Studies investigating the association between interleukin10 (IL10) -592 promoter polymorphism and gastric cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship.

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in cancer etiology. The -765G>C and 8473T>C polymorphisms have been implicated in cancer risk. However, the results on the association between the two COX-2 polymorphisms and cancer risk are conflicting. To derive a more precise estimation of the association between them, we performed a meta-analysis of 8,090 cancer cases and 11,010 controls concerning -765G>C polymorphism and 14,283 cancer cases and 15,489 controls concerning 8473T>C polymorphism from 33 case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the -765GC or GC/CC genotypes were associated with higher cancer risk than those with the -765GG genotype and in the stratified analysis this effect maintained in colorectal carcinoma or esophageal cancer of Asian descents. Overall, no significant cancer risk of 8473T>C polymorphism was found. Stratified by cancer types, the variant 8473CC was associated with a decreased risk in breast cancer, compared with the TT or TC/TT genotypes and in lung cancer subgroup after sensitive analysis, there was a decreased risk in CC versus TT, TC versus TT and the dominant models. Moreover, a decreased risk of lung cancer was observed among smokers in the dominant model. In summary, this meta-analysis suggesting that -765G>C may cause an increased risk of colorectal carcinoma and esophageal cancer in Asian descents while 8473T>C polymorphism may cause a decreased risk of breast and lung cancer.

Studies on the polymorphisms of Xeroderma Pigmentosum Group D (XPD) have shown inconclusive trends in the risk of bladder cancer. The purpose of this study is to evaluate the role of XPD single nucleotide polymorphisms in bladder cancer susceptibility. We performed a meta-analysis on all available studies, which included 5,368 and 6,683 XPD Lys(751)Gln cases and controls and 3,220 and 4,391 Asp(312)Asn cases and controls, respectively. Overall, Significant risk effects of Lys(751)Gln genotype was found under recessive model contrast [Gln/Gln vs. (Gln/Lys + Lys/Lys)] [P = 0.04, OR = 1.12; 95% CI (1.01, 1.26)], and subtle but insignificantly increased risks between Lys(751)Gln and bladder cancer were observed under allele contrast (Gln vs. Lys) and homologous contrast (Gln/Gln vs. Lys/Lys) in all subjects. The (751)Gln allele had no significant effect on bladder cancer in all subgroups (Asian, Caucasian and USA). Significant risk effects of Asp(312)Asn polymorphism on bladder susceptibility were observed in all subjects under all genetic contrasts, however, stratified analyses showed that the (312)Asn allele showed different risk effects in USA and Caucasian. The Gln/Gln genotype acts as a risk factor in its association with bladder cancer, and the effect of Lys(751)Gln polymorphism on bladder susceptibility should be studied with larger, stratified population; the (312)Asn allele has an important role in the etiology of bladder cancer whereas the ethnic background should be carefully concerned in further studies.

Pharmacogenetic studies investigating the relationship between MTHFR gene polymorphisms and response to fluorouracil-based chemotherapy in patients with colorectal cancer have produced inconclusive results. In an attempt to interpret these results, a meta-analysis of all eligible studies published up until January 2009 was carried out.

The association of polymorphisms of tumor suppressor gene TP53 with breast cancer has widely been reported; however, the results are inconsistent. Here, we selected three commonly studied TP53 polymorphisms: codon 72 Arg > Pro, IVS3 16 bp Del/Ins, and IVS6 + 62A > G to explore their association with breast cancer risk by meta-analysis of published case-control studies. The results showed that codon 72 was not associated with breast cancer risk among 37 combined case-control studies (23,567 cases and 25,995 controls). However, a significant association with decreased risk of breast cancer was found in the Mediterranean studies (PP + PR vs. RR: OR = 0.32, 95% CI = 0.24-0.44, P < 0.001; PP vs. RR: OR = 0.35, 95% CI = 0.21-0.60, P < 0.001). IVS3 16 bp Del/Ins was significantly associated with an increased risk of developing breast cancer in a pooled 8 study dataset (2,470 cases and 2,825 controls; Ins/Ins + Del/Ins vs. Del/Del: OR = 1.15, 95% CI = 1.01-1.30, P = 0.04; Ins/Ins vs. Del/Del: OR = 1.75, 95% CI = 1.20-2.37, P = 0.003). No significant association was observed between IVS6 + 62A > G and breast cancer risk in a total of 10 studies (8,537 cases and 9,586 controls). These results suggest that IVS3 16 bp Del/Ins is likely an important genetic marker contributing to susceptibility of breast cancer, and codon 72 has a potential role in association with breast cancer risk within certain populations or regions.

