CC+GC versus GG), heterozygous model (GC versus GG), and allele comparison (C versus G). Chi-square-based Q test was used to assess the heterogeneity between studies, and P < 0.10 was considered as significant heterogeneity exists. The fixed-effects model (the Mantel-Haenszel method) [P values were two-sided, and a P < 0.05 was considered as statistically significant.Crude ORs and their corresponding 95% CIs were used to evaluate the strength of associations between method)  was used method)  would be method) . The asy method) . Subgrou method) . All theAs shown in For those studies , 16, 21  MDM2 SNP285 polymorphism and cancer risk are shown in The overall results for the MDM2 SNP285 polymorphism and risk of cancer under the dominant model (P = 0.043) and allele comparison (P = 0.014), but not under the heterozygous model (P = 0.120). Hence, we used the random-effects model to generate wider CIs. Finally, leave-one-out sensitivity analysis indicated that no single study could alter the pooled ORs obviously (data not shown).Substantial heterogeneities were observed for theP = 0.939; heterozygous model: P = 0.997; and allele comparison: P = 0.886). These suggested that publication bias might not have severe influence on the results of the current meta-analysis on the association between MDM2 SNP285 polymorphism and cancer risk.The shape of the funnel plot seemed symmetry for the SNP285 polymorphism  and no s MDM2 SNP285 polymorphism and cancer risk has been investigated by several research groups, but the conclusions were inconsistent. The most possible reason for the differences between studies is the small sample size in individual studies, which limits the statistical power to detect the real effects of polymorphism. We performed the current meta-analysis to combine the results of all available studies through a systematic search of relevant literatures, which may be useful for evaluating the contribution of SNP285 polymorphism to cancer. In this meta-analysis, which included 16 published studies of 14,573 cases and 9,115 controls, we found that MDM2 SNP285 polymorphism was significantly associated with a decreased overall cancer risk in the heterozygous model. Furthermore, the subgroup analysis showed that the association was more evident in the studies of ovarian cancer, Caucasians subjects, and relatively large sample size.The association between MDM2 gene could potentially dysregulated both transcription and translation.MDM2 encodes a protein that binds to and facilitates the degradation of the p53 tumor suppressor protein via the ubiquitination pathway , 33. The MDM2 SNP285G>C is a newly discovered polymorphism, and this is the first report on the association of this polymorphism and cancer risk. It has been suggested that the MDM2 SNP285C allele might reduce the risk of female cancers , due to the estrogen receptor (ESR) reported to be as a transcriptional activator with Sp1 [ MDM2 P2 promoter overlapped with the Sp1 binding site harboring SNP285 [ MDM2 SNP285 polymorphism and ovarian cancer, and a much lower OR was found for breast cancer than that for male cancers (lung and prostate cancer), which was consistent with previous studies.Thewith Sp1  and one g SNP285 . In the  MDM2 SNP285 polymorphism with cancer susceptibility and the total sample size was relatively small, which may lead to relatively weak power to detect the real association. Secondly, only published studies were included in this meta-analysis. It may be possible that some related unpublished studies as well as literatures published in languages other than English and Chinese were not included, which might lead to a bias to some extent. Thirdly, in the subgroup analysis, only one study was carried out in Africans. This subgroup did not have enough statistical power for us to investigate the real relationship. Fourthly, genotyping methods were different in each study, which will affect the bias. Additionally, our results were based on unadjusted estimates of ORs without adjustment for individual's age, sex, smoking status, drinking status, environmental factors, and other lifestyles.There are some limitations in our meta-analysis that remain to be addressed. Firstly, there is a limited number of studies that have actually analysed MDM2 SNP285 polymorphism was significantly associated with a decreased overall cancer risk with the heterozygous model. However, large and well-designed studies are warranted to validate our finding. Moreover, further studies estimating the effect of gene-gene and gene-environment interactions may provide a better, comprehensive understanding of the association between MDM2 SNP285 polymorphism and cancer risk.In summary, this meta-analysis suggests that


