Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma

The caspase proteins are essential for the regulation of normal B cell development and regulation of apoptosis. We investigated five single nucleotide polymorphisms in four key caspase genes, CASP3 [Ex8-280C>A (rs6948) and Ex8+567T>C (rs1049216)], CASP8 Ex14-271A>T (rs13113), CASP9 Ex5+32G>A (rs1052576) and CASP10 Ex3-171A>G (rs3900115) to determine whether they alter risk for non-Hodgkin lymphoma (NHL) in a population-based case-control study of women in Connecticut (461 cases and 535 controls). Variants in CASP3 and CASP9 were significantly associated with a decreased risk for NHL, particularly follicular lymphoma [e.g. CASP3 Ex8+567T>C odds ratio (OR)(CC+TC) = 0.4, 95% confidence interval (CI) = 0.3-0.7; and CASP9 Ex5+32G>A OR(AA+AG) = 0.6, 95% CI = 0.4-1.0]. Further, variants in CASP3, CASP8 and CASP10 were associated with a decreased risk of marginal zone lymphoma and variants in CASP3 and CASP10 were associated with a lower risk of chronic lymphocytic leukemia and related subtypes. The striking protective associations observed for polymorphisms in all four genes for NHL and/or one or more subtypes suggest that genetic variation in CASP genes may play an important role in the etiology of NHL.     

Polymorphisms in apoptosis and cell cycle control genes and risk of brain tumors in adults.

Despite the potential importance of the cell cycle and apoptosis pathways in brain tumor etiology, little has been published regarding brain tumor risk associated with common gene variants in these pathways. Using data from a hospital-based case-control study conducted by the National Cancer Institute between 1994 and 1998, we evaluated risk of glioma (n = 388), meningioma (n = 162), and acoustic neuroma (n = 73) with respect to 12 single nucleotide polymorphisms from 10 genes involved in apoptosis and cell cycle control: CASP8, CCND1, CCNH, CDKN1A, CDKN2A, CHEK1, CHEK2, MDM2, PTEN, and TP53. We observed significantly decreased risk of meningioma with the CASP8 Ex14-271A>T variant [odds ratio (OR)(AT), 0.8; 95% confidence interval (95% CI), 0.5-1.2; OR(AA), 0.5; 95% CI, 0.3-0.9; P(trend) = 0.03] and increased risk of meningioma with the CASP8 Ex13+51G>C variant (OR(GC), 1.4; 95% CI, 0.9-2.1; OR(CC), 3.6; 95% CI, 1.0-13.1; P(trend) = 0.04). The CT haplotype of the two CASP8 polymorphisms was associated with significantly increased risk of meningioma (OR, 1.7; 95% CI, 1.1-2.6), but was not associated with risk of glioma or acoustic neuroma. The CCND1 Ex4-1G>A variant was associated with increased risk for glioma, and the Ex8+49T>C variant of CCNH was associated with increased risk of glioma and acoustic neuroma. The MDM2 Ex12+162A>G variant was associated with significantly reduced risk of glioma. Our results suggest that common variants in the CASP8, CCND1, CCNH, and MDM2 genes may influence brain tumor risk. Future research in this area should include more detailed coverage of genes in the apoptosis/cell cycle control pathways.     

Folate metabolism genes, vegetable intake and renal cancer risk in central Europe

