Myeloperoxidase (MPO) is a metabolic/oxidative lysosomal enzyme secreted by reactive neutrophils at the sites of inflamed organs and tissues during phagocytosis. MPO has been either directly or indirectly linked to neoplasia, which is a well- established risk factor for many types of cancer. A large number of studies have reported the role of MPO G-463A polymorphism regarding breast-cancerrisk. However, the published findings are inconsistent. Therefore, we conducted a meta-analysis to determine more precise estimations for the relationship. Eligible studies were identified by searching several electronic databases for relevant reports published before June 2012. According to the inclusion criteria and exclusion criteria, a total of five eligible studies were included in the pooled analyses. When the five eligible studies concerning MPO G-463A polymorphism were pooled into this meta-analysis, there was no evidence found for a significant association between MPO G-463A polymorphismandbreast-cancerrisk in any genetic model. We also categorized by ethnicity (Caucasian or Asian) for subgroup analysis; according to this subgroup analysis, we found no significant association between MPO G-463A polymorphismandbreast-cancerrisk in any genetic model. However, in the stratified analysis for the premenopausal group, women carrying the AA genotype were found to have a significantly reduced risk (OR = 0.56, 95% CI 0.34–0.94, p = 0.027). Under the recessive model, there was a significant association between MPO G- 463A polymorphismandbreast-cancerrisk (OR = 0.57, 95% CI 0.34–0.93, p = 0.025). We conclude that MPO-G463A polymorphism might not be a good predictor of breast-cancerrisk, though menopausalstatus modified women’s risk of developing breastcancer.
Cao et al.  in 2011 showed that the MDM2 SNP309 polymorphism might be a risk factor for CRC, the variant genotype was associated with a significant increased CRC risk among the overall populations (GT vs. TT: OR=1.19, 95% CI=1.06–1.35) and Asians (GT vs. TT: OR=1.28, 95% CI=1.10–1.50). Another meta-analysis including 7 studies by Fang et al. , performed almost at the same time and quite similar in methods, drew opposite conclusion. The authors revealed that the MDM2 SNP309 polymorphism played a protective role in CRC susceptibility in Asians (GG vs. TT: OR = 0.51, 95% CI = 0.41–0.64; GG vs. TG: OR = 0.64, 95% CI = 0.53–0.78; GG+TG vs. TT: OR = 0.59, 95% CI = 0.49–0.71; GG vs. TG+TT: OR = 0.69, 95% CI = 0.57–0.82). The previous meta-analyses did not cover all eligible studies especially studies published in Chinese. Some studies were only indexed in the CBM database but not indexed in the databases selected in the meta-analyses by Cao et al. and Fang et al., which could lead to location bias and might bias the effect estimate of a meta-analysis. Furthermore, a number of new case–control studies have been published after these two meta-analyses. Hence, to provide the most comprehensive assessment of the associations between the MDM2 SNP309 polymorphism with CRC risk, we performed an updated meta-analysis of all available studies. The meta-analysis was carried out by critically reviewing 14 individual case–control studies on MDM2 SNP309 polymorphismand CRC risk. Subgroup analyses were mainly done by ethnicity, p53 mutation status, gender, and HWE in controls. Heterogeneity analysisand sensitivity analysis were also critically performed to ensure the epidemiological credibility of this meta-analysis. We found that the MDM2 SNP309 polymorphism was associated with an increased CRC risk among Asians (TG vs. TT: OR = 1.197, Table 2. Characteristics of studies included in this meta-analysis.
