Association between XPF polymorphisms and cancer risk: a meta-analysis

Background

Xeroderma pigmentosum complementation group F (XPF or ERCC4) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. A series of epidemiological studies have examined associations between XPF polymorphisms and cancer risk, but the findings remain inconclusive.

Methodology/Principal Findings

In this meta-analysis of 47,639 cancer cases and 51,915 controls, by searching three electronic databases (i.e., MEDLINE, EMBASE and CNKI), we summarized 43 case-control studies from 29 publications on four commonly studied polymorphisms of XPF (i.e., rs1800067, rs1799801, rs2020955 and rs744154), and we did not find statistical evidence of any significant association with overall cancer risk. However, in stratification analyses, we found a significant association of XPF-rs1799801 with a reduced cancer risk in Caucasian populations (4,845 cases and 5,556 controls; recessive model: OR = 0.87, 95% CI = 0.76–1.00, P = 0.049, P = 0.723 for heterogeneity test, I² = 0). Further genotype-phenotype correlation analysis showed that the homozygous variant CC genotype carriers had higher XPF expression levels than that of the TT genotype carriers (Student’s t test for a recessive model: P = 0.046). No publication bias was found by using the funnel plot and Egger’s test.

Conclusion

This meta-analysis suggests a lack of statistical evidence for the association between the four XPF SNPs and overall risk of cancers. However, XPF-rs1799801 may be associated with cancer risk in Caucasian populations, which needs to be further validated in single large, well-designed prospective studies.     

Association between the TP53 polymorphisms and lung cancer risk: a meta-analysis

The previous published data on the association between TP53 codon 72, intron 6, and intron 3 16 bp polymorphisms and lung cancer risk remained controversial. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. 38 publications with 51 studies were selected for this meta-analysis, including 17,337 cases and 16,127 controls for TP53 codon 72 (from 43 studies), 2,201 cases and 2,399 controls for TP53 intron 6 (from four studies), and 4,322 cases and 4,558 controls for TP53 intron 3 16 bp (from four studies). When all the eligible studies were pooled into the meta-analysis of codon 72 polymorphism, there was significant association between lung cancer risk and codon 72 polymorphism in any genetic model (dominant model: OR = 1.13, 95 % CI 1.05–1.21; recessive model: OR = 1.14, 95 % CI 1.02–1.27; additive model: OR = 1.19, 95 % CI 1.05–1.33). In the subgroup analysis by ethnicity, histological type, source of control, and smoking status, significantly increased risks were observed in subgroups such as Asians, Caucasians, lung squamous cell carcinoma patients for Asians, population-based study, hospital-based study, non-smokers, and smokers. When all the eligible studies were pooled into the meta-analysis of intron 6 polymorphism, there was significant association between lung cancer risk and intron 6 polymorphism in dominant model (OR = 1.27, 95 % CI 1.11–1.44). When all the eligible studies were pooled into the meta-analysis of intron 3 16 bp polymorphism, there was significant association between lung cancer risk and intron 3 16 bp polymorphism in dominant model (OR = 1.12, 95 % CI 1.02–1.23) and additive model (OR = 1.41, 95 % CI 1.04–1.90). Additionally, when one study was deleted in the sensitive analysis, the results of TP53 intron 3 16 bp duplication polymorphism were changed in the dominant model (OR = 1.11, 95 % CI 0.87–1.42) and additive model (OR = 1.01, 95 % CI 0.65–1.56). In summary, this meta-analysis indicates that codon 72 and intron 6 polymorphisms show an increased lung cancer risk. A study with the larger sample size is needed to further evaluated gene-environment interaction on TP53 codon 72, intron 6, and intron 3 16 bp polymorphisms and lung cancer risk.     

Association between MTHFR polymorphisms and orofacial clefts risk: a meta-analysis

BACKGROUND The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta-analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). RESULTS A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06-1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05-1.76). CONCLUSIONS This meta-analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations.     