P < 0.001) and disease free survival (DFS)  but not disease specific survival (DSS)  of HNSCC patients. Subgroup analysis indicted that high expression of CD133 , Oct-4 and Nanog  could predict poor OS in HNSCC patients respectively whereas overexpression of Bmi-1 was not related to the reduced OS in HNSCC patients . Therefore, we concluded that CSC markers, especially CD133, Nanog and Oct-4, might be predictive factors in HNSCC patients.Bmi-1, CD133, Nanog and Oct-4 have been reported as cancer stem cell (CSC) markers in head and neck squamous cell carcinoma (HNSCC). However, the prognostic value of them in HNSCC remains controversial. Hence, this meta-analysis was conducted to access the association between the four CSC markers and survival outcome of HNSCC patients. A total of 22 articles with 27 studies met the inclusion criteria and the combined hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated. Data analysis showed that high expression of CSC markers was associated with poor overall survival (OS) (HR = 1.93; 95% CI: 1.46–2.55,  Head and neck squamous cell carcinoma (HNSCC) is the most common histological type of head and neck cancer which is the sixth leading cancer by incidence worldwide, leading to more than 200,000 deaths annually13Accumulated evidence suggests that cancer stem cells (CSCs) may played an important role in the progression and prognosis of cancers, including HNSCC781011In the present study, we collected the available literatures and conducted this meta-analysis to combine the evidence of CSC markers  in patients with HNSCC, in order to address controversial issues.The literature selection process of the eligible studies was presented in 131415161718192021222324252627282930313233P < 0.001) although with heterogeneity . However, there was obvious heterogeneity  without obvious heterogeneity , Oct-4  and Nanog  except Bmi-1. Interestingly, poor DSS in patients was significantly associated with high expression of Bmi-1 . There were consistent findings in Asian  and Caucasian  between CSC markers and OS. However, overexpression of CSC markers did not predict poor DSS in Asians . According to the subgroup analysis of tumor location, poor OS was related to CSC markers in oral/oropharyngeal squamous cell carcinoma (OSCC) , laryngeal squamous cell carcinoma (LSCC)  and nasopharyngeal carcinoma (NEPC)  without esophageal squamous cell carcinoma (ESCC) . When it comes to the sample size, there was no significance between CSC markers and poor OS in large sample size  but in small sample size .Subgroup analysis stratified by different CSC markers, ethnicity, sample size and tumor location were performed to detect the potential source of heterogeneity . AccordiP = 0.06, I2 = 62, Ph = 0.03), LSCC and OS , and NPEC and OS , which was shown to be no significance.Seventeen studies13141517181920212223242526282930P = 0.120; Egger’s test: P = 0.500).We performed a Begg’s funnel plot with using Begg’s test and Egger’s test to assess the publication bias of the included studies of OS. As showed in This meta-analysis of 27 studies including 2143 patients assessing the prognostic value of 4 CSC markers in HNSCC showed that a high expression level of CSC markers was a promising prognostic factor for lower DFS and OS in HNSCC patients. However, the expression of CSC markers had no obvious influence on DSS of HNSCC patients. According to the current results, CSC markers may play an important role in the relapse of HNSCC rather than death from HNSCC. However, considering that the sample sizes about DSS and DFS are relatively limited, our results need to be cautiously interpreted.2 = 0%, Ph = 0.47). It is worth noting that there was high heterogeneity between OS and HNSCC . We tried to find what caused this. When we ruled out the study of Chen 2013Bmi-1 was related to multiple human cancers which played an indispensable role in maintaining the self-renewal ability of both normal and malignant cancer stem cells. It has been reported that high expression of Bmi-1 could significantly lead to a poor OS in gastric cancer patientsCD133, also named prominin-1, has been verified to be a CSC marker in many cancers. Previous meta-analyses showed that high expression of CD133 was responsible for the reduced OS of ovarian cancer, gastric cancer, non-small cell lung cancer and hepatocellular carcinoma patients373839et al.Nanog and Oct-4, also known as embryonic stem cells markers, both have the ability in maintaining the self-renewal capacity in embryonic stem cells41P < 0.001, I2 = 10, Ph = 0.34) if we discarded the study of Chen 2013In the subgroup analysis of tumor location, poor OS was related to CSC