After an initial search, a total of 151 published articles relevant to the topic were identified from databases (PubMed, Embase, CBM and CNKI). With additional filters, 120 of these articles were excluded (26 for duplication of titles, 10 for not being case-control studies, five for an association with cancer treatment, 72 for irrelevance to gene polymorphisms andcancer, six reviews and one case-control study for overlapping data). After this step, 31 qualified and original papers fit the inclusion criteria. After a manual search of the bibliography lists from retrieved articles, another two articles were included (Figure 1). Afterwards, six case-control studies were excluded because the number of genotypes in the control group statistically deviated from HWE. Overall, 27 total case-control studies on the association between the STK15 F31I polymorphismandcancerrisk were recruited in this meta- analysis. Among the 27 case-control studies, ten investigated breastcancer [8,9,14-21], four investigated colorectal cancer [10,22-24], and three investigated esophageal cancer [11,25,26]. The other studies investigated gastric cancer, lung cancer, renal cell carcinoma, bladder cancer, glioblastoma, hepatocellular carcinoma, and ovarian cancer [27-36]. As for subjects in these studies, 11 were Asian [9,11,19-21,23,25-29] and 16 were Caucasian [8,10,14-18,22,24,30-36]. Characteristics of populations andcancer types in each individual study recruited in the meta-analysis are listed in Table 1. The distribution of the STK15 F31I polymorphismand allele among patients and controls is listed in Table 2. Results of the meta-analysis from different comparative genetic models are summarized in Table 3, Table 4, and Table 5.
A total of 22 articles were achieved by literature search from PubMed and EMBASE. As shown in Figure 1, 11 eligible studies were retrieved for detailed evaluation. We excluded four studies (two with duplicated results, one not focus on ADPRT Val762Ala and APE1 Asp148Glu, and one with lack of usable data). Finally, a total of 7 studies fulfilling the inclusion criteria were identified [15– 21]. In one of these studies, the genotype frequencies were presented separately according to Caucasian study and African- American study, and thus each study in the literature was considered separately for meta-analysis. Therefore, a total of 8 studies were included in the meta-analysis with 2521 cases and 2652 controls for ADPRT Val762Ala polymorphismand with 2539 cases and 2572 controls for APE1 Asp148Glu polymor- phism. The studies identified and their main characteristics are summarized in Table 1 and Table 2. All studies indicated that the distribution of genotypes in controls was in agreement with HWE and the minor allele frequencies (MAFs) were also calculated for the controls (all were greater than 0.05 except one group) (Tables 2).
The differences in demographic characteristics and common risk factors for breastcancer between the cases and controls were tested using the x 2 test (for categorical variables) or Student’s t-test (for continuous variables). Differences in fever frequency between cases and controls were tested using the Mann-Whitney U test. The Hardy–Weinberg equilibrium for IFN-c rs2069705 was evaluated using a goodness-of-fit x 2 test to compare the observed genotype frequency with the expected one among the controls. Multivariate logistic regression models were used to assess the effects of fever history and genotype on breastcancerrisk, controlling for age and for the potential risk factors of breastcancer (age, BMI, age at menarche, marital status, education, parity, menopausalstatus, and family history of breastcancer), which were defined categorically with the exception of age (Table 1). Models were fit using fever frequencies as categorical variable. For evaluating the dose-response association between fever frequency and the risk of breastcancer, tests for trends were performed by entering the categorical variables as continuous variables in the model. Stratified analyses for the associations between fever frequency, genotype, and the risk of breastcancer were performed by menopausalstatus, BMI, and clinical characteristics. The heterogeneity of the odds ratios between the different clinical characteristics levels was assessed using a multivariable logistic regression model restricted to cases (case-
DNA repair deregulation is a crucial factor in the multistep process of carcinogenesis, and the ERCC5 gene is a vital component of the DNA repair machinery. It has been observed that deficiency of ERCC5 may result in severe autosomal recessive diseases including XP, CS and TTD  characterized by solar hypersensitivity of the skin, high predisposition for developing cancers (mainly epithelial and melanoma) on areas exposed to sunlight. Furthermore, studies have suggested that ERCC5 SNPs are associated with development of some cancers, such as breastcancer  and smoking-related cancers [23,24]. These suggest a possible link between the ERCC5 function and development of cancer. The biological mechanisms of the ERCC5 gene in carcinogenesis may be complicated, among which nsSNPs, leading to an amino acid change in the protein product and modulating the