Emerging evidence showed that the common polymorphism (+61A>G, rs4444903) in the promoter region of epidermal growth factor (EGF) gene might be associated with melanoma susceptibility in humans. But individually published results are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of the association between EGF +61A>G polymorphism and melanoma risk. The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to July 1st, 2012. Seven case-control studies were included with a total of 2367 melanoma cases and 4184 healthy controls. Meta-analysis results showed that there was no significant relationship between EGF +61A>G polymorphism and the risk of melanoma (G vs A: odds ratio [OR]=1.08, 95% confidence interval [CI]: 0.91-1.28, P=0.386; GG+AG vs AA: OR=1.05, 95%CI: 0.88-1.26, P=0.580; GG vs AA+AG: OR=1.10, 95%CI: 0.81-1.49, P=0.552; GG vs AA: OR=1.06, 95%CI: 0.80-1.41, P=0.700; GG vs AG: OR=1.12, 95%CI: 0.81-1.56, P=0.494). Further subgroup analyses based on source of controls, country, detection samples, genotype methods, and Breslow thickness of tumor, we also found no significant association between EGF +61A>G polymorphism and melanoma risk. In conclusion, this meta-analysis indicates that EGF +61A>G polymorphism might not be a primary determinant in melanoma development and progression; EGF gene might be expected to interact with other genes in different signaling pathways to initiate and promote the carcinogenic process.

The results of studies investigating the association between ADIPOQ gene polymorphisms and risk of cancer have been inconsistent and often contradictory. The present meta-analysis was conducted in order to overcome the limitations of any individual study and to provide a more precise overall effect estimate. Relevant studies were identified by searching PubMed and Embase for articles published through May 2012. The strength of the relationship between the ADIPOQ gene and risk of cancer was assessed using odds ratios (ORs). Either a fixed-effects or a random-effects model was used to calculate the overall risk estimates. Fifteen studies were included and five SNPs were considered. A significant association was found between SNP rs2241766 and risk of cancer in the recessive genetic model (OR: 0.768, 95% CI: [0.626,0.942], P=0.011); a significant relationship was also found between SNP rs1501299 and risk of cancer in both an allele contrast (OR: 0.141, 95%CI: [0.113,0.176], P<0.001) and the dominant genetic model (OR: 0.904, 95%CI: [0.830,0.985], P=0.021); no association was found with the rs266729, rs822395, or rs822396 SNPs. Adjusted ORs were also considered, but no statistically significant association was found in homozygote contrasts for any of the five SNPs after adjustment. Our results suggest that two polymorphisms, SNP rs2241766 and SNP rs1501299, of the ADIPOQ gene may be associated with reduced risk of cancer. However, the overall strength of association is mild to moderate, and additional well-designed studies are needed to confirm the present conclusion.

Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-β1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies.

The genetic polymorphism of p53 codon 72 Arg/Pro has been implicated in oral cancer risk, but the results of previous studies remain controversial and ambiguous. To estimate the effect of the p53 codon 72 Arg/Pro polymorphism on the risk of oral cancer, a meta-analysis was performed. Based on a comprehensive search in PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) databases, we identified all available publications assessing the association between p53 codon 72 Arg/Pro polymorphism and oral cancer risk. The pooled odds ratio (OR) with its corresponding 95 % confidence interval (CI) was calculated to assess the association. Subgroup analyses by ethnicity and study quality were performed to further identify the correlation. Totally, 17 studies with 2,975 cases and 3,413 controls were included into this meta-analysis. There was no statistically significant association between the p53 codon 72 Arg/Pro polymorphism and oral cancer risk in all genetic contrast models (OR(Pro allele vs. Arg allele) = 1.05, 95 % CI 0.94-1.18, P(OR) = 0.379; OR(Pro/Pro vs. Arg/Arg) = 1.11, 95 % CI 0.89-1.40, P(OR) = 0.356; OR(Pro/Arg vs. Arg/Arg) = 1.10, 95 % CI 0.93-1.30, P(OR) = 0.256; OR(Pro/Arg + Pro/Pro vs. Arg/Arg) = 1.10, 95 % CI 0.93-1.31, P(OR) = 0.263; and OR(Pro/Pro vs. Arg/Arg + Pro/Arg) = 1.03, 95 % CI 0.90-1.18, P(OR) = 0.647). In the subgroup analysis of high-quality studies, we failed to find the susceptibility of p53 codon 72 Arg/Pro polymorphism to oral cancer. Moreover, the results were similar among Asians, Caucasians, and mixed populations when stratifying by ethnicity. Sensitivity analysis further confirmed the stability of the results. The present meta-analysis of currently available data shows no association between the p53 codon 72 Arg/Pro polymorphism and oral cancer risk.