MTHFR polymorphisms and ovarian cancer risk: a meta-analysis

The C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been reported to alter the risk of ovarian cancer. However, the results are still inconclusive. For better understanding of the effect of these two polymorphisms on ovarian cancer risk, a meta-analysis was performed. An extensive search was performed to identify all case–control studies investigating such association. The strength of association between these two polymorphisms and ovarian cancer risk was assessed by odds ratio (OR) with the corresponding 95?% confidence interval (95?% CI). 3,496 cases and 3,631 controls for C677T polymorphism and 3,280 cases and 3,346 controls for A1298C polymorphism were included in this meta-analysis. The results suggested that there were no significant associations between C677T and A1298C polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (For C677T: TT vs. CC: OR?=?0.94, 95?% CI?=?0.71–1.24, P?=?0.65; CT vs. CC: OR?=?1.03, 95?% CI?=?0.93–1.14, P?=?0.57; TT/CT vs. CC: OR?=?1.01, 95?% CI?=?0.88–1.16, P?=?0.87; TT vs. CC/CT: OR?=?0.93, 95?% CI?=?0.72–1.20, P?=?0.58. For A1298C: CC vs. AA: OR?=?1.05, 95?% CI?=?0.88–1.25, P?=?0.65; CA vs. AA: OR?=?0.98, 95?% CI?=?0.88–1.08, P?=?0.66; CC/CA vs. AA: OR?=?0.99, 95?% CI?=?0.90–1.09, P?=?0.85; CC vs. AA/CA: OR?=?1.06, 95?% CI?=?0.90–1.26, P?=?0.46). Subgroup analysis based on ethnicities and influence analysis did not perturb the results. In conclusion, the results of this meta-analysis indicate that the MTHFR C677T and A1298C polymorphisms are not associated with ovarian cancer risk, especially in Caucasians.     

Association of IL-6 polymorphisms with gastric cancer risk: evidences from a meta-analysis

The findings of associations between IL-6 polymorphisms and risk of gastric cancer are controversial. We conducted a meta-analysis of the IL-6 gene to provide evidences for the current understanding of the genetic association with gastric cancer. We searched for relevant studies without language restriction in PubMed, EMBASE and Cochrane Library published up to November 2011. The strengths of the associations between IL-6 polymorphisms and gastric cancer risk were estimated by odds ratios (OR) with 95% confidence interval (95% CI). We identified seven case-control studies involving 1364 gastric cancer cases and 1748 controls for the analysis. Because of limited eligible data, our meta-analysis specifically focused on three SNPs of the IL-6 gene, -174 G/C, -572 G/C and -597 G/A. We found no significant associations of IL-6-174 G/C, -572 G/C and -597 G/A polymorphisms with gastric cancer risk in the overall population (all p>0.05). Subgroup analysis did not show significant associations in Asian population or Caucasian population either (all p>0.05). Begg's test and Egger's test suggested no evidence of publication (all p>0.05). Our findings showed that polymorphisms of IL-6-174 G/C, -572 G/C and -597 G/A are not associated with gastric cancer risk. However, the results should be interpreted with caution due to the limited number of studies available.     

Association between cyclooxygenase-2 gene polymorphisms and risk of periodontitis: a meta-analysis involving 5653 individuals

There ?765G > C, ?1195G > A, and 8473T > C polymorphisms in cyclooxygenase-2 (COX-2) gene polymorphisms and periodontitis risk were investigated based on published studies; however, their results could not give a conclusive result. Hence, we performed this meta-analysis of six published studies with eight case–control studies including these three polymorphisms which searched from PubMed and Web of Science up to October 15th, 2013. Odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the association between the three polymorphisms of COX-2 and periodontitis risk. The results from 2,580 periodontitis patients and 3,073 healthy controls showed that none of ?765G > C, ?1195G > A, or 8473T > C polymorphism was not associated with periodontitis susceptibility [Take ?765G > C for example: OR = 0.94, 95 % CI = (0.57–1.53) for C vs. G; OR = 2.34, 95 % CI = (0.72–7.62) for CC vs. GG; OR = 0.68, 95 % CI = (0.46–1.01) for CG vs. GG; OR = 0.81, 95 % CI = (0.52–1.27) for (CG+GG) vs. GG; OR = 2.57, 95 % CI = (0.80–8.29) for CC vs. (GG+CG)]. In subgroup analyses according to the type of periodontitis and ethnicity for ?765G > C and ?1195G > A, and deviations in Hardy–Weinberg equilibrium for ?765G > C, we only observe a boundary association between ?1195G > A polymorphism and Asian population. However, due to limitations of this meta-analysis, the results should treat with caution and we suggest the further researches should be carried out to verify our results.     

