Published data on the association between manganese superoxide dismutase (MnSOD) Val(16)Ala polymorphism and prostate cancer (PCA) risk are inconclusive. To derive a more precise estimate of the association between them, a meta-analysis was performed.

Quantitative analysis of circulating cell free DNA is considered as a possible aid for lung cancer screening. We aimed to comprehensively review the evidence for use of circulating cell free DNA to screen for lung cancer.

The limitation of small sample size of functional genomics experiments has made it necessary to integrate DNA microarray experimental data from different sources. However, experimentation noises and biases of different microarray platforms have made integrated data analysis challenging. In this work, we propose an integrative computational framework to identify candidate biomarker genes from publicly available functional genomics studies.

Transforming growth factor-beta1 (TGFbeta1) plays a significant role in regulating cellular proliferation and apoptosis. The TGFbeta1 T29C polymorphism reportedly affects cancer risk, but pertinent studies offer conflicting results. We therefore performed a meta-analysis based on 40 studies from 32 publications, assessing the strength of the association using odds ratios with 95% confidence intervals. Overall, no evidence has indicated that individuals carrying CC or CT genotypes had significantly increased cancer risks, compared with TT genotype carriers [CC vs. TT: odds ratio (OR)=1.10, 95% confidence interval (95% CI)=1.00-1.21, P=0.06; CT vs. TT: OR=1.07, 95% CI=0.99-1.16, P=0.09). However, stratified analysis by cancer type and ethnicity indicated a significantly increased risk of prostate cancer (CT vs. TT: OR=1.28, 95% CI=1.01-1.61, P=0.04) and cancer in those of Asian descent (CC vs. TT: OR=1.26, 95% CI=1.03-1.53, P=0.02; CT vs. TT: OR=1.20, 95% CI=1.01-1.43, P=0.04). This association was also observed in the dominant model for prostate cancer. Although not all bias could be eliminated, this meta-analysis suggested that TGFbeta1 29C was a low-penetrant risk factor for prostate cancer and cancer in Asians. A larger single study is still required to evaluate any association with other types of cancer or in other populations.

To investigate the effect of c-kit mutation on the prognosis of gastrointestinal stromal tumors.

Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and gastric cancer risk have reported conflicting results. Therefore, we conducted this meta-analysis to provide more precise evidence.

The SULT1A1 R213H polymorphism is suggested to be implicated in the development and progression of breast cancer. However, the published findings are inconsistent. We therefore performed a meta-analysis of 8,454 breast cancer cases and 11,800 controls from 14 published case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association of the R213H polymorphism with breast cancer risk. Overall, our results suggested that there is no significant relationship between SULT1A1 R213H polymorphism and the risk of breast cancer. However, further ethnic population analysis revealed a significantly increased risk of breast cancer for HH allele carriers among Asians (for HH vs. RR: OR = 2.27, 95% CI = 1.11-4.63, P (heterogeneity) = 0.63; for the recessive model: OR = 2.03, 95% CI = 1.00-4.41, P (heterogeneity) = 0.62). Taken together, this meta-analysis suggests that the SULT1A1 R213H may be a low-penetrant risk factor for developing breast cancer in Asian population.

Published data on the association between present/null polymorphism of glutathione S-transferase M1 (GSTM1) and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the GSTM1 present/null polymorphism and breast cancer risk. The pooled ORs were performed for null versus present genotype. A total of 59 studies including 20,993 cases and 25,288 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with null genotype when all studies were pooled into the meta-analysis (OR = 1.10, 95% CI = 1.04-1.16). In the subgroup analysis by ethnicity, significantly increased risks were found for Caucasians (OR = 1.05, 95% CI = 1.00-1.10) and Asians (OR = 1.21, 95% CI = 1.08-1.35). When stratified by population-based studies or hospital-based studies, statistically significantly elevated risks were found among population-based studies (OR = 1.11, 95% CI = 1.03-1.20). In the subgroup analysis by menopausal status, statistically significantly increased risks were found among postmenopausal women (OR = 1.15, 95% CI = 1.04-1.28). In conclusion, this meta-analysis suggests that the GSTM1 null genotype is a low-penetrant risk factor for developing breast cancer.