markers in OSCC, LSCC and NEPC except ESCC. Interestingly, when we tried to find the origin of the heterogeneity in CSC markers and ESCC, we found that, as same as the result of the association of Bmi-1 and OS, the heterogeneity was lower and the result was significantly changed .Considering the subgroup of ethnicity, the OS of the Asian and Caucasian was the same to the overall OS. The DSS of the Asian was consistent with the overall DSS while the DSS of the Caucasian was changed to be significant without heterogeneity. In the subgroup analysis of sample size, we used the median as the boundary because most of the sample size of our included studies were relatively small. As showed in This meta-analysis has the following limitations that must be taken into consideration. First, both the number of included studies about each CSC markers and the number of included HNSCC patients in each study are relatively small, which, to some extent, may reduce the power and precision of our subcategory analyses. Second, most of the included studies were conducted in Asian and a few studies were about the Caucasians but no studies were about the black populations, which may produce potential population selection bias. Third, nonuniform cut-off value defining high and low expression of CSC markers may impact the results of this meta-analysis. Despite these limitations, we provided a comprehensive analysis of the association between CSC markers and OS/DFS/DSS of HNSCC patients. To the best of our knowledge, this meta-analysis is the first to systematically assess the association of Bmi-1, Oct-4, Nanog and CD133 expression with survival outcome of HNSCC. So far, there are some meta-analyses showed that high expression of CSC markers, including ALDH1, CD44 and SOX2, could predict poor OS/DFS in head and neck cancer patients1011In summary, our meta-analysis revealed that high expression of CSC markers was significantly associated with poor OS and DFS but not DSS of HNSCC patients. However, because of certain limitations, different subgroup showed to some extent inconsistent results, which prompted future large-sample, well-designed with long-term follow-up to confirm and update the findings of this. Nevertheless, our study still gave some hints that CSC markers have prognostic value in HNSCC patients.The databases of PubMed, Web of Science, the Cochrane library and China National Knowledge Infrastructure (CNKI) were thoroughly searched until July, 2016 without language restriction. The search strategy was listed as follows: (CD133 OR Bmi-1 OR Oct-4 OR Nanog) and  AND (cancer* OR tumor* OR carcinoma* OR neoplasm*))). Two reviewers (F. Z. N and L. M. X) inspected all candidate articles independently. Discrepancies were resolved in consensus.The inclusion criteria were: 1) the diagnosis of HNSCC was made based on pathological examination; 2) the expression of CD133 or Bmi-1 or Oct-4 or Nanog with OS/DSS/DFS about HNSCC was reported; 3) HRs and 95% CIs were provided in text or sufficient data was provided for the calculation of HRs and 95% CIs; 4) articles published as original research. In order to avoid duplicate inclusion of data, we selected only the more recent or complete article when multiple reports described the same population.The exclusion criteria were:1) reviews, meeting abstracts, letters; 2) nonhuman studies; 3) sample size <50 patients.Two reviewers (C. X. B and W. J) independently extracted the following information from included studies: author, year of publication, study country, sample size, clinicopathological parameters, cut-off value of CD133 or Bmi-1 or Oct-4 or Nanog, survival data and the tumor location. Disagreements were resolved by discussion.Two reviewers (L. X. Y and W. H. F) independently assessed the quality of included studies by the NOSet al.2 statistic. Cochran Q test’ P value < 0.10 or I2 > 50% indicated large heterogeneity between studies and we used random effects models to calculate the pooled HR and 95% CI. Otherwise, the fixed effects model was used. We used the median as the boundary between the large and small sample size. Studies with sample size >72 were regarded as large sample size, otherwise was considered as small sample studies. Subgroup analyses stratified by different stem cell marker, ethnicity, sample size and tumor location were carried out. Sensitivity analysis were applied to high-quality studies (NOS > 6). The Begg’s funnel plots were used to evaluate publication bias. All statistical analysis were performed by using Review manager 5.3 software  and Stata 12.0 statistical software . A two-tailed P < 0.05 was considered statistically significant.Hazard ratio (HR) was used as a summary statistic for survival outcomes as described by Parmar How to cite this article: Fan, Z. et al. Prognostic Value of Cancer Stem Cell Markers in Head and Neck Squamous Cell Carcinoma: a Meta-analysis. Sci. Rep.7, 43008; doi: 10.1038/srep43008 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis.Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food ( Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide. According to the International Agency for Research on Cancer’s GLOBOCAN database, 1.1 million men were diagnosed with PCa in 2012, accounting for 15% of all cancers in men ,4,5. IndThis hypothesis has further been supported by four previous meta-analyses of epidemiological studies, all of which showed a protective association between soy consumption and PCa ,11,12,13This meta-analysis was conducted following PRISMA and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines ,17. StudWe conducted a thorough literature search of PubMed, Web of Science, and the Cochrane Library, using a combination of the following key words and their variants: prostate cancer, prostate neoplasm, soy, soymilk, soy milk, isoflavone, bean curd, tofu, soy protein, daidzein and genistein (up to 25 May 2017). The keyword search yielded a comprehensive list of titles and abstracts of articles that were screened for relevance against the listed study selection criteria. These screened articles were evaluated in full text for study inclusion. Finally, we conducted a reference list search  and works cited search  from the articles identified as meeting the inclusion criteria. The studies identified through this process were further assessed using the same inclusion criteria, with this process being repeated until all relevant articles were identified. Three authors  individually considered all articles obtained in full text for inclusion or exclusion, and any discrepancies were discussed and resolved. The following information was extricated from each article: name of first author; year of publication; location of study; study period; number of cases, controls and total number of participants in the study; age of participants; total years of follow-up; exposure values of soy (serum/plasma and/or intake); relative risk ratios for PCa; adjustments made for any covariates; and study type. The term RR (relative risk) will be used in this study as a general term to denote the following: relative odds (cumulative incidence data), rate ratio (incidence-rate data) and odds ratios . Study quality was examined using the Newcastle–Ottawa Scale, which is a validated scale used to assess the quality for case-control and non-randomized cohorts in a meta-analysis . This scI2 statistic [I2 result, as markers of study heterogeneity [I2 value of less than 50% (I2 < 50%) signified low-to-moderate heterogeneity between studies, so a fixed effect model was used to determine RR estimates. An I2 value of greater than or equal to 50% (I2 ≥ 50%) signified moderate-to-substantial heterogeneity between studies, so a random effects model was used to determine RR estimates. When results from fixed and random effects models were conflicting and studies showed moderate heterogeneity (I2 = 30–60%), we presented the latter as it represents a more conservative approach [STATA/IC version 14.2  was used to analyze the data. Because OR is nearly equivalent to RR when considering low incidence of diseases , RR and tatistic . Fixed aogeneity . An I2 vapproach ,22. p-value of less than 0.05 was considered statistically significant for all analyses.Because studies reported different exposure categories as tertiles, quartiles or quintiles, we used the study specific RR for the highest quantile of dietary soy intake and/or circulating (serum or plasma) isoflavone concentrations. Potential publication bias was assessed by using funnel plots ,24, EggeIn total, 3356 articles were identified from the library search engines. After removing duplicates and adding articles identified from reference lists, 2531 articles remained. Of the 2531 articles that were screened by abstract, 39 articles were found to contain potentially relevant information and were evaluated by full text review. Upon reviewing the full text articles for the aforementioned inclusion criteria, 30 articles were included in the final analysis ,55,56. OOf the 30 articles included for analysis, fifteen ,49,52,56Quality scores were assigned to each article using the criteria outlined by the Newcastle–Ottawa scales for case-control and cohort studies. The average score for case-control studies was 6.93 (standard deviation = 0.7); 6 was the lowest score and 8 was the highest score given. Cohort and NCC studies received an average score