Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.

Esophageal cancer (EC) is a complex multifactorial disorder, where environmental and genetic factors play major role. NADPH:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) are phase II cytosolic enzymes that catalyze metabolism of quinones, important in the detoxification of environmental carcinogens. A case-control study was performed to investigated the associations of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility to EC in a high-risk Kashmiri population of India in 135 EC patients and 195 unrelated healthy controls using PCR-RFLP. We also performed a meta analysis of nine published studies (1,224 cases and 1,740 controls) on NQO1 609C>T and evaluated the association between the NQO1 609C>T polymorphisms and esophageal cancer risk. A significant difference in NQO1 609C>T and NQO2 -3423G>A genotype distribution between EC cases and corresponding controls groups was observed (OR = 2.65; 95 % CI = 1.29-5.42 and OR = 1.88; 95 % CI = 1.02-3.49 respectively). Further, gene-gene interaction showed significantly increased risk for esophageal adenocarcinoma with variant genotypes of NQO1 609C>T and NQO2 -3423G>A polymorphisms and interaction with environmental risk factors revealed pronounced risk of EC with NQO1 609C>T TT genotype in high salted tea users of Kashmir valley (OR = 3.72, 95 % CI = 0.98-14.19). Meta analysis of NQO 609C>T polymorphism also suggested association of the polymorphism with EC in Asians as well as Europeans. In conclusion, NQO1 609C>T and NQO2 -3423G>A genetic variations modulate risk of EC in high-risk Kashmir population.

Gastric adenocarcinoma (gastric cancer, GC) is a major cause of global cancer mortality. Identifying molecular programmes contributing to GC patient survival may improve our understanding of GC pathogenesis, highlight new prognostic factors and reveal novel therapeutic targets. The authors aimed to produce a comprehensive inventory of gene expression programmes expressed in primary GCs, and to identify those expression programmes significantly associated with patient survival.

Glutathione S-transferases (GSTs) are postulated to be involved in the detoxification of potential carcinogens, and gene variation may alter susceptibility to lymphomas. Results from several previous epidemiologic studies have been inconsistent. Hence a meta-analysis was conducted to verify the role of GST genetic polymorphisms in lymphoma risk. Eleven trials involving 1626 patients and 2892 controls were analyzed. Pooled results showed that the GSTT1 null polymorphism might increase the risk of lymphoma (odds ratio [OR] 2.26, 95% confidence interval [CI] 1.20, 4.24; p = 0.01; random-effects model), whereas the impact of GSTM1 and GSTP1 Ile105Val polymorphisms was not significant. Subgroup analysis showed the GSTT1 null genotype to be a risk factor for non-Hodgkin lymphoma (NHL) (OR 2.75, 95% CI 1.17, 6.45; p = 0.02; random-effects model) but not for Hodgkin lymphoma (HL), and the effect remained evident in females (OR 1.43, 95% CI 1.04, 1.97; p = 0.03; I(2) = 41.0%, p for heterogeneity = 0.15; fixed-effects model). An effect of GSTM1 and GSTT1 double null genotype on lymphoma risk was also shown (OR 2.09, 95% CI 1.31, 3.33; p = 0.01; random-effects model). In conclusion, the GSTT1 null genotype appears to be associated with a modest increase in the risk of NHL, whereas the GSTM1 and GSTP1 Ile105Val polymorphisms are unrelated to lymphoma risk.

Angiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990-July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C>T, -460T>C, +405G>C, -1154G>A, and -2578C>A) identified a significant prognostic relationship: VEGF +405G>C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60-0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G>C were significantly associated with improved survival in a meta-analysis of multiple cancer sites.