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with unknown aetiology which is considered to be the most common endocrine disorder in women of reproductive age. In this work we investigated the association of insulin receptor (IotaNSR) and insulin receptor substrates (IRSs) polymorphisms with the risk of developing PCOS. The meta-analysis of eleven studies (889 cases, 1303 controls) yielded a significant association for IRS-1 Gly972Arg (G972R) polymorphism concerning the GR vs. GG genotype (OR: 1.77, 95% CI: 1.28, 2.45), with no between-studies heterogeneity. Concerning IotaNSR His1058 C/T, the meta-analysis of eight studies (795 cases, 576 controls) found no significant evidence for association with PCOS (OR for the TT+CT vs. CC comparison equal to 1.28 with 95% CI: 0.88, 1.85) and a moderate between studies variability (I(2)=44.6%). No evidence for publication bias was found in these meta-analyses. Following a multivariate Mendelian randomization approach, the overall OR was unaffected but the overall mean difference of fasting insulin levels between carriers of GR and RR genotypes in controls was significant (2.18, 95% CI: 0.36, 4.01). These results suggest that IRS-1 Gly972Arg polymorphism is significantly associated with the risk of developing PCOS and that this association is primarily mediated by increasing the levels of fasting insulin. The particular polymorphism is located in a region nearby two phosphorylation sites that interact physically with INSR and PI 3-kinase and there is enough evidence from the literature suggesting that the Arg972 variant is associated with decreased PI 3-kinase activity and impaired insulin-stimulated signaling.

Studies on polymorphism of X-ray repair cross-complementing group 1 (XRCC1), group 3 (XRCC3), and colorectal cancer risk are inconclusive. The purpose of this study is to evaluate the role of XRCC1 R399Q, R194W, and XRCC3 T241M genotypes in colorectal cancer susceptibility.

Steroid 5-alpha-reductase type 2 (SRD5a2) is a critical enzyme in androgen metabolism. Two polymorphisms in the SRD5a2 gene, V89L (rs523349) and A49T (rs9282858), have been studied for associations with prostate cancer risk, with conflicting results. The authors conducted a systematic review and meta-analysis (1997-2007) to examine these associations and compared the results with findings from genome-wide association studies of prostate cancer. The meta-analysis included 24 case-control studies (10,088 cases and 10,120 controls for V89L and 4,998 cases and 5,451 controls for A49T). The authors found that prostate cancer was not associated with V89L (L allele vs. V allele: odds ratio = 0.99, 95% confidence interval: 0.94, 1.05) and was probably not associated with A49T (T allele vs. A allele: odds ratio = 1.10, 95% confidence interval: 0.86, 1.40). These results could have been distorted by spectrum-of-disease bias, convenience sampling of cases and controls, genotype misclassification, and/or confounding. Neither V89L nor A49T was included in microarray chips used for published genome-wide association studies. Analysis of well-designed population-based studies with pathway-based arrays containing common genetic variants could be useful for identifying genetic factors in prostate cancer.

The nicotinic 15q25 locus has been implicated in lung cancer risk, with an odds ratio of approximately 1.3. The same locus is associated with nicotine dependence due to cigarette smoking and with smoking-associated chronic obstructive pulmonary disease, which is a risk factor for lung cancer. Our meta-analysis of reported studies shows that this locus was not associated with lung cancer risk in >1000 never-smoker cases and >1800 controls. Review of exposure-response data for lung cancer risk showed that less than a half-cigarette per day may confer the same risk of lung cancer as that conferred by the 15q25 locus. Given the lack of effect in never-smokers and the known common and variable underreporting of smoking habit in studies on smoking-associated diseases, we cannot exclude that the association between the 15q25 locus and lung cancer risk is indirect, deriving from association of the same locus with smoking habit. Since nicotine is not carcinogenic, available data do not provide plausibility of the association between the nicotinic 15q25 locus and lung cancer pathogenesis. Thus, a direct link between the 15q25 locus and lung cancer risk has yet to be established.