Association between polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and risk of cancer metastasis: a meta-analysis

Background

A variety of studies have evaluated the associations between polymorphisms in the promoter regions of Matrix metalloproteinases (MMPs) and cancer metastasis. However, the results remain inconclusive. To better understand the roles of MMP polymorphisms in metastasis, we conducted a comprehensive meta-analysis.

Methods

Electronic databases were searched (from January 2000 to June 2011) for any MMP genetic association studies in metastasis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the associations between MMP polymorphisms and metastasis. Statistical analysis was performed with Review Manager 5.0 and STATA11.0.

Results

Thirty-three studies addressing five MMP polymorphisms were analyzed among 10,516 cancer cases (4,059 metastasis-positive cases and 6,457 metastasis-negative cases). For MMP1 (−1607)1G/2G, genotype 2G/2G increased the overall risk of metastasis under the recessive model (OR = 1.44, 95% CI = 1.05–1.98). In subgroup analysis based on cancer type, associations were found in head/neck and breast cancer under the recessive model, and also in breast cancer under the dominant model. For MMP3 (−1171) 5A/6A, the polymorphism decreased the overall risk of metastasis under two genetic models (recessive: OR = 0.80, 95%CI = 0.64–0.99, dominant: OR = 0.72, 95%CI = 0.56–0.93). The polymorphisms of MMP7 (−181) A/G and MMP9 (−1562) C/T increased metastatic risk. However, no association was observed between MMP2 (−1306) C/T and metastasis.

Conclusions

Our investigations demonstrate that polymorphisms in the promoter regions of MMP1, 3, 7 and 9 might be associated with metastasis in some cancers. Further studies with large sample size for MMP2 should be conducted.     

The association between ATM IVS 22-77 T>C and cancer risk: a meta-analysis

Background and Objectives

It has become increasingly clear that ATM (ataxia-telangiectasia-mutated) safeguards genome stability, which is a cornerstone of cellular homeostasis, and ATM IVS 22-77 T>C affects the normal activity of ATM proteins. However, the association between the ATM IVS 22-77 T>C genetic variant and cancer risk is controversial. Therefore, we conducted a systematic meta-analysis to estimate the overall cancer risk associated with the polymorphism and to quantify any potential between-study heterogeneity.

Methods

A total of nine studies including 4,470 cases and 4,862 controls were analyzed for ATM IVS 22-77 T>C association with cancer risk in this meta-analysis. Heterogeneity among articles and their publication bias were also tested.

Results

Our results showed that no association reached the level of statistical significance in the overall risk. Interestingly, in the stratified analyses, we observed an inverse relationship in lung and breast cancer.

Conclusion

Further functional research on the ATM mechanism should be performed to explain the inconsistent results in different cancer types.     

ADIPOQ gene polymorphisms and cancer risk: A meta-analysis

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.     

Association between the OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and lung cancer risk: a meta-analysis