individual DNA repair capacity phenotype [113,114], may account for some of the known genetic variations related to risk of cancers. However, our meta-analysis suggests that there is no statistical evidence for an association between the ERCC5 Asp1104His polymorphismand overall cancerrisk, which is consistent with the previous two meta-analyses conducted in breastcancerand melanoma, respectively. The former included some studies departure from HWE in the control population, and the latter only contained three studies. Although we excluded the inappropriate studies and expanded the sample size, the null results were not altered. Furthermore, as far as our knowledge is concerned, none of the SNPs in NER have ever been identified as susceptibility locus in the published genome-wide association studies (GWAS) for common diseases including cancers based on common SNPs, which are similar to our results. This is a challenge to the theory of common variants and common diseases . It is likely that, as NER genes are considered susceptibility genes, the role of NER variants in cancer development may be dependent on the degree of exposures that cause damage to DNA. Therefore, without detailed information about such exposures for further adjustment or stratification, the results of the observed associations may be either biased or masked. For example, XP patients can drastically reduce risk of developing skin cancer by avoiding exposure to sunlight. Another possibility is that the common
Methodology/Principal Findings: An electronic search was conducted of several databases, including PubMed, the Cochrane library, Web of Science, EMBASE, CBM and CNKI, for papers that describe the association between Fok1, poly-A repeat, Bsm1, Taq1 or Apa1 polymorphisms of the VDR gene andbreastcancerrisk. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effect model (FEM) or random-effect model (REM), depending on the absence or presence of significant heterogeneity. A total of 39 studies met the inclusion criteria. A meta-analysis of high- quality studies showed that the Fok1 polymorphism of the VDR gene was associated with an increased risk of breastcancer (ff vs. Ff+FF, OR: 1.09, 95%CI: 1.02 to 1.16, p = 0.007). No significant associations were observed between the other polymorphisms andbreastcancerrisk. No positive results were detected by pooling the results of all relevant studies.
The association between this polymorphismand the disease has already been studied by groups from several countries, without a direct relationship being established. An Indian study revealed that the frequency of T-allele of MMP- 9–1562 C/T promoter polymorphism was found to be pre- dominant in breastcancer group compared with controls, with a 1.44 folds increased risk for breastcancer. 19 Merdad et al 20 showed that MMP-9 is a reliable potential candidate diagnostic biomarker and drug target in breastcancer. An Iranian study, 18 published in 2015, found association be- tween higher risk of developing breastcancerand MMP-9 polymorphism, as the presence of mutant allele increased the susceptibility to the disease by 1.87 times (OR ¼ 1.87, IC95: 1.05–3.33, p ¼ 0.035). Similarly, a large meta-analy- sis, 7 also from 2015, showed an association between TT genotype of MMP-9–1562 C/T polymorphismand a higher risk for breastcancer. This result was in contrast to our study, which was supported by a South Brazilian research (p ¼ 0.23) 21 and a meta-analysis conducted by Zhou et al, 22 which involved more than 5,000 patients. Both studies found no evidence that the 1562 C/T polymorphism (rs3918242) is correlated with a higher risk for breastcancer. Several studies have described the role of MMPs in breastcancer progression and metastasis development, as MMPs are involved in the degradation of basement membranes. 23 In a meta-analysis 24 including more than 10,000 cancer cases, MMP-9 (1562 C/T) was shown to increase the risk of cancer metastasis, correlating the polymorphism with a more aggressive disease (OR ¼ 1.25, IC95: 1.03 - 1.51, p ¼ 0.07). Our results were inconsistent with this ﬁnding,
Genetic epidemiological studies have suggested the relation- ship between different SNPs and disease. However, robust statistical powers with genotype-phenotype investigation are essential to detect the mild, moderate or strong association with the disease. The progesterone hormone mediates its physiolog- ical function through the PgR, a steroid receptor of class I nuclear receptor super-family. Two different isoforms of PgR (PgRA and PgRB), which are transcribed from two different promoters of the same gene [31,32] are co-expressed in equal levels in normal mammary epithelial , ovarian  and endometrial cells . The relative expression of this two isoform is altered in malignant transformation. The PgR +331 G/A polymorphism in the promoter results in the introduction of a TATA box that selectively enhances the production of the PgRB isoform, causing an altered PgRA: PgRB protein ratio . The PgR +331 G/A promoter polymorphism has been extensively studied because of its relationship in different cancers such as breast, endometrial and ovarian cancer. However, the results from these studies were ambiguous. Apart from the PgR +331 G/A polymorphism, there are additional Meta-Analysis of +331G/A PgR andCancerRisk