The GSTM1, GSTT1 and GSTP1 polymorphisms might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. However, studies investigating the association between GSTM1, GSTT1 or GSTP1 polymorphisms and prostate cancer (PCa) risk report conflicting results, therefore, we conducted a meta-analysis to re-examine the controversy.

X-ray repair cross-complementing group 1 (XRCC1), a DNA repair enzyme, plays a crucial role in the base excision repair by generating a single nucleotide repair patch. It has been demonstrated that the XRCC1 Arg399Gln gene polymorphism was associated with variations in XRCC1 enzyme activity. The aim of this study was to quantitatively summarize the association between the XRCC1 Arg399Gln polymorphism and susceptibility to colorectal cancer (CRC). A comprehensive search of the PubMed, Embase, and China National Knowledge Infrastructure databases was conducted for studies on the association between the XRCC1 Arg399Gln polymorphism and CRC risk. Summary odds ratio (OR) with its corresponding 95 % confidence interval (95 %CI) was estimated, in a fixed-effects model or a random-effects model when appropriate, to assess the association. Totally, 26 case-control studies with 6,979 cases and 11,470 controls were included into this meta-analysis. The pooled results of total studies showed that the XRCC1 Arg399Gln polymorphism was significantly associated with increased risk of CRC in all genetic contrast models (OR(A vs. G) = 1.13, 95 %CI 1.03-1.23, P (OR) = 0.008; OR(Gln/Gln vs. Arg/Arg) = 1.24, 95 %CI 1.04-1.46, P (OR) = 0.015; OR(Gln/Gln vs. Arg/Gln + Arg/Arg) = 1.19, 95 %CI 1.03-1.38, P (OR) = 0.021; OR(Gln/Gln + Arg/Gln vs. Arg/Arg) = 1.14, 95 %CI 1.02-1.28, P (OR) = 0.022), except for the additive contrast model (OR(Arg/Gln vs. Arg/Arg) = 1.11, 95 %CI 0.99-1.25, P (OR) = 0.064). The statistically significant association between the XRCC1 Arg399Gln polymorphism and CRC risk was observed among studies with high quality and in Asians, but not in Caucasians. Sensitivity analyses by sequential omission of any individual studies further identified the significant association. Publication bias was inexistent in this meta-analysis. The meta-analysis suggests that the XRCC1 Arg399Gln polymorphism is associated with increased risk of CRC.

To clarify any association between the hOGG1 Ser326Cys polymorphism and susceptibility to hepatocellular carcinoma (HCC).

The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer.

Prostate cancer is currently the most frequently diagnosed malignancy in men and the second leading cause of cancer-related deaths in industrialized countries. Worldwide, an increase in prostate cancer incidence is expected due to an increased life-expectancy, aging of the population and improved diagnosis. Although the specific underlying mechanisms of prostate carcinogenesis remain unknown, prostate cancer is thought to result from a combination of genetic and environmental factors altering key cellular processes. To elucidate these complex interactions and to contribute to the understanding of prostate cancer progression and metastasis, analysis of large scale gene expression studies using bioinformatics approaches is used to decipher regulation of core processes.

A number of case-control studies were conducted to investigate the association of glutathione S-transferase (GST) genetic polymorphisms and hepatocellular carcinoma (HCC) risk. However, these studies have yielded contradictory results. We therefore performed a meta-analysis to derive a more precise estimation of the association between polymorphisms on GSTM1, GSTT1 and HCC.

Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10(-8); odds ratio 1.29, 95% CI: 1.18-1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC.

Fibroblast growth factor receptor 2 (FGFR2) is a member of a receptor tyrosine kinase gene superfamily, involved in cell growth, invasiveness, motility, and angiogenesis, which has attracted considerable attention as a candidate gene for breast cancer (BC) since it was first identified through genome-wide association approach. In the past few years, the relationship between FGFR2 and BC has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 37 studies involving a total of 288,142 subjects for rs2981582, rs1219648, and rs2420946 polymorphism of the FGFR2 gene to evaluate the effect of FGFR2 on genetic susceptibility for BC. Overall, significantly increased BC risk was associated with these polymorphisms when all studies were pooled into the meta-analysis. In addition, our data indicate that FGFR2 is involved in BC susceptibility and confer its effect primarily in estrogen receptor-positive and progesterone receptor-positive tumors. When stratified by ethnicity, significantly increased risks were found in Caucasian and East Asian populations. However, no significant associations were detected among African descent populations. There was strong evidence of heterogeneity (P < 0.05), which largely disappeared after stratification by ethnicity. This meta-analysis demonstrated that FGFR2 polymorphism is a risk factor associated with increased BC susceptibility, but these associations vary in different ethnic populations.