The previous published data on the association between the 8-oxo-guanine glycosylase-1 (OGG1) and apurinic/apyrimidinic-endonuclease-1 (APEX1/APE1) polymorphisms and lung cancer risk remained controversial. Several polymorphisms in the OGG1 and APEX1 gene have been described, including the commonly occurring Ser326Cys in OGG1 and Asp148Glu in APEX1. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 37 studies were identified to the meta-analysis, including 9,203 cases and 10,994 controls for OGG1 Ser326Cys (from 25 studies) and 3,491 cases and 4,708 controls for APEX1 Asp148Glu (from 12 studies). When all the eligible studies were pooled into the meta-analysis of OGG1 Ser326Cys polymorphism, significantly increased lung cancer risk was observed in recessive model (OR?=?1.17, 95?% CI?=?1.03–1.33) and in additive model (OR?=?1.21, 95?% CI?=?1.03–1.42). In the stratified analysis, significantly increased risk of lung cancer was also observed on the population-based studies (recessive model: OR?=?1.26, 95?% CI?=?1.08–1.46, additive model: OR?=?1.42, 95?% CI?=?1.06–1.73) and non-smokers (dominant model: OR?=?1.20, 95?% CI?=?1.02–1.42, recessive model: OR?=?1.20, 95?% CI?=?1.02–1.40, additive model: OR?=?1.35, 95?% CI?=?1.08–1.68). Additionally, when one study was deleted in the sensitive analysis, the results of OGG1 Ser326Cys were changed in Asians (recessive model: OR?=?1.16, 95?% CI?=?1.06–1.27, additive model: OR?=?1.23, 95?% CI?=?1.09–1.38). When all the eligible studies were pooled into the meta-analysis of APEX1 Asp148Glu polymorphism, there was no evidence of significant association between lung cancer risk and APEX1 Asp148Glu polymorphism in any genetic model. In the stratified analysis, significantly decreased lung adenocarcinoma risk was observed in recessive model (OR?=?0.68, 95?% CI?=?0.48–0.97, P _h?=?0.475, I²?=?0.0?%). Additionally, when one study was deleted in the sensitive analysis, the results of APEX1 Asp148Glu were changed in Asians (recessive model: OR?=?1.21, 95?% CI?=?1.03–1.43) and smokers (dominant model: OR?=?1.62, 95?% CI?=?1.08–2.44, additive model: OR?=?1.37, 95?% CI?=?1.02–1.84). In summary, this meta-analysis indicates that OGG1 Ser326Cys show an increased lung cancer risk in Asians and non-smokers, APEX1 Asp148Glu polymorphism may be associated with decreased lung adenocarcinoma risk, and APEX1 Asp148Glu polymorphism show an increased lung cancer risk in Asians and smokers. However, a study with the larger sample size is needed to further evaluated gene-environment interaction on OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and lung cancer risk.     

Association between the ERCC5 Asp1104His polymorphism and cancer risk: a meta-analysis

Background

Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G>C) and cancer susceptibility generated conflicting results.

Methodology/Principal Findings

To derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism and overall cancer risk, we performed a meta-analysis of 44 published case-control studies, in which a total of 23,490 cases and 27,168 controls were included. To provide additional biological plausibility, we also assessed the genotype-gene expression correlation from the HapMap phase II release 23 data with 270 individuals from 4 ethnic populations. When all studies were pooled, we found no statistical evidence for a significantly increased cancer risk in the recessive genetic models (His/His vs. Asp/Asp: OR = 0.99, 95% CI: 0.92–1.06, P = 0.242 for heterogeneity or His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93–1.03, P = 0.260 for heterogeneity), nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression.

Conclusions/Significance

This meta-analysis suggests that it is unlikely that the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk.     

Association of CYP1A1 polymorphisms with prostate cancer risk: an updated meta-analysis

Epidemiological studies have evaluated the association between 3801T>C and 2455A>G polymorphisms of cytochrome P450 1A1 (CYP1A1) and prostate cancer risk. However, controversy exists regarding the role of these polymorphisms. In this work, a meta-analysis was performed to derive a more precise estimation of the relationship. PubMed and ISI Web databases were searched for all cases dated until March 2012. Crude odds ratios with 95?% confidence intervals were used to assess the strength of the association between CYP1A1 polymorphisms and prostate cancer risk. Sensitivity analysis, excluding the studies that deviated from the Hardy–Weinberg equilibrium (HWE), was performed. A total of 17 studies fulfilled our inclusion criteria in this meta-analysis, 12 of which were eligible (1,645 cases and 1,801 controls) for 3801T>C, and eleven (1,640 cases and 1,959 controls) were eligible for 2455A>G. Overall, the 2455A>G polymorphism resulted in a significantly increased susceptibility to prostate cancer. In addition, no significant associations between 3801T>C polymorphism and prostate cancer susceptibility were found in all genetic models. Only an elevated risk was observed for TC versus CC in Asian studies. However, no relationship was found in the Asian group for TC versus CC after excluding the studies that deviated from HWE. Thus, this meta-analysis finds the 2455A>G allele to be a risk factor for prostate cancer, whereas the 3801T>C status does not seem to be capable of modifying prostate cancer risk.     