Radiation-induced hemorrhagic cystitis may be acute or chronic, at doses >30 Gy in the whole bladder and doses >60 Gy in a portion of the bladder. Among 11 children aged 6 years or older treated for pelvic rhabdomyosarcoma, 7 were irradiated and presented with enuresis and abnormal bladder capacity. In another 40 patients with the same disease, 9 of the 19 irradiated patients had bladder problems; those receiving doses of 40 Gy had higher incidence of urinary symptoms, and everyone receiving doses >50 Gy had bladder complications. RT >50 Gy in the lumbar spine or sacrum resulted in damage to peripheral nerves leading to neurogenic bladder. (18)
In the Kaplan Meier method, an estimation of the survival function during time is analyzed by log-rank statistics and the fraction of patients surviving at each time after surgery and/or treatment is plotted (15, 16). In logistic regression, a statistical regression method is applied where the independent variable determines an outcome in which there are only two possible outcomes (alive or deceased; relapse, or no relapse). It was demonstrated that the predictive accuracy could be markedly enhanced by the application of logistic regression analysis, in comparison to conventional Kaplan Meier approaches, which are often based upon incomplete or greatly right-censored clinical data (17, 18). The Cox proportional hazards model is a statistical regression model that allows investigating the effect of several variables that may impact patient outcome and it assumes a constant risk of death/relapse during time, known as the hazard/odds ratio (19), in contrast to the Kaplan Meier estimator that assesses the impact of a single factor in a varying proportion of deceased/relapsed patients during time (16).
The association strength between ESR1 gene polymorphisms and prostate cancer susceptibility was measured by odds ratios (ORs) and 95% confidence intervals (CIs) under five genetic models: allele model (mutant [M] allele versus wild [W] allele), dominant model (WM+MM versus WW), recessive model (MM versus WW+WM), homozygous model (MM versus WW), and heterozygous model (MM versus WM). The statistical significance of the pooled OR was examined using the Z test. Between-study heterogeneities were estimated using Cochran’s Q-statistic with a P ,0.05 as statistically significant heterogeneity . We also quantified the effect of heterogeneity using the I 2 test (ranged from 0 to 100%), which represents the proportion of inter-study variability that can be contributed to heterogeneity rather than to chance . When a significant Q-test has P ,0.05 or I 2 . 50%, it indicates that heterogeneity among studies existed and the random effects model (DerSimonian Laird method) was conducted for meta-analysis; otherwise, the fixed effects model (Mantel- Haenszel method) was used. To establish the effects of heteroge- neity based on the results from the meta-analyses, we also performed subgroup analysis by ethnicity, country, source of controls, and genotype methods. We tested whether genotype frequencies of controls were in HWE using the x 2 test. Sensitivity analysis was performed through omitting each study in order to assess the quality and consistency of the results. Begger’s funnel plots and Egger’s linear regression test were used to evaluate publication bias . All tests were two-sided and a P value of,0.05 was considered statistically significant. All analyses were calculated using the STATA software, version 12.0 (Stata Corp, College Station, TX, USA).
Our previous candidate gene association study investigated the association of pepsinogen C (PGC) and excision repair cross complementing group 6 (ERCC6) with the risk of gastric cancer, and found that PGC gene rs4711690 CRG, rs6458238 GRA, and rs9471643 GRC polymorphisms had protective effects against atrophic gastritis . PGC had protective effects on the normal stomach and showed low expression in gastric cancer, and the loss of protection was associated with the occurrence of gastric cancer . ERCC6 is a member of the DNA repair family which participates in the repairing DNA damage in carcinogenesis . ERCC6 rs1917799 T .G polymorphism in the promoter region was associated with increased gastric cancerrisk in a Chinese population . Let-7a is a tumor suppressor, and recent studies found that the function of mature let-7a is closely related to the incidence and development of gastric cancer, and decreased expression of let-7a is associated with malignant biological behavior [17,18]. However, let-7a genetic variants were not examined for their associations and gastric cancer risks. Rs10739971 is a SNP located 2559 bp upstream of let-7a-1, which might be a promoter region of let-7a- 1. In the Hapmap database, the minimum allele frequency of rs10739971 is $5% in both Europeans and Asians. But whether there is an association between rs10739971 and disease risk, and interactions between rs10739971 and other polymorphisms, remain unknown. We hypothesized that the above-mentioned variants may be optimal candidates to investigate potential SNP- SNP interactions at two or more loci contributing to gastric cancer etiology.
