The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Interleukin-6 (IL-6) is implicated in the pathophysiology of hematologic neoplasia.

X-ray repair cross complementing 1 (XRCC1) plays a key role in DNA repair, genetic instability and tumorigenesis. A series of epidemiological studies have examined associations between XRCC1 polymorphisms and cervical cancer risk, but the findings remain inconclusive. We searched three electronic databases (MEDLINE, EMBASE and CNKI) for studies on the association between XRCC1 polymorphisms and cervical cancer risk published before June 2013. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated to estimate risk associations. A total of 28 case-control studies from 15 publications with 5,890 cervical cancer cases and 7,626 controls were identified. There was a significant association between rs25487 and cervical cancer risk in Asian populations (Dominant model: OR = 1.25, 95 % CI =1.04-1.50, P = 0.051 for heterogeneity test). After excluding three studies deviated from Hardy-Weinberg equilibrium, we observed a significant association of rs1799782 with cervical cancer risk in all populations and in Asian populations (Recessive model: OR = 1.62 and 1.72, 95 % CI = 1.22-2.14 and 1.29-2.30, P = 0.090 and 0.266 for heterogeneity test, respectively). However, there was no significant association between rs25489 and cervical cancer risk. These findings were further confirmed by false-positive report probability analysis. No publication bias was found by using the funnel plot and Egger's test. This meta-analysis provides strongly statistical evidence for the association between rs1799782 and cervical cancer risk, as well as its association with rs25487 only in Asian populations. However, single large, well-designed prospective studies are needed to confirm these findings.

The role of hypoxia-inducible factors-1 alpha (HIF-1α) expression in gastric cancer remains controversial. We performed a systematic review of the literature with meta-analysis. Electronic databases were used to identify published studies before December 1, 2012. Pooled hazard ratio (HR) or odds ratio (OR) with 95 % confidence interval (95 % CI) was used to estimate the strength of the association between HIF-1α expression and survival of gastric cancer patients. Heterogeneity and publication bias were also assessed. Final analysis of 1,268 patients from 9 eligible studies was performed. High HIF-1α expression was significantly correlated with poor overall survival (OS) of gastric cancer patients (HR = 2.14, 95 % CI = 1.32-3.48). Subgroup analysis indicated that HIF-1α over-expression had an unfavorable impact on OS in Asian patients (HR = 2.35, 95 % CI = 1.41-3.92). Moreover, up-regulation of HIF-1α was significantly associated with the depth of invasion (OR = 2.49, 95 % CI = 1.28-4.83), lymph node metastasis (OR = 2.15, 95 % CI = 1.27-3.66), and vascular invasion (OR = 2.23, 95 % CI = 1.20-4.14). HIF-1α expression might be a predicative factor of poor prognosis for gastric cancer particularly in Asia.

Many studies have examined the association between the VEGF +936C/T (rs833061) and +460C/T (rs3025039) gene polymorphisms and oral cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, we performed a meta-analysis. The PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases were searched for case-control studies that were published up to January 2013. Data were extracted and pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated. Ultimately, six studies were included, comprising 1006 oral cancer cases and 1016 controls. Overall, the pooled OR for VEGF +936 T allele carriers (TC + TT) versus the wild-type homozygotes (CC) was 1.28 (95 % CI 1.04-1.58; P = 0.228 for heterogeneity), the pooled OR for TT versus CC was 1.64 (95 % CI 1.34-1.98; P = 0.315 for heterogeneity), and the pooled OR for the T allele versus the C allele was 1.42 (95 % CI 1.22-1.76; P = 0.286 for heterogeneity). In the stratified analysis by ethnicity, significant risks were found among Caucasians but not Asians. However, there were no associations between VEGF +460C/T and oral cancer risk in only two of the included studies. In conclusion, this meta-analysis demonstrates that the VEGF +936 T allele may be associated with an increased risk of oral cancer, especially among Caucasian populations.

Results conflict on the association between progesterone receptor gene (PRG) polymorphism PROGINS and ovarian cancer risk, despite wide-ranging investigations. We therefore performed a meta-analysis of 4,285 ovarian cancer cases and 6,257 controls from 11 published case-control studies. The strength of association between PROGINS polymorphism and ovarian cancer susceptibility was assessed using pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs). The results suggest no significant associations exist between PROGINS polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (T2T2 vs. T1T1: OR = 1.37, 95 % CI = 0.89-2.12, P = 0.15; T1T2 vs. T1T1:OR = 1.09, 95 % CI = 0.88-1.35, P = 0.41; T1T2 + T2T2 vs. T1T1:OR = 1.15, 95 % CI = 0.94-1.40, P = 0.17; T2T2 vs. T1 T1 + T1T2:OR = 1.34, 95 % CI = 0.87-2.07, P = 0.18). In conclusion, the results of this meta-analysis indicate that the PRG polymorphism PROGINS is not associated with ovarian cancer risk when multiple ethnic groups or regions were considered overall.