To explore the impact of common variation on the risk of developing lung cancer, we conducted a two-phase genome-wide association (GWA) study. In phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (SNP) in 1,952 cases and 1,438 controls; in phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P values from phase 1 and two other GWA studies of lung cancer. In the combined analysis of phases 1 and 2, the strongest associations identified were defined by SNPs mapping to 15q25.1 (rs12914385; P = 3.19 x 10(-16)), 5p15.33 (rs4975616; P = 6.66 x 10(-7)), and 6p21.33 (rs3117582; P = 9.13 x 10(-7)). Variation at 15q25.1, but not 5p15.33 or 6p21.33, was strongly associated with smoking behavior with risk alleles correlated to higher consumption. Variation at 5p15.33 was shown to significantly influence induction of lung cancer histology. Pooling data from the four series provided 21,620 genotypes for 7,560 cases and 8,205 controls. A meta-analysis provided increased support that variation at 15q25.1 (rs8034191; P = 3.24 x 10(-26)), 5p15.33 (rs4975616; P = 2.99 x 10(-9)), and 6p21.33 (rs3117582; P = 4.46 x 10(-10)) influences lung cancer risk. The next best-supported associations were attained at 15q15.2 (rs748404: P = 1.08 x 10(-6)) and 10q23.31 (rs1926203; P = 1.28 x 10(-6)). These data indicate few common variants account for 1% of the excess familial risk underscoring the necessity of having additional large sample series for gene discovery.

To examine the association between 2 mitochondrial manganese superoxide dismutase (MnSOD) genetic polymorphisms (Ala-9Val and Ala-16Val) and prostate cancer susceptibility.

Colorectal cancer is the third most common form of cancer and the fourth most frequent cause of cancer deaths worldwide. Its development is influenced by both environmental and genetic factors. The glutathione S-transferase P1 gene (GSTP1) is a particularly attractive candidate for colorectal cancer susceptibility because it codes the enzyme involved in the metabolism of environmental carcinogens such as polycyclic aromatic hydrocarbons (PAHs). However, epidemiologic findings have been inconsistent. To investigate a putative association of GSTP1 Ile105Val polymorphism with the risk of colorectal cancer, we performed a meta-analysis and HuGE review of 16 published case-control studies (involving a total of 4386 colorectal cancer patients and 7127 controls). We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, the comparison of Val versus Ile allele showed no differential susceptibility to colorectal cancer (OR=0.98, 95% CI: 0.92-1.04). A protective effect was found in recessive, with an OR of 0.86 (95% CI: 0.76-0.98). Whereas no significant association was observed in either dominant or codominant model. In stratified subgroup analysis, no effect of Val allele was seen in subjects of Caucasian and Asian descent, and in healthy and hospital controls. In conclusion, the meta-analysis suggests that the GSTP1 Ile105Val polymorphism is unlikely to increase considerably the risk of sporadic colorectal cancer, and it should be confirmed in further studies.

Published data on the association between tumour necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 or DR4) polymorphisms rs20575 (C626G), rs2230229 (A1322G) and rs20576 (A683C) and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of nine studies, among which eight articles including 2941 cases and 3358 controls described C626G genotypes, three articles including 736 cases and 668 controls described A1322G genotypes and three studies totalling 1550 cases and 2257 controls described A683C genotypes were involved in this meta-analysis. Overall, all three polymorphisms were associated with cancer susceptibility. For C626G polymorphism, there was no association between C626G polymorphism and the risk of cancer in all genetic models when all the eligible studies were pooled into the meta-analysis. In the subgroup analysis by source of controls, statistically significantly reduced cancer risks were found among groups with population-based controls for CG versus CC (OR=0.77, 95% CI:0.65-0.91, P(heterogeneity)=0.007) and dominant model (OR=0.84, 95% CI:0.72-0.99, P(heterogeneity)=0.409). For A1322G polymorphism, we found it was associated with a significantly elevated cancer risk of all cancer types in different genetic models (homozygote comparison: OR=2.80, 95% CI:1.16-6.76, P(heterogeneity)=0.905; dominant model comparison: OR=1.57, 95% CI:1.02-2.41, P(heterogeneity)=0.167; and recessive model comparison: OR=1.22, 95% CI:0.94-1.60, P(heterogeneity)=0.535). Similar results were obtained from A683C polymorphism (homozygote comparison: OR=3.21, 95% CI:1.26-8.20, P(heterogeneity)=0.012; dominant model comparison: OR=1.61, 95% CI: 1.09-2.36, P(heterogeneity)=0.000; and recessive model comparison: OR=2.79, 95% CI: 1.17-6.68, P(heterogeneity)=0.025). In summary, this meta-analysis suggests that TRAIL-R1 C626G polymorphism is marginally associated with cancer susceptibility, and both TRAIL-R1 A1322G G allele and A683C C allele are associated with increased risk for cancer.