The conclusions of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) A/G gene polymorphism and the histological types of lung cancer are still debated. GSTP1 is one of the important mutant sites reported at present. This meta-analysis was performed to evaluate the association between GSTP1 and histological types of lung cancer. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Seventeen reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and histological types of lung cancer. The G allele and GG genotype were not associated with the susceptibility of risk of squamous cell carcinomas, adenocarcinomas, small cell carcinoma, non-small cell carcinoma or large cell carcinoma. However, in the sub-group analysis, there was an association between G allele/GG genotype with the risk of squamous cell carcinomas in East-Asians and GG genotype was associated with the risk of small cell carcinoma in Caucasians. In conclusion, GSTP1 A/G gene polymorphism is not associated with the susceptibility of squamous cell carcinomas, adenocarcinomas, small cell carcinoma, non-small cell carcinoma or large cell carcinoma.

Previous studies investigating the association between TP53 Arg72Pro polymorphism and bladder cancer risk reported controversial results. To quantify the strength of association between TP53 Arg72Pro polymorphism and bladder cancer risk, we performed this meta-analysis. We searched PubMed, Embase and Wangfang databases for studies relating the association between TP53 Arg72Pro polymorphism and bladder cancer risk. We used the pooled odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) to assess the association. Finally, data were available from a total of 16 case-control studies including a total of 5, 545 subjects (2,345 cases and 3,200 controls). Meta-analysis of all 16 studies showed TP53 Arg72Pro polymorphism was not associated with bladder cancer risk (All P values were more than 0.10). Subgroup analyses by ethnicity showed that TP53 Arg72Pro polymorphism contributed to bladder cancer risk in East Asians in three genetic models (For Pro vs. Arg, Fixed-effects OR 1.18, 95 % CI 1.05-1.32; For ProPro vs. ArgArg, Fixed-effects OR 1.40, 95 % CI 1.11-1.77; For ProPro vs. ArgPro/ArgArg, Fixed-effects OR 1.32, 95 % CI 1.07-1.62). However, there was no significant association in Caucasians and the others (All P values were more than 0.05). Heterogeneity analyses suggested ethnicity was the major sources of heterogeneity. Thus, meta-analyses of available data suggest the Pro variant of TP53 Arg72Pro contributes to bladder cancer risk in East Asians. Besides, TP53 Arg72Pro polymorphism may have race-specific effects on bladder cancer risk and further studies are needed to elucidate this possible effect.

Many studies investigated the relationship between matrix metalloproteinase 2 (MMP-2) overexpression and survival in patients with colorectal cancer (CRC), but yielded inconsistent results. To derive a more precise estimate of the prognostic significance of MMP-2 overexpression, we reviewed published studies and carried out a meta-analysis. Eligible articles were identified for the period up to March 2012 in electronic databases. To evaluate the correlation between MMP-2 overexpression and the prognosis in CRC, pooled hazard ratio (HR) and its 95 % confidence interval (95 % CI) for poorer overall and progression-free survival were appropriately derived from fixed-effects or random-effects models using standard meta-analysis techniques. Thirteen studies with a total of 1,919 CRC patients stratifying overall survival (OS) and/or progression-free survival in CRC patients by MMP-2 expression status were eligible for analysis. Ten studies investigated the OS in a total of 1,612 cases with CRC, and five studies investigated the progression-free survival in a total of 508 patients CRC. The combined HR estimate for OS and progression-free survival was 1.74 (95 % CI, 1.34-2.26) and 1.35 (95 % CI, 1.07-1.80), respectively. Both subgroup analyses and sensitivity analysis further identified the prognostic role of MMP-2 overexpression in patients with CRC. There was no evidence for publication bias. In conclusion, MMP-2 overexpression is associated with poorer overall and progression-free survival in patients with CRC.