In a multicenter case-control study of renal cell carcinoma (RCC) conducted in central and eastern Europe, we reported a strong inverse association with high vegetable intake and RCC risk. The odds ratio (OR) for high compared to the lowest tertile of vegetable intake was OR = 0.67; (95% confidence interval (CI): 0.53-0.83; p-trend < 0.001). We hypothesized that variation in key folate metabolism genes may modify this association. Common variation in 5 folate metabolism genes (CBS: Ex9+33C > T (rs234706), Ex13 +41C > T (rs1801181), Ex18 -391 G > A (rs12613); MTHFR: A222V Ex5+79C > T (rs1801133), Ex8-62A > C (rs1801131); MTR: Ex26 20A > G (rs1805087), MTRR: Ex5+136 T > C (rs161870), and TYMS:IVS2-405 C > T (rs502396), Ex8+157 C > T (rs699517), Ex8+227 A > G (rs2790)) were analyzed among 1,097 RCC cases and 1,555 controls genotyped in this study. Having at least 1 variant T allele of MTHFR A222V was associated with higher RCC risk compared to those with 2 common (CC) alleles (OR = 1.44; 95% CI: 1.17-1.77; p = 0.001). After stratification by tertile of vegetable intake, the higher risk associated with the variant genotype was only observed in the low and medium tertiles (p-trend = 0.001), but not among those in the highest tertile (p-interaction = 0.22). The association remained robust after calculation of the false discovery rate (FDR = 0.05). Of the 3 TYMS SNPs examined, only the TYMS IVS2 -405 C (rs502396) variant was associated with a significantly lower risk compared to the common genotype (OR = 0.73; 95% CI: 0.57-0.93). Vegetable intake modified the association between all 3 TYMS SNPs and RCC risk (p-interaction < 0.04 for all). In summary, these findings suggest that common variation in MTHFR and TYMS genes may be associated with RCC risk, particularly when vegetable intake is low.     

Association of polymorphisms in base excision repair genes with the risk of breast cancer: a case-control study in North Indian women

Inheritance of common genetic variants at one or more base excision repair (BER) genes may result in a reduced DNA repair capacity and in an increased risk of cancers like breast cancer. The present case-control study with 390 north Indian women (155 breast cancer cases and 235 controls) was aimed to investigate the association of seven nonsynonymous BER gene polymorphisms viz. rs1130409/T1865G (APEX1), rs1799782/T22142C (XRCC1), rs25487/G23990A (XRCC1), rs4989588/T3337A (FEN1), rs4989586/ G3259A (FEN1), rs4989587/C3315T (FEN1), and rs1050525/G6941T (PCNA) with breast cancer susceptibility. Statistically significant association with breast cancer risk was observed for rs1130409 homozygous mutant GG [odds ratio (OR) 3.35, 95% confidence interval (CI) 1.36-8.26), heterozygous GT (OR 2.42, 95% CI 1.56-3.76), and combined mutant (GT + GG) (OR 2.52, 95% CI 1.65-3.86] genotypes and rs25487 homozygous mutant AA (OR 2.91, 95% CI 1.66-5.10) and combined mutant (AA + AG) (OR 1.41, 95% CI 0.903-2.19) genotypes, whereas protective association was exhibited by rs1799782 homozygous mutant CC (OR 0.413, 95% CI 0.082-2.08), heterozygous TC (OR 0.351, 95% CI 0.189-0.650), and combined mutant (TC + CC) (OR 0.357, 95% CI 0.199-0.641) genotypes. Association study using reconstructed haplotypes of XRCC1 gene showed positive association for the TA haplotype (OR 2.014, 95% CI 1.462-2.775) and a protective association for the CG haplotype (OR 0.173, 95% CI 0.052-0.576) pertaining to breast cancer risk. The results indicate that the polymorphisms rs1130409 (APEX1) and rs25487 (XRCC1) might be involved in contributing towards breast cancer susceptibility, while rs1799782 (XRCC1) might have protective influence.     

Association between Polymorphisms of ERCC5 Gene and Susceptibility to Gastric Cancer: A Systematic Review and Meta-Analysis

Background: several epidemiological studies have suggested that polymorphisms of the Excision Repair Cross Complementing Group-5 (ERCC5) gene might be related to gastric cancer risk; however, the results have been inconsistent or controversial. Therefore, we have performed a systematic review and meta-analysis to clarify the association between the ERCC5 gene polymorphisms and gastric cancer risk. Materials and Methods: An electronic search was conducted of several databases, including PubMed, Web of Science, and Google Scholar for articles that describe the association between polymorphisms of the ERCC5 gene and susceptibility of gastric cancer. Results: A total of 33 case control studies in 15 publications were included in the present meta-analysis. There were significant associations between gastric cancer susceptibility and ERCC5 gene rs751402 C>T (T vs. C: OR = 1.166, 95% C = 1.066-1.274, p= 0.001; TT vs. CC: OR = 0.723, 95% CI = 0.587-0.890, p = 0.002; TT+TC vs. CC: OR = 0.853, 95% CI = 0.757-0.961, p = 0.009; TT vs. TC+CC: OR = 0.793, 95% CI = 0.659-0.955, p = 0.015), rs2296147 T>C (C vs. T: OR = 1.268, 95% C = 1.049-1.532, p= 0.014), rs873601 G>A polymorphisms (A vs. G, OR = 1.087, 95% C = 1.021-1.159, p= 0.010; AA vs. GG, OR = 1.184, 95% CI = 1.043-1.343, p = 0.009, AA vs. AG+GG, OR = 1.156, 95% CI = 1.040-1.284, p = 0.007), but not rs2094258 C>T and rs1047768 T>C. Conclusion: the current meta-analysis demonstrates that rs751402 C>T, rs2296147 T>C, and rs873601 G>A polymorphisms of ERCC5 gene are associated with the susceptibility of gastric cancer.     

Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuan Wei, China

We conducted a population-based case-control study in Xuan Wei, China, where lung cancer rates are among the highest in China due to exposure to indoor coal combustion products, to evaluate the association between polymorphisms in immunoregulatory genes and lung cancer risk. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled in Xuan Wei, China. Fifty single-nucleotide polymorphisms (SNPs) in 23 immunoregulatory genes involved in inflammation were genotyped and analyzed by logistic regression to assess the risk of lung cancer. A global test of association for 42 SNPs, which excluded eight SNPs that were in very tight linkage disequilibrium with other SNPs, was statistically significant (P = 0.01), suggesting that overall genetic variation in this pathway contributes to lung cancer risk. In addition, the IL1B -1060TT (i.e. -511TT) genotype was associated with increased lung cancer risk compared with the CC genotype [odds ratio (OR) = 2.27, 95% confidence interval (CI) = 1.05-4.91]. The IL8RA Ex2+860 GC or CC (OR = 0.27, 95% CI = 0.11-0.67), ICAM1 Ex2+100 AT or TT (OR = 0.39, 95% CI = 0.18-0.88) and IL12A Ex7+277 GA or AA (OR = 0.43, 95% CI = 0.22-0.84) genotypes were associated with decreased lung cancer risk. The protective effect of the IL8RA variant was stronger among subjects with high cumulative smoky coal use (> or = 130 tons) (OR = 0.11, 95% CI = 0.03-0.44; P(interaction) = 0.03). In conclusion, genetic variation in immunoregulatory genes may play an important role in the development of lung cancer in this population.     

Association of IL-10 rs1800871 and rs1800872 Polymorphisms with Breast Cancer Risk: A Systematic Review and Meta-Analysis

Background: The rs1800871 and rs1800872 polymorphisms of interleukin 10 (IL-10) gene has been indicated tobe associated with breast cancer (BC) risk, but study results are still debatable. To derive a more precise evaluation, weperformed a comprehensive meta-analysis. Methods: Multiple electronic databases were searched to identify studiesassessing the IL-10 rs1800871 and rs1800872 polymorphisms with BC risk. Results: A total of 21 case-control studieswith 6054 cases and 6355 controls were included in this met-analysis. There was a significant association between thers1800871 polymorphism and BC risk (CT vs. TT: OR= 1.17, 95% CI 1.01-1.35, p=0.02; and CC+CT vs. TT: OR= 1.29,95% CI 1.00-1.66, p=0.04). Moreover, increased BC risks were also associated with the rs1800872 polymorphism (Cvs. A: OR= 1.29, 95% CI 1.04-1.60, p=0.01; CC vs. AA: OR= 1.54, 95% CI 1.03-2.30, p=0.03; CC+CA vs. AA: OR=1.43, 95% CI 1.01-2.01, p=0.03; and CC vs. CA+AA: OR= 1.23, 95% CI 1.01-1.51, p=0.04). A pooling of the studieswas also conducted by ethnicity, but failed to show an association of IL-10 rs1800871 and rs1800872 polymorphismwith BC risk in Asians and Caucasians. Conclusions: Our results are inconsistent with previous meta-analysis suggeststhat IL-10 rs1800871 and rs1800872 polymorphisms might contribute to BC susceptibility in overall population, butnot by ethnicity.     