To explore the association between XPD codon 751 polymorphism and esophageal cancer (EC) by systematically reviewing the risk of the original studies.

Interleukin-6 (IL-6) is a cytokine involved in different physiologic and pathophysiologic processes including carcinogenesis. In 2003, a single nucleotide polymorphism (-174G/C) of the IL-6 gene promoter has been linked to breast cancer prognosis in node-positive (N+) breast cancer patients. Since, different studies have led to conflicting conclusions about its role as a prognostic and/or diagnostic marker. The primary aim of our study was to investigate the link between -174G/C polymorphism and breast cancer risk on the one hand, and -174G/C polymorphism and prognosis in different groups of patients: sporadic N+breast cancers (n=138), sporadic N- breast cancers (n=95) and familial breast cancer (n=60) on the other hand. The variables of interest were disease-free survival and overall survival. The secondary aim of the study was to screen IL-6 gene promoter using direct sequencing to identify new polymorphisms in our French Caucasian breast cancer population. No association or trend of association between -174G/C polymorphism of IL-6 gene promoter gene and breast cancer diagnosis or prognosis was shown, even in meta-analyses. Furthermore, we have identified four novel polymorphic sites in the IL-6 gene promoter region: -764G-->A, -757C-->T, -233T-->A, 15C-->A.

Caspase-8 (CASP8) is an initiator caspase implicated in the process of apoptosis in breast cancer cells. Attention has been drawn upon two polymorphisms: CASP8 D302H (rs1045485) and, more recently, CASP8 -652 6N del (rs3834129). The CASP8 -652 6N del polymorphism remains an open field, as studies are controversial. This meta-analysis aims to examine: (i) the association between CASP8 -652 6N del and breast cancer risk, separately in Chinese and Caucasian populations, and (ii) the association between CASP8 D302H and breast cancer risk. Eligible articles were identified by a search of MEDLINE, Cochrane, and EMBASE bibliographical databases for the period from June 1996 to July 2009. Regarding -652 6N del, five case-control studies were eligible (12,439 breast cancer cases, 13,253 controls) and four case-control studies were eligible for D302H (18,791 breast cancer cases, 20,318 controls). In case significant heterogeneity was detected, the random effects model was chosen; nevertheless, the fixed effects estimates are also secondarily reported as an alternative approach. Where appropriate, power calculations were performed. CASP8 -652 6N del was associated with reduced breast cancer risk at a borderline level (for del carriers: pooled OR = 0.884, 95% CI: 0.761-1.028); the power calculation pointed to lack of power in the individual studies. In the Caucasian populations, the same results seem valid (for del carriers: pooled OR = 0.944, 95% CI: 0.884-1.008). The random effects model in Chinese subjects has not reached statistical significance (for del carriers: pooled OR = 0.811, 95% CI: 0.492-1.338). CASP8 D302H was associated with reduced breast cancer risk (for H carriers: pooled OR = 0.874, 95% CI: 0.834-0.917). In conclusion, both CASP8 -652 6N del and D302H polymorphisms are associated with reduced cancer risk. Further studies are needed to gain the optimal power on -652 6N del, especially in Chinese subjects, as well as to gain insight into D302H in Chinese populations.

