Increasing evidence suggests that variants of common and low-penetrance genes are involved in pancreatic cancer (PC) carcinogenesis. We undertook a meta-analysis of published studies to assess evidence regarding the risk associated with these genes. Medline, Web of Science, ProQuest, Google Scholar, and international conference proceedings were searched and citations in relevant primary and review articles were collected. The studies that we considered eligible included all reports that investigated an association between genetic polymorphisms and PC. We identified 23 studies that evaluated the risk effects on PC of common alleles for 13 gene polymorphisms. A significant association was recognized between ALDH 2*1*2 polymorphisms and PC [odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.07-1.75, P = 0.01] based on only two studies. Although the overall results for MTHFR T677T are negative, sensitivity analysis stratified by ethnic background showed a significant association between Caucasian and MTHFR T677T polymorphisms and PC (OR = 1.66, 95% CI = 1.10-2.52, P = 0.02). The risk for PC was higher in individuals with MTHFR C677T or TT polymorphisms and a smoking habit (OR = 2.52, 95% CI = 1.05-6.09, P = 0.04). These findings lead us to support the hypothesis that MTHFR T677T and ALDH 2*1*2 polymorphisms may play a carcinogenetic role in PC and represent the candidates for low-penetrance susceptibility alleles identified to date. Although their genetic risks are modest, the high frequency in the population shows that they may have a considerable impact on the incidence of PC. Definite conclusions will be contingent on studies with a larger sample size that determine the risk estimates associated with other variants, gene-gene, and gene-environment interactions.

P21 (CDKN1A), a key cell cycle regulatory protein that governs cell cycle progression from G1 to S phase, can regulate cell proliferation, growth arrest, and apoptosis. The Ser31Arg polymorphism is located in the highly conserved region of p21 and may encode functionally distinct proteins. Although many epidemiological studies have been conducted to evaluate the association between the p21 Ser31Arg polymorphism and cancer risk, the findings remain conflicting. This meta-analysis with 33 077 cases and 45 013 controls from 44 published case-control studies showed that the variant homozygous 31Arg/Arg genotype was associated with an increased risk of numerous types of cancers in a random-effect model (homozygote comparison: OR = 1.17, 95% CI = 0.99 to 1.37, P = 0.0002 for the heterogeneity test; recessive model comparison: OR = 1.16, 95% CI = 1.01 to 1.33, P = 0.0001 for the heterogeneity test). Stratified analysis revealed that increased cancer risk associated with the 31Arg/Arg genotype remained significant in subgroups of colorectal cancer, estrogen-related cancer, Caucasians, population-based studies, studies with matching information or a larger sample size. Heterogeneity analysis showed that tumor type contributed to substantial between-study heterogeneity (recessive model comparison: Χ(2) = 21.83, df = 7, P = 0.003). The results from this large-sample sized meta-analysis suggest that the p21 31Arg/Arg genotype may serve as a potential marker for increased cancer risk.

The association between glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms and oral cancer is not consistent across studies, and data on their interaction with smoking in oral cancer are lacking. The authors systematically searched PubMed and SciVerse Scopus for case-control studies examining the association between null genotypes of the GSTM1 and GSTT1 genes and oral cancer. Twenty-eight case-control studies published in English were identified. Summary odds ratios were derived via random-effects models. The summary odds ratio for the GSTM1 null genotype was 1.43 in Asians (95% confidence interval (CI): 1.14, 1.78; P < 0.01, I (2) = 73%) and 0.98 in Caucasians (95% CI: 0.76, 1.28; P = 0.91, I (2) = 0%). Case-only analysis of 6 studies (552 cases) showed an inverse multiplicative interaction between GSTM1 null polymorphisms and smoking (ever/high levels of smoking vs. never/low levels) (odds ratio (OR) = 0.51, 95% CI: 0.32, 0.82; P = 0.01, I (2) = 34%). The GSTT1 null genotype was not significantly associated with oral cancer in Asians (OR = 1.07, 95% CI: 0.82, 1.38; P = 0.63, I (2) = 65%) or Caucasians (OR = 1.04, 95% CI: 0.41, 2.65; P = 0.93, I (2) = 55%). In conclusion, the GSTM1 null genotype may be associated with a higher risk of oral cancer in Asians but not in Caucasians, and this effect may be modified by smoking status. The GSTT1 null genotype may not be associated with oral cancer.

Studies investigating the association between p21 genetic polymorphism Ser31Arg and cervical cancer (CC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for p21 polymorphism and CC risk.