This meta-analysis aims to examine whether the genotype status of MspI, Ile462Val, and Thr461Asn polymorphisms in Cytochrome P450 1A1 (CYP1A1) is associated with ovarian cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: October 2010). Pooled odds ratios (ORs) were appropriately derived from fixed effects or random effects models. Concerning MspI polymorphism, seven studies were eligible (1,051 cases and 1,613 controls); 11 studies were eligible (1,680 cases and 3,345 controls) for Ile462Val and three studies were eligible (349 cases and 785 controls) for Thr461Asn. Ile462Val polymorphism seemed to confer elevated ovarian cancer risk concerning homozygous carriers (pooled OR = 2.65, 95 % CI: 1.40-5.03, p = 0.003, fixed effects), as well as at the recessive model (pooled OR = 2.10, 95 % CI: 1.13-3.92, p = 0.020, fixed effects); these findings were replicated upon Caucasian subjects. MspI polymorphism was not associated with ovarian cancer risk (for heterozygous TC vs TT carriers pooled OR = 1.10, 95 % CI: 0.91-1.34, p = 0.329, fixed effects; for homozygous CC vs. TT carriers pooled OR = 1.11, 95 % CI: 0.65-1.90, p = 0.693, fixed effects). With respect to Thr461Asn polymorphism a finding of borderline statistical significance emerged, pointing to marginally elevated ovarian cancer risk in heterozygous Thr/Asn carriers (pooled OR = 1.62, 95 % CI: 0.97-2.70, p = 0.066, fixed effects), but not in homozygous Asn/Asn carriers (pooled OR = 1.40, 95 % CI: 0.18-10.89, p = 0.749, fixed effects). Ile462Val status seems to represent a meaningful risk factor for ovarian cancer in Caucasians. Additional case-control studies of high methodological quality are needed in order to further substantiate and enrich the present findings. Special attention should be paid upon the design of future studies; Asian and African populations should represent points of focus.

Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.

The association between Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma (PPAR) and polycystic ovary syndrome (PCOS) has been investigated in several studies, whereas results were often incompatible. We conducted a meta-analysis to evaluate the association of Pro12Ala polymorphism in PPAR with PCOS susceptibility. A meta-analysis was performed on the published studies before November, 2011. Meta-analysis was performed for genotypes CG versus CC, CG+GG versus CC and G allele versus C allele in a fixed effect model. The combined odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to estimate the strength of the association. A total of 13 studies including 1,598 cases and 1,881 controls were enrolled. Ultimately, sensitivity analysis demonstrated that, in total, there was no significant association between Pro12Ala polymorphism and PCOS in the contrast of G allele versus C allele OR = 0.84 (95 % CI 0.69-1.04) and in Europeans, no significant association in the comparison of G allele versus C allele (OR = 0.84, 95 % CI 0.67-1.06) was also indicated. In summary, according to the results of our meta-analysis, strictly, the Pro12Ala polymorphism did not significantly associate with PCOS, though the protective trend of G allele existed.

The tumor suppressor gene TP53 and its negative regulator murine double minute 2 are involved in multiple cellular pathways. Two potentially functional single nucleotide polymorphisms (SNPs) MDM2 SNP309 and TP53 R72P have been extensively investigated to be associated with breast cancer risk. However, the original studies as well as the subsequent meta-analysis, have yielded contradictory results for the individual effect of the two SNPs on breast cancer risk, plus that conflicting results also existed for the combined effects of MDM2 SNP309 and TP53 R72P on breast cancer risk. This meta-analysis aimed to clarify the individual and combined effects of these two genes on breast cancer risk. We performed a meta-analysis of publications with a total 9,563 cases and 9,468 controls concerning MDM2 SNP309 polymorphism and 19,748 cases and 19,962 controls concerning TP53 R72P. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the association. In overall meta-analysis, individuals with the MDM2 SNP309TG genotype were associated with a borderline higher breast cancer risk than those with TT genotype (OR = 1.11, 95 % CI: 1.00-1.24, P (heterogeneity) = 0.007), whereas the TP53 R72P CC or GC genotype had no effects on breast cancer risk. In the stratified analyses, a significant association between MDM2 SNP309 and breast cancer risk were observed in Asian, but null significant association between TP53 R72P and breast cancer risk were found even in various subgroups. Moreover, no significant combined effects of MDM2 SNP309 and TP53 R72P were observed on breast cancer risk. The borderline association between MDM2 SNP309 and breast cancer risk in overall analysis should be treated with caution, and no significant combined effects for the two SNPs on breast cancer risk suggested functional investigations warranted to explore the molecular mechanism of the TP53-MDM2 circuit genes.