P53 is a tumor suppressor gene and plays important roles in the etiology of breast cancer. Studies revealing conflicting results on the role of p53 codon 72 polymorphism (G>C) on breast cancer risk led us to perform a meta-analysis to investigate this relationship. Thirty-nine published studies, including 26,041 breast cancer cases and 29,679 controls were identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results suggested that the variant genotypes were associated with a significantly reduced breast cancer risk (GC vs. GG: OR = 0.91, 95% CI: 0.83-1.00; CC/GC vs. GG: OR = 0.90, 95% CI: 0.82-0.99). In the stratified analyses, significantly decreased risks were also found among European populations (GC vs. GG: OR = 0.89, 95% CI: 0.80-0.99; CC/GC vs. GG: OR = 0.88, 95% CI: 0.80-0.98) and studies with population-based controls (GC vs. GG: OR = 0.88, 95% CI: 0.78-0.98; CC/GC vs. GG: OR = 0.87, 95% CI: 0.78-0.97). The results suggested that p53 codon 72 polymorphism may contribute to susceptibility to breast cancer, especially in Europeans. Additional well-designed large studies were required to validate this association in different populations.

No clear consensus has been reached on the TP53 Arg72Pro polymorphism (G12139C) and lung cancer risk. Thus, a meta-analysis was conducted to summarize the possible association. There was no statistical association between 12139C (Pro allele) and lung cancer risk in Caucasians compared with 12139G allele. However, the association was observed in all subjects (9,387 patients and 9,922 controls, p=0.04, OR=1.08, 95% CI 1.00-1.17), as well as in Asians (p=0.0004, OR=1.14, 95% CI 1.06-1.22). The association was also found in Asians under recessive genetic model (p<0.00001, OR=1.37, 95% CI 1.20-1.57) and homozygote comparison (CC vs. GG) (p<0.0001, OR=1.34, 95% CI 1.16-1.56). 12139C allele might increase the lung adenocarcinoma risk compared with 12139G allele (p=0.01, OR=1.11, 95% CI 1.02-1.21), and the effect was also found under recessive genetic model (p=0.003, OR=1.28, 95% CI 1.09-1.50) and homozygote comparison (CC vs. GG) (p=0.007, OR=1.28, 95% CI 1.07-1.52). There was an elevated association between the 12139C and the stage I lung cancer under dominant genetic model (p=0.04, OR=1.48, 95% CI 1.02-2.16), but no association was observed in other stages. No association of smoking was found between 12139C allele and lung cancer under recessive genetic model. Our result indicated that 12139C might increase the risk of lung cancer under recessive genetic model in adenocarcinoma, in Asians, and in lung cancer stage I. More studies stratified for lung cancer stage-genotyping interaction should be performed to clarify the role of TP53 Arg72Pro polymorphism in the development of lung cancer.

Glutathione S-transferase (GST) enzymes are known to metabolize tobacco-related carcinogens. Previous studies on the association of functional polymorphisms of GST genes with esophageal squamous cell carcinoma have yielded conflicting but overall null results. A few studies of esophageal adenocarcinoma were likewise conflicting, but the scarcity of data is striking. We aimed to study associations of the GSTM1 and GSTT1 null deletion polymorphisms as well as the GSTP1 Ile105Val polymorphism with risks for esophageal and gastric cardia cancers. DNA was prepared from 96 and 79 cases of esophageal adenocarcinoma and squamous cell carcinoma, respectively, 126 cardia cancer cases, and 471 population-based controls. Pyrosequencing typed the GSTP1 Ile105Val polymorphism, while multiplex PCR detected GSTM1 and GSTT1 deletions. Logistic regression modeling estimated odds ratios (ORs) with 95% confidence intervals (CIs). None of the studied polymorphisms were related to the risk of esophageal adenocarcinoma, but the variant GSTP1 Val(105) allele was associated with an increased risk of esophageal squamous cell carcinoma (OR = 1.7; 95% CI 1.0-2.9) and tended to be weakly, positively linked to cardia cancer (OR = 1.4; 95% CI 0.9-2.1). Finally, we performed a meta-analysis and found that GSTP1 polymorphism seems to be associated with the risk of esophageal squamous cell carcinoma among Caucasian population (OR = 1.4; 95% CI 1.0-2.2; p value for heterogeneity test 0.34).