Human 8-hydroxyguanine glycosylase (hOGG1) is one of the DNA repair genes, which can repair damaged DNA by specifically excising 8-dihydro-8-oxoguanine (8-OH-G). A considerable number of studies investigating hOGG1 Ser326Cys polymorphism were in relation to various cancers. However, the association of hOGG1 Ser326Cys polymorphism with risk of lung cancer is inconsistency. The aim of this study is to assess the association of hOGG1 Ser326Cys polymorphism with risk of lung cancer by conducting a meta-analysis.

The xeroderma pigmentosum group G (XPG or ERCC5) and group F (XPF or ERCC4) play an important role in DNA repair, and produce dual incision 3' and 5' to the damaged nucleotide fragment. Several polymorphisms in the XPF and XPG gene have been described, including the commonly occurring Asp1104His in XPG and Arg415Gln in XPF. The published data on the association between these polymorphisms and breast cancer remained controversial. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 17 studies were identified to the meta-analysis, including 5,235 cases and 5,685 controls for XPG Asp1104His (from ten studies) and 3,910 cases and 3,985 controls for XPF Arg415Gln (from seven studies). Overall, no significantly elevated breast cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (for XPG Asp1104His Asp/His vs. Asp/Asp: OR 1.02, 95% CI 0.94-1.11; His/His vs. Asp/Asp: OR 0.96, 95% CI 0.83-1.11; dominant model: OR 1.01, 95% CI 0.94-1.09; and for XPF Arg415Gln Arg/Gln vs. Arg/Arg: OR 1.00, 95% CI 0.89-1.12; Gln/Gln vs. Arg/Arg: OR 2.40, 95% CI 0.62-9.22; dominant model: OR 1.03, 95% CI 0.90-1.18). In stratified analyses, we observed an overall OR of 5.20 (95% CI 2.08-12.95) for breast cancer developing risk in the Caucasian ethnicity, comparing Gln/Gln type to wild-type Arg/Arg for Arg415Gln polymorphism. In conclusion, this meta-analysis suggests that XPG Asp1104His polymorphism is not associated with increased breast cancer risk, and XPF Arg415Gln may be a low-penetrant risk factor in the Caucasian ethnicity for developing breast cancer.

Randomized controlled trails (RCTs) where cetuximab added to first-line platinum-based chemotherapy for patients with advanced/metastatic non-small-cell lung cancer (NSCLC) have yielded conflicting results. This meta-analysis intended to evaluate the efficacy and safety of cetuximab-based therapy (CBT) in that setting. We analyzed four eligible RCTs that included 1,003 and 1,015 patients randomized to CBT and control intervention, respectively. As compared with the noncetuximab group, CBT demonstrated an 9% reduction in the risk of disease progression [hazard ratio (HR) = 0.91; (CI = 0.83-1.00); p = 0.06], a 13% reduction in the risk of death [HR = 0.87; (CI = 0.78-0.96); p = 0.005], and an approximately 50% increase in objective response rate [odds ratio (OR) = 1.48; (CI = 1.22-1.80); p < 0.0001]. CBT-related adverse events were similar across comparisons except for toxicities known to be associated with anti-EGFR therapy. CBT produced significant clinical benefit with acceptable toxicity as a first-line strategy in patients with advanced/metastatic NSCLC. Further research is needed to identify markers predictive of cetuximab benefit in that disease.

p21 protein is a cell cycle regulator that induces G1 arrest, leading to DNA repair or apoptosis. Previous studies have shown that p21 polymorphism in codon 31 (Ser 31 Arg) may play a role in susceptibility to cancer. However, the results from the published studies are conflicting. To derive a more precise estimation of association between the p21 Ser31Arg polymorphism and risk of cancer, we performed a meta-analysis of 33 120 cancer cases and 44 954 controls from 49 publications with 66 individual case-control studies for the polymorphism. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, no significant association was found between p21 Ser31Arg polymorphism and cancer risk. However, in the subgroup analysis by ethnicity, a significantly elevated risk was found among whites (for Arg/Arg versus Ser/Ser: OR = 1.48, 95% CI = 1.20-1.83; for Arg/Arg versus Ser/Arg +Ser/Ser: OR = 1.49, 95% CI = 1.20-1.83). Interestingly, when stratifying by cancer types, significantly increased risks were observed for breast cancer and 'other cancers' among whites and significantly decreased risks were found for oesophageal cancer and gastric cancer among Asians. When stratifying by sample size of studies, a significantly elevated risk was found among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects). Moreover, a significantly increased risk was observed among smokers in all models except for homozygotes comparison. This meta-analysis suggests that the p21 31Arg allele is a low-penetrant risk factor for cancer development, especially among whites.