of 7.73 (standard deviation = 0.7); 6 was the lowest score and 9 was the highest score given. Individual quality assessment scores are provided in n = 16) [n = 11) [n = 8) [n = 10) [n = 10) [n = 6) [n = 5) [n = 3) [n = 2) [n = 1) [Twenty-four articles evaluated dietary soy and soy isoflavone intake and PCa risk. These articles were further divided into groups that analyzed risk pertaining to total soy (n = 16) ,47,49,52[n = 11) ,47,49,52 [n = 8) ,45,46,47[n = 10) ,45,48,55[n = 10) ,45,48,55 [n = 6) ,45,53,55 [n = 5) ,43,46,47 [n = 3) ,36,46, s [n = 2) ,49, and p < 0.001) (p = 0.300) nor Egger’s linear regression test (p = 0.052) for bias were significant. Heterogeneity amongst studies was analyzed using the I2 index to show high variation between studies (68.9%).Articles that reported soy intake as either a combination of multiple soy food items or as a single soy food item were classified as total soy intake. Sixteen articles reported the association between total soy intake and PCa risk. The pooled RR for this association was 0.71  A. Neithep < 0.001), and the pooled RR for fermented soy foods and risk of PCa was 0.86   nor Egger’s linear regression test  for bias were significant. The I2 index showed high heterogeneity amongst studies included in the unfermented (60.3%) and fermented (66.6%) groups.When selecting articles for evaluating the association between unfermented or fermented soy food intake and PCa risk, studies had to have explicitly stated which soy food items were being reported. Examples of commonly reported unfermented soy foods included soy milk, tofu and soybeans; fermented soy foods included miso and natto. The pooled RR for unfermented soy foods and risk of PCa was 0.65 , and the pooled RR for daidzein and risk of PCa was 0.84  , and Egger’s linear regression test was significant for both measurements . The I2 index showed moderate heterogeneity between studies included in the genistein (31.0%) and daidzein (50.5%) groups.Ten articles reported soy intake as a measurement based on the calculation of genistein and daidzein present in soy foods. The pooled RR for genistein and risk of PCa was 0.90  (p = 0.707) nor Egger’s linear regression test (p = 0.802) for bias were significant. The I2 index showed moderate heterogeneity between studies (44.9%). Notably, the inclusion of these studies in the total soy analysis did not significantly change the RR of dietary soy intake and PCa risk.Six articles reported isoflavone intake without disclosing the sources of the isoflavones. These studies were analyzed separately, so as not to interfere with measurements based solely on soy intake because isoflavones are found in other food items, such as seed sprouts and pulses. The pooled RR for isoflavone intake and PCa risk was 1.03  F. Neithep = 0.013), the pooled RR for miso and PCa risk was 1.01 , and the pooled RR for soy milk and PCa risk was 0.58 . None of the groups were significant for bias using Begg’s correlation test  or Egger’s linear regression test . The I2 index showed low heterogeneity amongst the studies included in the tofu (4.5%) and miso (0.0%) groups and high heterogeneity amongst studies included in the soy milk (63.1%) group.Finally, articles were further stratified into specific soy food groups, which included tofu, miso and soy milk. Few studies were available to accurately represent meta-analysis data on these points, so RR are reported here, but not included in further subgroup analyses. The pooled RR for tofu and PCa risk was 0.73  [n = 7) [n = 2) [p = 0.236) (p = 0.738). None of the studies were significant for bias using Begg’s correlation test  or Egger’s linear regression test . The I2 index showed high heterogeneity amongst the studies included in the circulating genistein (76.8%) and circulating daidzein (58.1%) groups and low heterogeneity amongst the circulating isoflavone group (0.0%). Funnel plots used to explore publication bias are shown in Nine articles measured circulating isoflavone concentrations and their associations with PCa risk. Specifically, these articles reported RR data for circulating genistein (n = 9) ,51,54,56 [n = 7) ,44,51,54 [n = 2) ,54. The = 0.236) A, the po= 0.236) B, and thp = 0.001) for case-control studies and a pooled RR of 0.90  for cohort and NCC studies. Studies conducted in both North America (p = 0.009) and Europe (p = 0.021) were significantly associated with a reduced PCa risk, whereas studies conducted in Asia (p = 0.064) were not. A complete subgroup analysis can be found in Articles reporting total soy intake and PCa risk had a pooled RR of 0.61  for case-control studies and a pooled RR of 0.91  for cohort studies. Studies were conducted in both