Previous evidence has indicated that the polymorphism of tumor necrosis factor-alpha (TNF-α) is a risk factor for various cancers, however, the association between TNF-α-308G/A polymorphism and nasopharyngeal carcinoma (NPC) remains controversial and ambiguous. The aim of this study is to clarify the association between TNF-α polymorphism and NPC using meta-analysis. A meta-analysis based on five eligible case-control studies involving 499 cases and 1,470 controls was carried out to summarize the data on the association between TNF-α-308G/A polymorphism and NPC risk. Odds ratios (OR) with 95 % confidence intervals (95 % CI) were used to assess the strength of this association in the fixed-effect model. The pooled analyses showed no significant association between TNF-α-308G/A polymorphism and NPC (AA vs. GG: OR = 1.38, P = 0.193; GA vs. GG: OR = 0.92, P = 0.585; GA + AA vs. GG: OR = 1.00, P = 0.972; AA vs. GA + GG: OR = 1.44, P = 0.138). We also categorized by geographic location (non-Asian or Asian) for subgroup analysis; the results also showed no significant association between TNF-α-308G/A polymorphism and NPC risk in all of the comparisons. No publication bias was observed in this study (t = -0.11, P = 0.918, 95 % CI = -4.893-4.559). No significant association was found between TNF-α-308G/A polymorphism and the risk for NPC.

Cdx2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestinal cells, and served as a potential biomarker of tumor progression in early intestinal-type gastric cancer. However, its prognostic value and significance in gastric cancer remain controversial. A meta-analysis based on published studies was performed to obtain an accurate evaluation of the association between the presence of Cdx2-positive in clinical samples and clinical outcome. A total of 13 eligible retrospective cohort studies with 1513 patients were included. Cdx2-positive cases were significantly associated with higher male-to-female ratio (RR=1.27, 95% CI: 1.17-1.38, P<0.00001 fixed-effect), lower (I+II) clinical stage (RR=1.63, 95% CI: 1.42-1.87, P<0.00001 fixed-effect), better histologic differentiation (RR=1.54, 95% CI: 1.34-1.76, P<0.00001 fixed-effect), and lower rate of vascular invasion (RR=1.23, 95% CI: 1.08-1.41, P=0.002 fixed-effect) and lymph node metastasis (RR=1.52, 95% CI: 1.33-1.73, P<0.00001 fixed-effect), as well as higher 5-year survival rate (HR=2.22, 95% CI: 1.78-2.75, P<0.00001 fixed-effect). However, the presence of Cdx2 was not associated with tumor size. In summary, Cdx2 is a prognostic factor in gastric cancer, which acts as a marker of good outcome in patients with gastric cancer. Further clinical studies are needed to confirm the role of Cdx2 in clinical practice.

Medullary thyroid carcinoma (MTC) is a rare tumor, partially explained by mutations in the rearranged during transfection (RET) proto-oncogene. The nonsynonymous RET polymorphism G691S has been reported as associated with MTC, but findings are discordant. We sought to clarify the role of G691S in MTCs through in silico analysis, genetic association in our patients and a meta-analysis with extensive literature revision. Ninety-three Italian patients were compared to 85 healthy individuals. Results were included in a meta-analysis together with 11 case-control association studies identified through PubMed, EMBASE and Web of Science, with a combined sample of 968 cases and 2,115 controls. No association of G691S with MTC was found in our sample; however, we observed an excess of homozygotes for the variant, significantly higher among females. The overall allelic association in the meta-analysis was significant under the fixed-effect model (odds ratio [OR] = 1.22 [95% confidence intervals: 1.06-1.39], p = 0.0049), but borderline under the random effect model (OR = 1.21 [0.99-1.46], p = 0.0575), with a moderate/high heterogeneity (I(2) = 44.6%, p = 0.047). Under the recessive model of transmission, applied to the eight studies with available genotype frequencies, results were significant under both effect models (OR = 2.016 and OR = 2.022, p = 0.0004). No heterogeneity was anymore detectable. In silico analyses on G691S confirmed a change of the phosphorylation pattern that might account for the enhanced signaling transduction previously reported for G691S in several cancers, thus also explaining its overrepresentation in MTCs. The G691S variant allele does increase the risk for MTC, with a recessive mechanism of action, apparently more evident among females.

Bisphosphonate-related osteonecrosis of the jaws (BONJ) is a severe complication in patients on bisphosphonate therapy. The study was conducted to verify the association between CYP2C8 (rs1934951) polymorphism and BONJ predisposition.