The association between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of head and neck cancer (HNC) were investigated in many published studies; however, the currently available results are inconclusive. Therefore, we conducted this meta-analysis for deriving a more precise estimation of association between VEGF polymorphisms and the risk of HNC. Finally, we yield eight case-control studies involving six polymorphisms contain 2,444 individuals from PubMed, Embase, and CNKI up to January 30, 2013 (last updated on May 4, 2013). The results of meta-analysis showed that all the six polymorphisms of VEGF were not associated with risk of HNC [OR 1.25, 95 % CI (0.60-1.58) for TT vs. CC for 936 C/T; OR 1.41, 95 % CI (0.79-2.52) for GG vs. AA for -1,154 A/G; OR 0.97, 95 % CI (0.38-2.50) for CC vs. GG for 405 G/C; OR 1.44, 95 % CI (0.80-2.61) for AA vs. CC for 2,578 C/A; OR 1.27, 95 % CI (0.77-3.72) for TT vs. CC for -460 C/T; and OR 0.87, 95 % CI (0.37-2.06) for GG vs. CC for -634 G/C]. When performed subgroup analysis according to ethnicity for VEGF 936 C/T, the results suggested that it was not associated with the risk of HNC for either Asians [OR 0.84, 95 % CI (0.27-2.56) for TT vs. CC] or Caucasians [OR 2.10, 95 % CI (0.82-5.37) for TT vs. CC]. However, due to the limitations of this meta-analysis, more well designed, larger sample size, and adjusted risk factors studies are suggested to further assess the findings.

Overexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer.

Previous studies regarding the association between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and oral cancer risk were contradictory. We performed a meta-analysis to derive a more precise estimation of the association. The PubMed and Web of Science were searched for eligible studies. Odds ratio (OR) with its 95% confidence interval (95% CIs) was used to assess the strength of the association. Nine individual studies with a total of 3,244 subjects were finally included into the meta-analysis. Overall, there was no association between XRCC1 Arg399Gln polymorphism and oral cancer risk under all genetic models (Gln versus Arg: OR = 1.09, 95% CI 0.86-1.37, P = 0.46; GlnGln versus ArgArg: OR = 1.11, 95% CI 0.69-1.79, P = 0.66; GlnGln versus ArgArg/ArgGln: OR = 1.04, 95% CI 0.68-1.61, P = 0.84; and GlnGln/ArgGln versus ArgArg: OR = 1.13, 95% CI 0.88-1.44, P = 0.34). After excluding studies on oral leukoplakia, there was still no association between XRCC1 Arg399Gln polymorphism and oral cancer risk under all genetic models. Subgroup analysis by ethnicity suggested that there was no association between XRCC1 Arg399Gln polymorphism and oral cancer risk in both Asians and Caucasians. In conclusion, the data from the meta-analysis suggests that XRCC1 Arg399Gln polymorphism is not associated with oral cancer risk.

Because of inconsistent results from previous studies on the association of IL-12B +1188 A/C polymorphism with cancer risk, a meta-analysis was performed to assess the association.

Vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Many studies investigated the association between VDR gene ApaI polymorphism and breast cancer, but the results were inconclusive. We performed this meta-analysis to evaluate the association between VDR gene ApaI polymorphism and breast cancer. Twelve studies with a total of 8,254 subjects were identified from PubMed and Wanfang databases. The pooled odds ratio (OR) and confidence intervals (95% CI) were used to assess the association. The meta-analysis indicated that VDR gene ApaI polymorphism was not associated with risk of breast cancer (a vs. A: OR = 0.97, 95% CI 0.91-1.04, P = 0.378; aa vs. AA: OR = 0.97, 95% CI 0.85-1.10, P = 0.618; aa vs. AA + Aa: OR = 1.00, 95% CI 0.89-1.12, P = 0.972; aa + Aa vs. AA: OR = 0.95, 95% CI 0.82-1.11, P = 0.550). Subgroup analysis by ethnicity further showed that VDR gene ApaI polymorphism was not associated with risk of breast cancer in both Asians and Caucasians. These data from the meta-analysis indicate that VDR gene ApaI polymorphism is not associated with breast cancer susceptibility.