O(6)-methylguanine-DNA methyltransferase is one of the rare proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. Its two common single-nucleotide polymorphisms, Leu84Phe and Ile143Val, had previously been identified to contribute to susceptibility of cancer. However, there are conflicting results in studies on the association of the two polymorphisms with cancer. Therefore, we conducted a meta-analysis to clarify the paradox with a large collected sample (13,069 cancer patients and 20,290 controls). We found significant association between the T allele (84Phe) and cancer risk, under the recessive genetic model [P = 0.023, odds ratio (OR) = 1.251, 95% confidence interval (CI) 1.031-1.517, P(heterogeneity) = 0.270], TT versus CC comparison (P = 0.035, OR = 1.239, 95% CI 1.015-1.511, P(heterogeneity) = 0.225) and TT versus CT comparison (P = 0.007, OR = 1.292, 95% CI 1.071-1.559, P(heterogeneity) = 0.374), using the random-effect model. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the recessive genetic model, homozygote comparison and TT versus TC comparison. In the tumour sites subgroup analysis, only the protective effects of Leu84Phe polymorphism were found in colorectal cancer, under CT versus CC comparison. No significant association between the G allele of Ile143Val and cancer risk was found. The G allele showed an increased lung cancer risk under the dominant genetic model and AG versus AA comparison in all Hardy-Weinberg equilibrium subjects, only when the fixed-effect model was used. However, it was insignificant in the random-effect model.

Published data on the association between TGFBR1*6A/9A polymorphism and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 32 studies including 13,662 cases and 14,147 controls were involved in this meta-analysis. Overall, significantly elevated cancer risks were associated with TGFBR1*6A in all genetic models (for allelic effect: OR = 1.11; 95% CI = 1.03-1.21; for 6A/6A vs. 9A/9A: OR = 1.30; 95% CI = 1.01-1.69; for 9A/6A vs. 9A/9A: OR = 1.08; 95% CI = 1.01-1.15; for dominant model: OR = 1.08; 95% CI = 1.02-1.15; for recessive model: OR = 1.29; 95% CI = 1.00-1.68). In the subgroup analysis by cancer types, significant associations were found in breast cancer (for allelic effect: OR = 1.16; 95% CI = 1.01-1.34) and ovarian cancer (for allelic effect: OR = 1.24; 95% CI = 1.00-1.54; for 6A/6A vs. 9A/9A: OR = 2.34; 95% CI = 1.03-5.33). However, no significant associations were found in colorectal cancer, bladder cancer, prostate cancer and lung cancer for all genetic models. In summary, this meta-analysis suggests that the TGFBR1*6A/9A polymorphism is associated with cancer susceptibility, increasing the risk of breast and ovarian cancer.

Variants of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes have been implicated as risk factors for chronic myeloid leukemia (CML). However, the genetic association studies that examined the relation between the null genotypes of GSTM1 and GSTT1 genes and risk of developing CML gave conflicting or inconclusive results. In an attempt to interpret these results, a meta-analysis of all available studies (nine studies, with 757 cases and 1959 controls) was performed. In the meta-analysis the pooled odds ratios (OR) were estimated using random effects models. The heterogeneity between studies, the sources of potential bias, and the consistency of genetic effects across ethnicities were explored. Cumulative meta-analysis was also performed. Overall, the meta-analysis showed nonsignificant association between GSTM1 null genotype and CML (OR = 1.00 [0.83-1.20]) and lack of heterogeneity between the studies (p(Q) = 0.87). The association was also nonsignificant in Whites, East Asians, and Indians: OR = 1.38 (0.43-4.46), 0.94 (0.65-1.35), and 1.16 (0.74-1.82), respectively. However, GSTT1 null genotype was associated with increased risk of CML (OR = 1.57 [1.13-2.17]) and the heterogeneity between studies was significant (p(Q) = 0.04). In Indians, the association was significant (OR = 2.89 [1.56-5.35]) whereas in East Asians it was not significant (OR = 1.07 [0.74-1.54]). The combined GSTM1 normal/GSTT1 null genotypes produced significant association (OR = 1.95 [1.17-3.24]). Cumulative meta-analysis for GSTT1 gene showed an upward trend in risk effect, whereas the trend was downward in GSTM1. There was a differential magnitude of effect in large versus small studies. In conclusion, the accumulated evidence indicated an association between GSTT1 null genotype and CML.