Genetic Association of XRCC1 Gene rs1799782, rs25487 and rs25489 Polymorphisms with Risk of Thyroid Cancer: a Systematic Review and Meta-Analysis

Background: A number of case-control studies have evaluated associations between the X-ray cross complementary group 1 protein (XRCC1) gene rs1799782 (Arg194Trp), rs25487 (Arg399Gln) and rs25489 (Arg280His) polymorphisms and thyroid cancer (TC) risk, but the results remain inconclusive. Materials and Methods: A systematic literature search was performed using PubMed and Google Scholar Search. According to defined criteria data were extracted and pooled odds ratios with 95% confidence intervals were calculated under five genetic models. Results: A total of 8 studies with 1,672 cases and 2,805 controls for the rs1799782 polymorphism, 14 studies with 2,506 cases and 5,180 controls for the rs25487 polymorphism, and 11 studies with 2,197 cases and 4,761 controls for the rs25489 polymorphism were included in this meta-analysis. Overall, there was a statistical association between XRCC1 rs1799782 polymorphism and TC risk with the homozygote genetic model (TT vs. CC: OR = 1.815, 95% CI = 1.115-2.953, p= 0.016) and the recessive genetic model (TT vs. TC+CC: OR = 1.854, 95% CI = 1.433-2.399, p= <0.001). In the subgroup analysis by ethnicity, significantly increased TC risk was observed only in Asians under the recessive model (TT vs. TC+CC: OR = 1.816, 95% CI = 1.398-2.358, p= <0.001). In addition, there was no positive association between XRCC1 rs25487 and rs25489 polymorphisms and risk of TC. However, there was a significant association between XRCC1 rs25487 polymorphism risk of TC among Caucasians with allele genetic comparison (A vs. G: OR= 0.882, 95% CI = 0.794-0.979, p= 0.136) and dominant genetic comparison (AA+AG vs. GG: OR=0.838, 95% CI = 0.728-0.965, p= 0.014). Conclusions: The results of our meta-analysis suggest an increased risk of TC with the XRCC1 rs1799782 and rs25487 polymorphisms. However, the XRCC1 rs25489 polymorphism appeared to be without influence.     

Genetic polymorphisms in alcohol metabolism, alcohol intake and the risk of stomach cancer in Warsaw, Poland

Genetic variations increasing blood levels of acetaldehyde, the first metabolite of alcohol, refrain their carriers from drinking alcohol but may also put them at increased risk of cancer because of the mutagenic and carcinogenic effect of acetaldehyde. In a population-based study of 305 cases and 428 controls in Warsaw, Poland, we evaluated the effect of polymorphisms in alcohol metabolizing genes, including ADH1B (Ex9+5C>T, Ex3+23A>G, Ex3+58A>T and Ex9+77A>G), ADH1C (Ex8-56A>G and Ex6-14G>A) and ALDH2 (Ex1+82A>G), on levels of alcohol drinking and susceptibility of stomach cancer. We found that among control subjects frequency of alcohol drinking varied by alcohol metabolizing genotype. In particular, the weekly consumption of individuals carrying the AA, GA and GG genotypes of ALDH2 Ex1+82A>G polymorphism were 3.75, 2.26 and 1.53 drinks, respectively (p=0.04). However, none of the assessed polymorphisms in these 3 genes had a measurable effect on stomach cancer risk. When stratified by ALDH2 Ex1+82A>G polymorphism, alcohol-related increases in stomach cancer risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR=2.63, 95% CI=1.00-6.88) and 3-fold risk (OR=3.66, 95% CI=1.19-11.24) among those with 40 or more drink-years. In summary, our results suggested that the ALDH2 Ex1+82 G allele may be functionally deficient in eliminating acetaldehyde and discourage alcohol drinking. Furthermore, heavy drinkers of alcohol who were genetically prone to accumulate acetaldehyde may face an increased risk of stomach cancer.     