North America (p = 0.014) and Asia (p = 0.005), and there was a significantly reduced risk of PCa in both continents. Studies of medium quality were significantly associated with a lower PCa risk (p < 0.001). Articles reporting unfermented soy food intake and PCa risk had a pooled RR of 0.55  for case-control studies and a pooled RR of 0.93  for cohort and NCC studies. Studies conducted in Asia (p = 0.004) showed a significantly reduced risk of PCa, while studies conducted in North America (p = 0.145) and Europe (p = 0.419) did not. Mid quality studies were significantly associated with a reduced risk of PCa (p = 0.007). The pooled RR for articles reporting dietary genistein intake and PCa risk was 0.81  for case-control studies and a pooled RR of 0.91  for cohort and NCC studies. Studies conducted in Asia (p = 0.012) showed a significantly reduced risk of PCa, while studies conducted in North America (p = 0.094) and Europe (p = 0.799) did not. High quality studies were significantly associated with a reduced risk of PCa (p = 0.042).The pooled RR for articles reporting dietary daidzein intake and PCa risk was 0.68  were significantly associated with a decreased risk of PCa, while studies conducted in Europe (p = 0.784) showed no significant association with circulating genistein levels and PCa risk. There was no significant association for case-control or NCC studies and risk of PCa for articles evaluating circulating levels of genistein. Only studies conducted in Asia  (p = 1.00) nor Egger’s linear regression test (p = 0.548) for bias were significant. The I2 index showed moderate heterogeneity between studies (45.7%). Funnel plots, used to explore publication bias, are shown in Seven ,45,50,53= 0.119) A. Neithen = 4) was 0.92 , the pooled RR for daidzein and PCa risk (n = 3) was 0.89 , and the pooled RR for total isoflavones and PCa risk (n = 2) was 0.91  , while there was substantially high heterogeneity between the studies reporting total isoflavone measurements (100.0%).When stratifying groups by combining dietary and circulating measurements of isoflavones, the pooled RR for genistein and PCa risk (= 0.337) B. The I2p < 0.001). This population-based evidence corroborates observations in both in vitro and in vivo studies, which have shown that soy isoflavones inhibit PCa development and growth [p = 0.008 and p = 0.018, respectively). These results support our finding that total soy food consumption is associated with decreased PCa risk, as genistein and daidzein are likely found in similar food products. This updated systematic review and meta-analysis provides a thorough evaluation regarding the association between soy food intake and PCa risk. Using the current pool of scientific literature, our results support the existing evidence, which indicates that total soy food intake is associated with a reduced risk of PCa , while fermented soy food products had no associations with PCa risk (p = 0.281). More studies provided food intake data for unfermented soy food products than fermented soy food products . While this meta-analysis failed to demonstrate a significant association between fermented foods and the risk of PCa, it should be recognized that there was wider variation in results reported by these studies than there was for studies using unfermented and other soy foods. This wider variation could have impacted the risk outcomes. Some concerns have been expressed in the literature regarding the effects of soy fermentation on the risk of developing certain cancers, such as gastric cancer [We also analyzed the potential relationship between unfermented or fermented soy food products and risk of PCa. We found that unfermented soy food products were associated with a decreased risk of PCa  despite the elevation of circulating genistein and daidzein levels after consumption of these isoflavones. However, peak circulating isoflavone levels can occur as soon as 30 min or as long as 6 h after feeding, depending on the specific isoflavones and foods consumed [Circulating levels of genistein and daidzein were not associated with the risk of PCa . While most dietary isoflavones are consumed from soy food products, examining the sources and types of isoflavones that were included in these analyses could provide insight as to why no association was observed. Notably, this analysis was based on the information found from a limited number of articles, so additional studies could strengthen these observations. No association was seen when we examined six articles that did not disclose the source of isoflavones measured from participants’ dietary intakes. For example, Bosetti et al. (2006) indicated that isoflavones were measured from