Vascular endothelial growth factor gene polymorphisms and colorectal cancer risk: a meta-analysis

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen involved in a number of pathologic processes, including angiogenesis, tumor growth and metastasis. Polymorphisms of the VEGF gene have been associated with susceptibility to colorectal cancer (CRC). However, the specific association still remains controversial. We made a meta-analysis of the association between VEGF gene polymorphisms and CRC risk. Only eight case-control studies were retrieved, with a total of 2337 CRC patients and 2032 healthy controls. Six VEGF gene polymorphisms were addressed in all studies included, +936C>T (rs3025039), -2578C>A (rs699947), -1154G>A (rs1570360), -634G>C (rs2010963), -460C>T (rs833061), and +405C>G (rs2010963). There was a significant association between -2578C>A polymorphism and susceptibility to CRC in the comparison of C allele carriers (CC + CA) versus AA (odds ratio = 0.77, 95% confidence interval = 0.62-0.96, P = 0.02). No association was found between +936C>T, -1154G>A, -634G>C, -460C>T, and +405C>G with susceptibility to CRC. We conclude that the C allele carrier (CC + CA) of VEGF -2578C>A polymorphism appears to be a protective factor for CRC.     

Association between interleukin-10 promoter polymorphisms and endometriosis: A meta-analysis

To investigate the influence of the interleukin-10 gene promoter polymorphisms on the susceptibility of endometriosis, we examined the association by performing a meta-analysis. The PubMed, Embase, HuGE Navigator and CNKI were searched to identify eligible studies. We then conducted a meta-analysis to examine the association between interleukin-10 gene promoter polymorphisms and endometriosis. Eight case–control studies which examined the association between the IL-10 gene promoter polymorphisms and the susceptibility to endometriosis were finally included in the meta-analysis. Meta-analysis of the IL-10 − 592 A/C polymorphisms showed a significant increased risk of endometriosis in the overall and Asian population in all genetic models and allele contrast. However, meta-analysis of the IL-10 − 1082 A/G and IL-10 − 819 T/C polymorphisms showed no association with endometriosis in all genetic models and allele contrast in the overall and Asian population samples. In addition, there was not a significant association between the IL-10 − 592 A/C gene promoter polymorphisms with the severity of endometriosis.     

Association between XPD Lys751Gln polymorphism and risk of head and neck cancer: a meta-analysis

Several studies have investigated the association between Lys751Gln polymorphism in the xeroderma pigmentosum group D (XPD) gene and risk of head and neck cancer; however, the published results are conflicting. We conducted a meta-analysis that comprised 15 published case-control studies examining the association of head and neck cancer risk with XPD Lys751Gln polymorphism in different populations, based on the data identified in Medline up to November 2010. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the strength of the association. Overall, significantly elevated head and neck cancer risk was associated with XPD Lys751Gln polymorphism when all studies were pooled into the meta-analysis [(Gln/Gln + Lys/Gln) vs Lys/Lys: OR = 1.12, 95%CI = 1.03-1.22, P < 0.01, heterogeneity P = 0.11]. In the subgroup analysis by ethnicity, borderline significantly increased risk was found for Europeans [(Gln/Gln + Lys/Gln) vs Lys/Lys: OR = 1.11, 95%CI = 1.00-1.23, P < 0.05]. In conclusion, our meta-analysis demonstrated that XPD Lys751Gln polymorphism could be a prediction marker for risk of head and neck cancer.