Epidemiological studies have assessed the association between HIF-1α polymorphisms and cancer risk. However, the results remained conflicting rather than conclusive. Therefore, we performed a systematic review to provide a complete picture and conducted a meta-analysis to derive a precise estimation. We searched PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases until July 2013 to identify eligible studies. Data sets (43) from 39 studies with a total of 10,841 cases and 14,682 controls were included. The most commonly investigated polymorphism was C1772T, followed by G1790A, C111A, and rs2057482. Overall, C1772T and G1790A but not rs2057482 were associated with increased risk for cancer. When stratified by cancer type, C1772T was associated with increased risk for cervical cancer (T/T vs. C/T+C/C: OR = 8.80, 95 % CI = 2.30-33.70), prostate cancer (T vs. C: OR = 1.54, 95 % CI = 1.04-2.30), and other cancers (T vs. C: OR = 1.42, 95 % CI = 1.07-1.89), but not oral, breast, colorectal, endometrial, lung, and bladder cancers or renal cell carcinoma. G1790A was associated with marginal but insignificant risk for prostate cancer (A vs. G: OR = 1.46, 95 % CI = 1.00-2.13, P = 0.056) and with increased risk for oral (A vs. G: OR = 9.66, 95 % CI = 1.31-71.15), lung (A vs. G: OR = 2.27, 95 % CI = 1.74-2.96), and other cancers (A vs. G: OR = 2.06, 95 % CI = 1.26-3.37) and renal cell carcinoma (A/A vs. G/A+G/G: OR = 3.05, 95 % CI = 1.36-6.84), but not breast, colorectal, cervical, or bladder cancer. Furthermore, we detected increased cancer risk in haplotypes TA and CA and in those carrying at least one risk allele, and decreased cancer risk in haplotype TG regarding C1772T and G1790A polymorphisms. Further well-designed studies on various cancer types are warranted to verify our findings.

Many studies have investigated on the association between TP53 Arg72Pro polymorphism and risk of glioma, but the impact of TP53 Arg72Pro polymorphism on glioma risk is unclear owing to the obvious inconsistence among those studies. To shed light on these inconclusive findings and get a quantitative assessment of the association between the TP53 Arg72Pro polymorphism and risk of glioma, we conducted a meta-analysis of eligible studies. We searched PubMed and Embase databases for studies investigating on the association between the TP53 Arg72Pro polymorphism and risk of glioma. The pooled odds ratios (OR) with their 95% confidence intervals (95% CI) was calculated to assess the association between the TP53 Arg72Pro polymorphism and risk of glioma. A total of 12 studies were finally included into the meta-analysis. Meta-analysis of the 12 studies showed that TP53 Arg72Pro polymorphism was not associated with the risk of glioma (OR(Pro vs. Arg) = 1.07, 95% CI 0.93∼1.22; OR(ProPro vs. ArgArg) = 1.02, 95% CI 0.85∼1.22; OR(ProPro/ArgPro vs. ArgArg )= 1.06, 95% CI 0.85∼1.34; and OR(ProPro vs. ArgArg/ArgPro) = 1.07, 95% CI 0.91∼1.27). Subgroup analyses by ethnicity further identified that TP53 Arg72Pro polymorphism was not associated with the risk of glioma in Caucasians. However, there was a mild association between the TP53 Arg72Pro polymorphism and risk of glioma in Asians (OR(ProPro vs. ArgArg/ArgPro) = 1.42, 95% CI 1.00∼2.02). Thus, there is limited evidence for the association between the TP53 Arg72Pro polymorphism and risk of glioma, and more studies are needed to provide a more comprehensive assessment of the association in Asians.

RAD51 135G>C can modify promoter activity and the penetrance of BRCA1/2 mutations, which plays vital roles in the etiology of various cancer. To date, previous published data on the association between RAD51 135G>C polymorphism and cancer risk remained controversial. Recent meta-analysis only analyzed RAD51 135G>C polymorphism with breast cancer risk, but the results were also inconsistent.

The predictive value of thymidylate synthase (TYMS) to sensitivity to pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is controversial. We conducted a meta-analysis of all relevant published data to assess the association of TYMS expression with the clinical outcomes of pemetrexed-based regimen in advanced NSCLC.

MicroRNAs (miRNAs) participate in various cellular processes such as cell growth, differentiation, cell death and play an important role in a variety of diseases, especially in cancer. Recently, a number of studies have investigated the association between single nucleotide polymorphisms (SNPs) on the hsa-miR-149 rs2292832 and susceptibility to cancer; however, the results remain inconclusive.

The association between polymorphisms on 5p12 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two wildly studied polymorphisms (rs10941679 and rs4415084) on 5p12.

The X-ray repair cross-complementing group 1 (XRCC1) protein plays a crucial role in base excision repair (BER) pathway by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, a comprehensive meta-analysis of all available studies was performed in this study.

In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.

Previous studies have investigated the association between single nucleotide polymorphisms (SNPs) located in microRNAs (miRNAs) and breast cancer susceptibility; however, because of their limited statistical power, many discrepancies are revealed in these studies. The meta-analysis presented here aimed to identify and characterize the roles of miRNA SNPs in breast cancer risk, and evaluate the associations of polymorphisms in miR-146a rs2910164, miR-196a rs11614913 and miR-499 rs3746444 with breast cancer susceptibility, respectively.