We have carried out melanoma case-control comparisons for six vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) and serum 25-hydroxyvitamin D(3) levels in order to investigate the role of vitamin D in melanoma susceptibility. There was no significant evidence of an association between any VDR SNP and risk in 1028 population-ascertained cases and 402 controls from Leeds, UK. In a second Leeds case-control study (299 cases and 560 controls) the FokI T allele was associated with increased melanoma risk (odds ratio (OR) 1.42, 95% confidence interval (CI) 1.06-1.91, p=0.02). In a meta-analysis in conjunction with published data from other smaller data sets (total 3769 cases and 3636 controls), the FokI T allele was associated with increased melanoma risk (OR 1.19, 95% CI 1.05-1.35), and the BsmI A allele was associated with a reduced risk (OR 0.81, 95% CI 0.72-0.92), in each instance under a parsimonious dominant model. In the first Leeds case-control comparison cases were more likely to have a higher body mass index (BMI) than controls (p=0.007 for linear trend). There was no evidence of a case-control difference in serum 25-hydroxyvitamin D(3) levels. In 1043 incident cases from the first Leeds case-control study, a single estimation of serum 25-hydroxyvitamin D(3) level taken at recruitment was inversely correlated with Breslow thickness (p=0.03 for linear trend). These data provide evidence to support the view that vitamin D and VDR may have a small but potentially important role in melanoma susceptibility, and putatively a greater role in disease progression.

Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. Several studies have been conducted on the association of TP53 codon 72 polymorphisms with susceptibility to nasopharyngeal carcinoma (NPC) and have yielded inconclusive results. The aim of the present study was to assess possible associations of NPC risk with TP53 codon 72 polymorphisms.

Meta-analysis was used to synthesize results of studies on emotional consequences of predictive genetic testing for BRCA1/2 mutations conferring increased risk of breast and ovarian cancer.

MDM2 SNP309 is a single nucleotide T > G polymorphism present in intron 1 of the MDM2 gene. A variety of case-control studies have been published evaluating the association between MDM2 SNP309 and breast cancer risk. However, the published studies, as well as the subsequent meta-analyses, have yielded contradictory results. This meta-analysis aims to examine whether MDM SNP309 polymorphism may exert a differential effect on breast cancer risk along with race. Eligible articles were identified by a search of MEDLINE, Cochrane and EMBASE bibliographical databases for the period July 1993 to June 2009; 16 case-control studies were eligible (12,986 breast cancer cases, 12,993 controls). Subanalyses in case-control studies conducted on Chinese (3 studies, 892 cases, 1,435 controls) and non-Chinese populations (13 studies, 12,094 cases, 11,558 controls) were performed. All pooled odds ratios (ORs) were derived from fixed-effects models given that the between-study heterogeneity was not statistically significant. Subanalysis on Chinese subjects demonstrated that GT and GG genotype were associated with increased breast cancer risk (pooled OR = 1.272, 95% CI 1.025-1.578 and pooled OR = 1.323, 95% CI 1.034-1.694, respectively); as a result the overall effect of the G allele was statistically significant (pooled OR = 1.287, 95% CI 1.048-1.579). On the contrary, no significant associations between MDM2 SNP309 status and breast cancer risk were demonstrated in non-Chinese populations. In conclusion, the association between MDM2 SNP309 and breast cancer is modified by race. MDM2 SNP309 represents a risk factor for breast cancer in Chinese women but not in non-Chinese women. This phenomenon is analogous to that described in the context of lung cancer.

The etiology of colorectal cancer is complex and multifactorial. Tobacco smoke has been found to be associated both with colorectal adenoma and cancer development. It was hypothesized that tobacco smoking could interact with genetic factors, providing different risk estimates according to different genetic predisposition. We reviewed and summarized by a meta-analytic approach the evidence from the literature on the interaction of smoking with the five most studied gene polymorphisms (GSTM1, GSTT1, mEH3, mEH4, NAT2). We calculated pooled Odds Ratios for each gene-smoking combination by random effects models, and provided a pooled P-value for gene-smoking interaction. Heterogeneity among studies was evaluated by the Q statistic and I(2). Overall, 27 case-control studies or nested case-control studies are included in this review: 12 presented data on GSTM1 polymorphism, eight on GSTT1, seven on mEH3, mEH4, and 10 on NAT2. We found a weak suggestion of an antagonistic effect of mEH3 low or medium metabolizer with smoking on colorectal adenoma risk (pooled P-value for the interaction: 0.02): smokers carriers of mEH3 low or medium metabolizer had slightly lower risk (Odds Ratio; 95% Confidence Interval: 1.6; 1.2-2.1) than smokers with mEH3 high metabolizer (1.8; 1.4-2.4). A non-significant positive interaction between GSTT1 null genotype and smoking was suggested for colorectal adenoma risk. None of the other common genetic polymorphisms involved in tobacco carcinogens metabolism seemed to modify the smoking-related risk of colorectal adenoma or cancer.