Fibroblast growth factor receptor 4 (FGFR4) contains a Gly388Arg functional polymorphism (rs351855) that has shown contrasting results in association studies. In this study, we assessed the association between the FGFR4 Gly388Arg polymorphism and cancer prognosis. Meta-analysis and pooled analysis of 6817 and 2537 cancer cases, respectively, were carried out by nodal status and overall survival. The study included the following types of cancer: brain, breast, colorectal, head and neck, larynx, lung, melanoma, prostate, sarcomas. A statistically significant association between the Arg388Arg genotype and nodal involvement was found in the meta-analysis (odds ratio=1.33, 95% confidence interval 1.01-1.74). In the pooled analysis, the Arg388 allele carriers showed an increased hazard of poor overall survival compared with homozygous carriers of the common Gly388 allele, even after adjusting for nodal status (hazard ratio=1.21, 95% confidence interval 1.05-1.40). These results provide evidence of a role for the FGFR4 Gly388Arg polymorphism in modulating patients' outcome in different types of cancer, thus offering to clinicians a new marker to predict predisposition to poor survival in cancer patients.

The cytochrome P450 1A1 (CYP1A1) is a phase I enzyme involved in many oxidative reactions that has attracted considerable attention as a candidate gene for lung cancer susceptibility based on its function as a key factor required for bioactivation of carcinogenic polycyclic aromatic hydrocarbons and catechol oestrogen formation. In the past decade, the relationship between CYP1A1 and lung cancer has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 71 studies involving a total of 30 368 subjects for the MspI and Ile-Val polymorphism of the CYP1A1 gene to evaluate the effect of CYP1A1 on genetic susceptibility for lung cancer. In a combined analysis, the summary per-allele odds ratios for lung cancer of the MspI and Ile-Val polymorphism were 1.19 [95% confidence interval (CI): 1.11-1.28] and 1.20 (95% CI: 1.08-1.33), respectively. Significant results were also observed using dominant or recessive genetic model. In the subgroup analysis by ethnicity, significantly increased risks were found for the MspI and Ile-Val polymorphism among East Asians in almost all genetic models. However, only marginal significant associations were detected for the MspI polymorphism among Caucasians and other population, while no significant associations were observed for the Ile-Val polymorphism in Caucasians and other population. This meta-analysis demonstrated that the MspI and Ile-Val polymorphism of CYP1A1 is a risk factor associated with increased lung cancer susceptibility, but these associations vary in different ethnic populations.

The renin-angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system. In addition to RAS enzymes in plasma, the RAS is present in various local organ systems. Moreover, local expression of the RAS has been shown in various malignant cells. In 1990, an insertion/deletion (I/D) polymorphism in the ACE gene was discovered, accounting for half of the variance of the serum ACE enzyme levels. Serum ACE concentrations were significantly higher in homozygotes with the shorter deletion allele (DD) than in heterozygotes (ID) or in homozygotes with the longer insertion allele (II). Since 2000, twenty-four studies have been published hypothesizing an association between the ACE I/D polymorphism and cancer risk. This review focuses on the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Furthermore a meta-analysis of the published studies was performed. Fourteen statistically non-significant studies were found, as well as ten studies with a statistically significant finding. The results of the meta-analyses performed were not consistent. However, both methods (one based on the Fisher p-value, and one on inverse variance weighted meta-analysis), indicated a (nearly) statistically significantly decreased risk in carriers of the II genotype in comparison to the DD genotype with regard to risk of prostate cancer and risk of (postmenopausal) breast cancer. Nevertheless, results show a large variation and are often contradictory. As this may be partly explained by a lack of power, genotyping techniques, and choice of study population, it is expected that future studies will shed more light on these associations.

More clinically meaningful diagnostic tests are needed in exocrine pancreatic cancer (EPC). K-ras mutations are the most frequently acquired genetic alteration in EPC. We analysed the diagnostic utility of detecting K-ras mutations through a systematic analysis of the literature.