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Matrix metalloproteinase (MMP) 1 and MMP3 are enzymes that degrade the extracellular matrix and have been implicated to play an important role in cancer development. Many studies have been carried out on the association between polymorphisms of MMP1 -1607 1G>2G and MMP3 -1171 5A>6A and cancer risk. However, results from these studies remain inconclusive. Here, we performed a meta-analysis of >38 000 subjects to better assess the purported associations. For MMP1, -1607 2G/2G genotype carriers were found to have an increased risk of colorectal cancer [2G/2G versus 2G/1G + 1G/1G, odds ratio (OR) = 1.48, 95% confidence interval (CI) (1.26-1.74), P(heterogeneity) = 0.066, I(2) = 49.3%], head and neck cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.61, 95% CI (1.26-2.07), P(heterogeneity) = 0.002, I(2) = 64.7%] and renal cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.82, 95% CI (1.38-2.39), P(heterogeneity) = 0.589, I(2) = 0.0%] risk. For MMP3, no association was found between -1171 5A>6A polymorphism and cancer risk in the overall group [6A versus 5A, OR = 1.00, 95% CI (0.95-1.05), P(heterogeneity) = 0.124, I(2) = 24.9%] and individual cancer subgroups, but stratified analysis by smoking status showed that this polymorphism had different effects on smokers and non-smokers under recessive genetic model. In summary, our study suggests that MMP1 -1607 2G may be associated with an increased cancer risk for certain types of cancers, MMP3 -1171 5A>6A may not be a major risk factor for cancer, but it may be modified by certain environmental factors. Future studies with larger sample sizes are warranted to further evaluate these associations in more detail.

Polymorphisms in methionine synthase (MTR) gene may be involved in carcinogenesis by affecting DNA methylation. However, association studies on MTR A2756G polymorphism in cancers have reported conflicting results. Therefore we performed a meta-analysis to better assess the associations. A total of 24 896 cancer patients and 33 862 controls from 52 articles for MTR A2756G were investigated. Overall, individuals carrying MTR 2756GG genotype had a subtly reduced cancer risk under a recessive genetic model (odds ratio (OR), 0.92; P=0.053; 95% confidence interval (95% CI), 0.84-1.00; I(2)=0.0%; P(heterogeneity)=0.61). In the subgroup analyses by ethnicity, 2756GG was associated with a significantly reduced cancer risk in European populations (OR, 0.83; P=0.001; 95% CI, 0.74-0.93; I(2)=0.0%; P(heterogeneity)=0.99). However, in Asian populations, a significantly elevated association between 2756GG genotype and cancer risk was observed (OR, 1.33; P=0.012; 95% CI, 1.06-1.65; I(2)=0.0%; P(heterogeneity)=0.50). In studies stratified by tumor site, there was a significantly reduced risk of acute lymphoblastic leukemia (ALL) (OR, 0.54; P=0.049; 95% CI, 0.29-1.00; I(2)=10.7%; P(heterogeneity)=0.33) and colorectal cancer (OR, 0.63; P=0.004; 95% CI, 0.47-0.87; I(2)=0.0%; P(heterogeneity)=0.73) in European populations. Our study indicates that MTR A2756G polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors. Large-scale, well-designed, and population-based studies are required to further investigate gene-gene and gene-environment interactions on MTR A2756G polymorphism and tissue-specific cancer risk in an ethnicity-specific population.

The use of adjuvant therapy in stage II colorectal cancer (CRC) remains controversial. There is a need to identify more effective predictors than the traditional staging system to aid therapeutic decision-making. We performed a systematic review and meta-analysis of gene expression profiles (GEPs) to assess their utility for risk stratification and prediction of poor outcomes in stage II CRC.