We used the mean value of the lower and upper boundaries of each category as the assigned dose. For open-ended lower categories, the assigned dose was calculated by dividing the cut-off point by 1.2. For open-ended upper categories, the cut-off point was multiplied by 1.2 . The non-linear trends between total fat, saturated fat, and unsaturated fat intake and the risk for Pca were fitted by modelling both tails (left-tail and right-tail) restricted cubic splines with three knots at fixed 10th, 50th, and 90th percentiles of exposure distribution . The Wald test was used to evaluate linearity or non-linearity trends by assuming the regression coefficient of the second spline equalled zero . Some studies reported RRs by subtypes (such as sex or area), in our meta-analysis we pooled the subtypes using a fixed-effect model before including them in the overall analysis [19, 27].
ical Medicine, China National Knowledge Infrastructure, Wang Fang Data and Chongqing VIP database (Last search was updated on December 20, 2013) using the terms ‘‘p53-binding protein 1 or TP53BP1 or 53BP1’’, ‘‘Asp353Glu or rs560191 or D353E’’, ‘‘cancer or tunor or carcinoma’’ and ‘‘polymorphism, variant or mutation’’. The selection was done without restriction on language, but we only included published articles written in English or Chinese. We used the PubMed option ‘‘Related Articles’’ for each study to retrieve additional potentially relevant articles. Reference lists were checked and researchers were contacted for additional literatures.
Genetic polymorphisms in genes whose products regulate the immune and antitumor responses in malignancies are good candidates for investigation. Many candidate genes were reported to be associated to cancerrisk, such as TLRs, CD14. TLRs are pattern recognition receptors (PRR) of the innate immune system that recognise a wide variety of molecules. With respect to CD14, it is a pattern-recognition receptor that plays a central role in innate immunity and directs the adaptive immune responses . As a co-receptor of TLRs, CD14 acts primarily by transferring LPS and other bacterial ligands from circulating LPS-binding protein to the TLR4/MD-2 signaling complex. Two common promoter polymorphisms have been identified in the CD14 gene at positions -260 and -651 from the AUG start codon, which correspond to -159 and -550 designated according to the transcription start site, respectively [35,36]. With regard to - 260C/T polymorphism, LeVan et al.  showed that the T allele has a decreased affinity for DNA/protein interactions at a GC box containing a binding site for SP1, SP2, and SP3 transcription factors and leads to an increased transcriptional activity. Consis- tently, Hartel et al.  reported that after in vitro stimulation of cord blood cultures with LPS, carriers of the -159T allele have higher levels of sCD14 compared with carriers of the -159C allele. Recently, the -260C/T polymorphism in CD14 gene has been investigated the association with many diseases, such as inflam- matory bowel disease , alcoholic liver disease , tuberculosis , sepsis , coronary heart disease , asthma  and allergic rhinitis . As for cancer, a previous meta-analysis conducted by Zhou et al. , evaluated the association between CD14 -260C/T polymorphismandrisk of cancer based on 12 studies including 2498 cases and 2696 controls and reported that the CD14 -159C/T gene polymorphism is not a genetic risk factor for cancer.