Methylenetetrahydrofolate reductase (MTHFR) is believed to be involved in folate metabolism which plays a critical role in carcinogenesis. To date, many case-control studies have investigated the association between MTHFR C677T polymorphism and colorectal cancer risk. However, the results were inconsistent. In order to derive a more precise estimation of the association, we conducted this meta-analysis. This meta-analysis recruited 61 published studies which were selected by a search of PubMed up to 31st September 2011, including 16,111 colorectal cancer cases and 23,192 controls. We used crude odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association between MTHFR C677T polymorphism and colorectal cancer susceptibility. Our results showed that MTHFR C667T polymorphism contributed to the decreased colorectal cancer risk in overall population (for TT vs. CC: OR = 0.89, 95 % CI = 0.82-0.97; for TT vs. CT/CC: OR = 0.88, 95 % CI = 0.83-0.92). In subgroup analysis by ethnicity, the results also indicated a correlation between the T allele of MTHFR C667T and the colorectal cancer risk in Asian population (for TT vs. CC: OR = 0.82, 95 % CI = 0.69-0.97; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.74-0.90). Additionally, the correlation was also observed in male subgroup in sub-analysis by gender (for TT vs. CC: OR = 0.82, 95 % CI = 0.71-0.93; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.71-0.92). In summary, our meta-analysis strongly indicated the MTHFR C667T polymorphism was associated with a reduced risk of CRC.

X-ray repair cross-complementing group 1 gene (XRCC1) has been implicated in risk for lung cancer. However, the results from different studies remain controversial. In this meta-analysis, we have assessed 44 published case-control studies regarding associations of lung cancer risk with three common polymorphisms, codon 194, codon 280 and codon 399, and -77 T > C in the promoter region of XRCC1. The results in total population showed that the risk for lung cancer was increased among the variant homozygote Trp/Trp of codon 194 polymorphism, compared with the wild type Arg/Arg (OR: 1.19; 95 % CI 1.01-1.39), and the variant genotype CC of -77 T > C polymorphism showed a significantly increased risk of developing lung cancer, compared to wild-type genotype TT (OR: 1.91; 95 % CI 1.24-2.94). However, no associations were found between lung cancer risk and codon 280, codon 399. In the subgroup analyses by ethnicity, the OR for the variant homozygote Trp/Trp of codon 194 was 1.21(95 % CI 1.02-1.43) for Asian. When stratified by source of control, we found a protective effect of codon 194 Arg/Trp genotype (OR: 0.87; 95 % CI 0.77-0.98) and risk effect of codon 399 combined Arg/Gln + Gln/Gln variant genotype (OR: 1.09; 95 % CI 1.01-1.18) for lung cancer on the basis of hospital control. Subgroup analyses by histological types of lung cancer indicated that the heterozygote Arg/Trp in codon 194 could decrease and the combined variant genotype Arg/Gln + Gln/Gln in codon 399 could increase the risk of non-small cell lung cancer (OR: 0.69; 95 % CI 0.57-0.85 and OR: 1.14; 95 % CI 1.04-1.24). In conclusion, this meta-analysis has demonstrated that codon 194, codon 399 and -77 T > C polymorphisms of XRCC1 gene might have contributed to individual susceptibility to lung cancer. To further evaluate effect of XRCC1 polymorphisms, gene-gene interaction and gene-environment interaction on lung cancer risk, a single large sample size study with thousands of subjects is required to get conclusive results.

The aim of this study was to assess the relationships between transforming growth factor β1-509C/T (rs1800469) and +869T/C (rs1800470) polymorphisms and the risk of upper digestive tract cancer (UDT cancer) by using a meta-analysis. We interrogated the databases of Medline, Embase and Wanfang (Chinese literature database) (latest update; December 15, 2011). Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were used to assess the strength of the associations. In total, 20 case-control studies were included in this meta-analysis. Overall, both TGF β1-509C/T and +869T/C polymorphisms were not associated with risk of UDT cancer [-509C/T: OR (95%CI) = 1.10 (0.99-1.22) for TT vs. C carries, P(heterogeneity) = 0.10; +869T/C: OR (95%CI) = 1.04 (0.88-1.23) for CC vs. T carriers, P(heterogeneity) = 0.02]. Subgroup analyses indicated that the -509T allele was associated with increased risk of UDT cancer in population-based studies (OR = 1.16 (1.04-1.31), P(heterogeneity) = 0.31 for TT vs. C carriers) and in small sample-sized studies (OR = 1.45 (1.15-1.84), P(heterogeneity) = 0.56 TT vs. C carriers). All subgroup analyses for the TGF β1+869T/C polymorphism indicated null association except for hepatocellular carcinoma. Interestingly, both the TGF β1-509T allele and the +869C allele were associated with decreased risk of hepatocellular cancer based on limited original studies. This meta-analysis indicated that TGF β1-509C/T rather than +869T/C is a potential risk factor for UDT cancer.