IGF-I CA repeat polymorphisms have been reported to influence the risk for breast cancer in many studies; however, the results still remains controversial and ambiguous. Therefore, to determine more precise estimations for the relationship, a meta-analysis was performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. A total of 9 studies including 5641 cases and 10471 controls were involved in this meta-analysis. All studies investigated the association between (CA)19 repeat polymorphism and breast cancer risk. Of those, four studies investigated the association between (CA)20 repeat polymorphism and breast cancer risk (2585 cases and 2847 controls), and three studies were for (CA)17 repeat polymorphism (2122 cases and 2225 controls). The overall odds ratio (OR) for the (CA)19 versus non-(CA)19 allele was 1.002 (95% CI 0.972-1.033). There was no suggestion of an overall effect either in recessive or dominant modeling of (CA)19 allele effects (dominant model: OR = 1.000 95% CI 0.872-1.147; recessive model: OR = 0.959 95% CI 0.888-1.036). The comparison of (CA)19 homozygosity versus non-(CA)19 homozygosity also showed no differential susceptibility to breast cancer (OR = 0.974, 95% CI 0.838-1.132). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found among premenopausal or postmenopausal women. When stratified by ethnicity, no significant association was found in all genetic models. Furthermore, there was no evidence that two other alleles associated with the risk of breast cancer (CA17 vs. non-CA17: OR = 1.165 95% CI 0.634-2.141; CA20 vs. non-CA20: OR = 1.019 95% CI 0.909-1.143). In conclusion, the current meta-analysis suggests that three IGF-I (CA) repeat polymorphisms had no association to breast cancer risk.

The accuracy of quantitative real-time PCR (qRT-PCR) is highly dependent on reliable reference gene(s). Some housekeeping genes which are commonly used for normalization are widely recognized as inappropriate in many experimental conditions. This study aimed to identify reference genes for clinical studies through microarray meta-analysis of human clinical samples.

For detecting low risk disease variants in genome-wide association panels, meta-analysis is a powerful strategy to increase power. We apply a composite likelihood-based method, which models association with disease in regions defined on a linkage disequilibrium map and combines the evidence across multiple genome-wide samples. This fixed region approach has the advantage that, as only one statistical test is made per region, there is no increased multiple testing penalty in higher marker density panels. Imputation of missing genotypes is also advantageous to increase coverage. Meta-analysis of three breast cancer data sets combines evidence from samples that show heterogeneity in phenotype and, particularly, in marker coverage. The FGFR2 gene has the highest rank, consistent with previous analysis of one of these samples and supported by the small number of early-onset breast cancer cases included. The 8q24 breast cancer region also ranks highly and is supported by evidence from both early-onset and post-menopausal breast cancer samples. The PIK3AP1 gene region is highlighted in this analysis as a strong candidate for further study.

Polymorphisms in the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene have been implicated in susceptibility to cancer, but the many published studies have reported inconclusive results. The objective of the current study was to conduct a meta-analysis investigating the association between polymorphisms in the CTLA-4 gene and the risk of cancer.

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.

Discuss the relationship between the X-ray repair cross complementing gene group 1 (XRCC1) 399 point polymorphisms and risk of hepatocellular carcinoma occurrence.

Fibroblast growth factor receptor 4 (FGFR4) displays multiple biological activities, including mitogenic and angiogenic activity, and plays important roles in the etiology and progression of prostate cancer. Gly388Arg polymorphism in FGFR4 gene has been reported to be involved in prostate cancer incidence and aggressiveness in several studies. To derive a more precise estimation of the relationship, a meta-analysis was performed.

Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). Three common polymorphisms in the promoter of interleukin-10 (IL-10) gene, -1082 A>G, -819 C>T and -592 C>A, have been implicated to alter the risk of PCa, but the results of relative studies are inconclusive or controversial. To derive a more precise estimation of the relationship, we performed an updated meta-analysis on the basis of 10 studies. A comprehensive search was conducted to examine all the eligible studies of IL-10 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Overall, there were no significant associations between increased risk of PCa and IL-10 -1082 A>G, -819 C>T and -592 C>A polymorphisms. However, meta-analysis suggested that IL-10 -819 C>T and -592 C>A polymorphisms might be modestly associated with PCa aggressiveness (T versus C, OR=1.162, 95% CI: 1.035-1.305, P=0.011; A versus C, OR=1.131, 95% CI: 1.012-1.264, P=0.030; respectively). IL-10 -819 C>T and -592 C>A polymorphisms might impact PCa progression. Variant alleles at both -819 and -592 were modestly associated with advanced stages of PCa. Additional well-designed studies are warranted to validate these findings.