In interpreting the results, some limitations of this meta-analysis should be addressed. Firstly, the subgroup meta-analyses on Asian populations are based on a small number of studies with such information available. Nevertheless, the total number of subjects included in this part of the analysis comprises the largest sample size so far. As studies among the Non-Caucasians are currently limited, further studies including a wider spectrum of subjects should be carried to investigate the role of these variants in different populations. Secondly, our results were based on unadjusted estimates, while a more precise analysis should be conducted if all individual raw data were available, which would allow for the adjustment by other co-variants including age, drinking status, obesity, cigarette consumption, and other lifestyle. Thirdly, heterogeneity is a potential problem when interpreting all
Although the exact biological mechanisms by which increased parity may decrease the risk of PC are not well established, a hypothesis that endogenous estrogens may be protective against PC has been proposed based on in-vitro and in-vivo studies [3,47]. Pregnancy elevates serum estrogen levels approximately 100-fold . Women with high parity are likely to have had longer periods of exposure to high levels of circulating estrogens which has been shown to inhibit the growth of preneoplastic pancreatic lesions or transplanted pancreatic carcinoma in rodent models [49–50]. In addition, sex-steroid biosynthetic enzymes (e.g., pancreatic homogenates and aromatase) and steroid hormone receptors have been detected in both normal and neoplastic human pancreatic tissue [51–54]. On the other hand, circulating insulin like growth factors (IGFs), which have been reported to increase PC risk through promoting cellular proliferation and inhibiting apoptosis , have been observed to be significantly lower in women with 4 births or more when compared with nulliparous women .
In term of stratified analyses by races, our findings indicated that TLR2 2196 to 2174 del had an significant association with cancerrisk in Caucasians and South Asians, but not in East Asians. However, the association between TLR4 rs4986791 andcancerrisk was significant in both South Asians and East Asians, but not in Caucasians. These differences may be induced by different genetic backgrounds and environmental exposures, as indicated by the difference of minor allele frequency in controls among the two populations (Table 1). For example, the MAF of TLR2 2196 to 2174 del in Caucasian controls varied from 0.05 to 0.15, but that in Asians was from 0.12 to 0.38. Allele frequency might reflect the natural selection pressures or a balance by other related functional genetic variants and/or environmental expo- sures. We also searched some public databases, such as Hapmap (http://hapmap.ncbi.nlm.nih.gov/) and SNPinfo (http://snpinfo. niehs.nih.gov/), and found that rs4986790 was in high linkage disequilibrium (LD) with rs4986791 in Caucasians (r 2 = 1), but not data was available in Asians because of low allele frequency of these two SNPs. In our analysis, the associations of rs4986790 and rs4986791 with cancerrisk were consistent in Caucasians, but inconsistent in Asians. These findings further indicate that the effect of genetic variants on cancerrisk may be different between multiple ethnic groups. Some limitations and potential bias should be addressed. First, the subgroups may have a relatively lower power based on a small number of studies. Second, a more precise analysis should be conducted, if individual data were available, allowing for the adjustment by some co-variants such as age, gender and other environmental factors. However, these informa- tion were unavailable from most of studies. Third, the controls in the included studies were recruited from different ways and not uniformly defined, which may have induced some bias for the meta-analysis. Last, the gene-gene interaction is important for the development of complex diseases including cancer because single genetic variation may only have a modest effect [63,64]. However, the original genotyping data of each publication was unavailable and we could not carry out gene-gene interaction analysis in this study.
In this meta-analysis, no association of the IL-10 21082A/G polymorphism with IS risk was found under all comparisons, and in subgroup analysis by ethnicity or source of controls. However, for Asians, after excluding the study deviating from HWE, the data indicated that IL-10 A allele was associated with increased risk of IS in Asians. The inconsistent outcome between Asians on subgroup analysis with overall estimates partly caused by genetic diversity in different ethnicities. In addition, the different subtypes of ischemic stroke may contribute to the conflicting results,for stroke in Asians is more often due to intracranial atherosclerosis than in other populations. Furthermore, as IS is a multifactorial disease, except genetic factors, environmental factors also take important parts in IS etiology. Thus, this discrepancy may also attribute to other environmental factors, such as different geographic distribution economic status, climate, lifestyle, diet,and so on. Importantly, there is currently no consensus for whether to include studies deviating from HWE. But if the results are different between including or excluding studies deviating from HWE, it is suggested that the analysis without studies departed from HWE may be more valid .