Published data have implicated NAT2 polymorphisms as risk factors for various cancers. A number of studies have focused on the association of NAT2 polymorphisms with susceptibility to oral carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship. We first carried out a deliberate search in the databases without a language limitation, covering all papers published up to Dec 2011. A total of seven case-control studies including 1,379 cases and 1,868 controls were selected and the relevant data were extracted for systematic meta-analyses. No significant association was found for the overall data (OR: 1.04, 95 % CI: 0.79-1.39). In subgroup analyses according to ethnicity, slow acetylators might increase oral cancer risk among Asians (OR: 1.38, 95 % CI: 1.04-1.82) but not Caucasians or Mixed races. The data suggested that NAT2 polymorphisms might be a low-penetrant risk factor for oral carcinoma in Asians.

A number of studies have investigated the role of matrix metalloproteinase 2 (MMP2) polymorphisms and expression in lung cancer, but have yielded inconsistent and inconclusive results. To derive a more precise estimate of the prognostic role of MMP2 expression and the susceptibility role of MMP2 polymorphisms in lung cancer, we reviewed published studies and carried out a meta-analysis. Eligible articles were identified in electronic databases. Case-control studies assessing the associations between MMP2 polymorphisms and lung cancer risk or cohort studies assessing the prognostic role of MMP2 expression in patients with lung cancer were included. Pooled odds ratio (OR) or hazard ratio (HR) with 95 % confidence interval (95 % CI) was used to assess the role of MMP2 polymorphisms and expression in lung cancer, respectively. Seven case-control studies (a total of 3,190 lung cancer cases and 3,013 controls) and 18 cohort studies (2,095 lung cancer patients) were eligible. Meta-analysis of seven case-control studies suggested that individuals with TT genotype of both MMP2 C735T and C1306T polymorphisms had obviously decreased risk of lung cancer compared with those with CC genotype (for MMP2 C735T, fixed effects OR = 0.69, 95 % CI 0.49-0.97, P = 0.032; for MMP2 C1306T, fixed effects OR = 0.54, 95 % CI 0.33-0.86, P = 0.010). Meta-analysis of 18 cohort studies suggested that patients with high MMP-2 expression had poorer overall survival (fixed effects HR = 1.82, 95 % CI 1.56-2.13, P < 0.001). Subgroup by study design, ethnicity and testing methods all further identified the prognostic value of MMP2 expression in lung cancer. In conclusion, MMP2 C735T and C1306T polymorphisms are both associated with lung cancer risk, and patients with high MMP2 expression levels have poorer overall survival compared with those with low MMP2 expression levels.

The murine double minute 2 gene encodes a negative regulator of the tumor protein p53. A single nucleotide polymorphism in murine double minute 2 promoter, SNP309 T>G, has been reported to alter murine double minute 2 protein expression and to accelerate tumor formation in humans. We carried out a meta-analysis to explore the association between this polymorphism and prostate cancer risk.

To derive a more precise estimation of the relationship between miR-149 C>T polymorphism and cancer risk, a meta-analysis was performed. A total of 8 studies including 4,677 cases and 4,830 controls were involved in this meta-analysis. Overall, no significantly elevated cancer risk was associated with miR-149 T allele when all studies were pooled into the meta-analysis (CT vs. CC: OR = 0.977, 95 % CI = 0.882-1.082; TT vs. CC: OR = 0.985, 95 % CI = 0.857-1.132; dominant model: OR = 0.984, 95 % CI = 0.893-1.084; recessive model: OR = 1.026, 95 % CI = 0.931-1.132). In the subgroup analysis by ethnicity or study design, no significantly increased risks were found under all models. When stratified by cancer type, there were no significant cancer risk changes for lung cancer, breast cancer or colorectal cancer when miR-149 T allele was included. In conclusion, this meta-analysis suggests that the miR-149 C>T polymorphism may not contribute to cancer susceptibility.