the FFQ, primarily based on consumption of soy and soy products, but also from “vegetable or bean soups and pulses” . Becausep = 0.119) or dietary and circulating levels of genistein (p = 0.381), daidzein (p = 0.227), or total isoflavones (p = 0.337), perhaps due to the lack of studies. Two double-blinded, randomized, placebo-controlled clinical trials have supplemented isoflavones in men awaiting radical prostatectomy. One study reported higher apoptotic activity in tumors of men treated with isoflavones when compared to tumors of the men in the placebo group [To our knowledge, this is the first meta-analysis to investigate the risk associations between soy and advanced PCa. Advanced PCa is defined as poorly differentiated, aggressive, and metastatic disease. Advanced PCa is often difficult to treat, as patients are typically less responsive to therapy. It is therefore imperative to identify other ways to prevent disease progression, such as through dietary modification. Relatively few studies have examined the relationship between diet and advanced PCa or reported information pertaining to stage or grade of PCa. Our results do not show a significant reduction in the risk of advanced PCa with total soy intake . This result is consistent with the result shown by Hwang et al. (2009) [Few studies have analyzed individual soy foods and their relationships with PCa risk. Tofu was the most investigated soy food found in the literature. Tofu showed a significant protective association with PCa (. (2009) . More stp = 0.009) and Europe (p = 0.021), although only one study was included in the European group. However, when looking at the individual dietary isoflavones, genistein and daidzein, Asia was the only continent to show a significant risk reduction for PCa . Similarly, Asia was the only continent to show a significant association between circulating genistein and risk of PCa (p = 0.031). Both North America (p = 0.014) and Asia (p = 0.005) showed a reduced risk of PCa when only considering unfermented soy foods. The variability in these associations makes it difficult to draw conclusions about whether ethnic differences, preparation methods, or eating patterns exist in soy food or isoflavone consumption and PCa risk. The research design of studies did not seem to bias our results, as case-control and cohort studies both reported significant and null results. It is important to note that case-control studies are generally considered to have a higher risk of bias than cohort studies; however, significant measurement error can occur for both cohort and case-control studies when evaluating a single exposure variable. To accurately account for all reported estimates of soy exposure and PCa risk, both study designs were included in the analysis. To this end, sensitivity analyses conducted for each subgroup showed that no studies significantly altered results or heterogeneity within subgroups. Separating results by continent showed that total soy intake was only associated with a decreased risk of PCa in North America , body mass index (BMI), smoking, or energy intake. The subgroup analyses in this study attempted to account for these limitations by highlighting some of these differences between studies, to account for variability in data adjustments and selection bias created by study design .In addition to attempting to address these study limitations, our analysis delved deeper into potential confounding factors, through meta-regression, to determine whether study quality, length, or the sample size impacted significant results of the study. None of these factors were found to impact our results, and as such were not included in our results. We also reported both dietary intakes and circulating levels of isoflavones to create a more comprehensive review of the existing literature. Finally, we analyzed any associations between soy and advanced PCa, which has not previously been reported.As the second most commonly diagnosed cancer in men worldwide, it is important to identify modifiable factors, such as diet, that may impact the risk of developing PCa. The current study provides an updated systematic review and meta-analysis of the available literature describing the associations between soy food consumption and PCa risk. Of the four meta-analyses previously published, all showed that soy intake was associated with a reduced risk for PCa. Our study further enhances this association by including additional studies for analysis, grouping soy foods by type of food and by isoflavone intake, adding groups of circulating isoflavone concentrations, and by evaluating the potential relationship between soy food intake and advanced PCa risk.