A number of case-control studies were conducted to investigate the association of IL6 gene polymorphisms with colorectal cancer (CRC). However, the results were not always consistent. We performed a systematic review and meta-analysis to examine the association between the IL6 gene polymorphisms and CRC. Data were collected from the following electronic databases: PubMed, EMBASE, Web of Science, BIOSIS Previews, HuGENet, and Chinese Biomedical Literature Database, with the last report up to July 2011. A total of 17 studies involving 4 SNPs were included (16 for rs1800795, 2 for rs1800796, 2 for rs1800797, and 1 for rs13306435). Overall, no significant association of these polymorphisms with CRC was found in heterozygote comparisons as well as homozygote comparison, dominant genetic model and recessive model. In subgroup analysis, among studies using population-based controls, fulfilling Hardy-Weinberg equilibrium, or using Taqman genotyping method, we did not find any significant association. However, the rs1800795 C allele was significantly associated with reduced risk for CRC among persons who regularly or currently took NSAIDs (four studies, OR = 0.750; 95 % CI, 0.64-0.88; P = 0.474 for heterogeneity test), and with increased risk for CRC among persons who drank (one study, OR = 1.97; 95 % CI, 1.32-2.94). Individuals with the rs1800795 C allele in the IL6 gene have a significantly lower risk of CRC, but in the setting of NSAIDs use. Further studies are merited to assess the association between the IL6 gene polymorphisms and CRC risk among persons who take NSAIDs, drink or smoke, etc.

The purpose of this study was to evaluate the association between X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln and Arg194Trp polymorphisms and childhood acute lymphoblastic leukemia risk (ALL) risk. A systematic search of three databases was conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) for XRCC1 polymorphisms and childhood ALL were calculated with fixed-effects models and random-effects models. This meta-analysis showed that Arg399Gln polymorphism was associated with increased risk of childhood ALL (Gln/Arg vs. Arg/Arg, OR = 1.25, 95% CI = 0.95-1.65, p = 0.032; Gln/Gln vs. Arg/Arg, OR = 1.44, 95% CI = 1.07-1.93, p = 0.448; dominant model, OR = 1.27, 95% CI = 0.98-1.66, p = 0.026; recessive model, OR = 1.16, 95% CI = 0.88-1.53, p = 0.646), while failing to detect links with the Arg194Trp polymorphism studied. In subgroup analyses, the pooled results showed that Arg399Gln polymorphism was associated with an increased risk of childhood ALL in Asians and larger sample size. However, no evidence of a significant association was observed in any subgroup of the Arg194Trp polymorphism. Our results provide evidence that the XRCC1 Arg399Gln polymorphism is associated with an increased risk of childhood ALL in the total population, especially Asians.

Epidemiological studies have evaluated the associations between interleukin-6 (IL-6) gene -174 C/G (rs1800795) and -572 C/G (rs1800796) polymorphisms and gastric cancer (GC) risk, but results and conclusions remain controversial. In order to derive a more precise estimation of the associations, we performed this meta-analysis.

MTHFR polymorphisms have been implicated as risk factors for several cancers. Studies have conducted on the associations of MTHFR polymorphisms with cervical carcinoma risk and have generated inconclusive results. The aim of the present study was to increase power demonstrating the possible relations. Meta-analyses examining the association between MTHFR C677T and A1298C polymorphisms and cervical carcinoma risk were performed. Separate analyses on ethnicity and source of controls were also implemented. Eligible studies were identified for the period up to Dec 2011. Eleven case-control studies containing 1859 cases and 2562 controls regarding MTHFR C677T polymorphisms were selected, of which four studies containing 461 cases and 832 controls described A1298C polymorphisms. For the overall data, no associations of MTHFR C677T polymorphisms with cervical carcinoma were observed (TT vs CC: OR = 1.07; 95 %CI = 0.73-1.58; dominant model: OR = 0.89; 95 %CI = 0.66-1.18; recessive model: OR = 1.13; 95 %CI = 0.84-1.52). In the subgroup analysis by ethnicity, MTHFR 677T allele was associated with decreased cervical cancer susceptibility among Caucasians (TT vs CC: OR = 0.65; 95 %CI = 0.45-0.93; dominant model: OR = 0.70; 95 %CI = 0.58-0.86) but not Asians. As for A1298C polymorphism, no marked associations of A1298C genetic variation with cervical cancer risk were observed (CC vs AA: OR = 1.01; 95 %CI = 0.60-1.73; dominant model: OR = 1.17; 95 %CI = 0.91-1.49; recessive model: OR = 0.99; 95 %CI = 0.60-1.63). Collectively, the results of the present study suggest that MTHFR 677T allele might play a preventive role for cervical carcinoma among Caucasians. A1298C polymorphisms might exert little effect on cervical cancerigenesis.