Caspase‐8 polymorphisms and risk of gallbladder cancer in a Northern Indian population

Caspase‐8 (CASP8) is a key controller of apoptosis, and its deregulation plays an important role in carcinogenesis. To evaluate the role of CASP8 polymorphisms in gallbladder cancer (GBC), we examined the risk associated with three single‐nucleotide polymorphisms (SNPs) in a case–control study in North Indian population. Genotypes and haplotypes of the CASP8 polymorphisms (?652 6N ins/del; rs3834129, Ex13 + 51G > C; rs1045485 and IVS12‐19 G > A; rs3769818) were determined for 230 GBC patients and 230 cancer‐free controls randomly selected from the population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in multivariate logistic regression analysis for the association of individual SNPs and haplotypes with GBC. Carriers for the “del” allele of rs3834129 SNP were associated with a 0.60‐fold decreased risk for GBC (95% CI = 0.42–0.88; P_trend = 0.005). In the combined analysis of the three CASP8 variants, we found that the individuals with the diplotypes carrying two copies of the common CASP8 del‐G‐G haplotype had 0.35‐fold reduced risk (95% CI = 0.14–0.85) when compared with the diplotype containing 0–1 copy. The false‐positive report probability (FPRP) approach advocated that these results were noteworthy (FPRP < 0.5). The molecular modeling results of rs1045485 polymorphism indicated that the overall configuration of both wild‐type and polymorphic CASP8 protein were similar, with negligible deviation at the site of the polymorphism itself. In summary, low penetrance variants in CASP8 gene may alter the susceptibility toward GBC. © 2010 Wiley‐Liss, Inc.     

A specific diplotype defined by PPP1R13L rs1970764, CD3EAP rs967591 and ERCC1 rs11615 and lung cancer risk in a Chinese population

Haplotypes defined by multiple loci may be more precise and useful than genotypes in providing risk estimates for particular cancers. Diplotype is defined as a specific combination of two haplotypes. A Chinese case-control analysis comprising 370 cases and 388 controls was conducted to evaluate the effects of the high-risk diplotype predefined as PPP1R13L rs1970764(AA)-CD3EAP rs967591(GG)-ERCC1 rs11615(AA) among Caucasians and three SNPs alone or other haplotypes combined for lung cancer risk. Both the variant G-allele of PPP1R13L rs1970764 and the variant A-allele of CD3EAP rs967591 were significantly over-represented among cases (P=0.03 and P=0.002, respectively). The variant GG-homozygotes of PPP1R13L rs1970764 had increased risk [GG versus AA: adjusted OR (95% CI)=1.30 (1.04-1.62), P=0.02]. The carriers of variant A-allele of CD3EAP rs967591 also presented increased risk [AA versus GG: adjusted OR (95% CI)=1.40 (1.12-1.75), P=0.004; AG versus GG: adjusted OR (95% CI)=1.47 (1.05-2.07), P=0.03 and AG+AA versus GG: adjusted OR (95% CI)=1.26 (1.07-1.48), P=0.005]. Interaction between CD3EAP rs967591 and smoking duration was observed (P=0.003). Only haplotype 1 (the common haplotype) defined as PPP1R13L rs1970764(G)-CD3EAP rs967591(A)-ERCC1 rs11615(G) showed marginally increased risk [OR (95% CI)=1.38 (1.09-1.75), P=0.009] after Bonferroni correction. The frequency of the high-risk diplotype predefined among Caucasians was 1% in controls and no significant evidence of the diplotype distribution between cases and controls was detected in present study. In conclusion, we found that variant alleles of PPP1R13L rs1970764 and CD3EAP rs967591 may contribute to risk factors of lung cancer, but the high-risk diplotype predefined among Caucasians was rare and the diplotype is unlikely to confer lung cancer risk in a Chinese population.     

Association of Single Nucleotide Polymorphisms in the Prostaglandin-endoperoxide Synthase 2 (PTGS2) and Phospholipase A2 Group IIA (PLA2G2A) Genes with Susceptibility to Esophageal Squamous Cell Carcinoma

Background: The prostaglandin-endoperoxide synthase 2 (PTGS2) and phospholipase A2 group IIA (PLA2G2A)genes encode enzymes that are involved in arachidonic acid and prostaglandin biosynthesis. Dysregulation ofboth genes is associated with inflammation and carcinogenesis, including esophageal squamous cell carcinoma(ESCC). We therefore hypothesized that there is an association between single nucleotide polymorphisms (SNPs)in these genes and susceptibility to ESCC. Methods: We performed a gene-wide tag SNP-based associationstudy to examine the association of SNPs in PTGS2 and PLA2G2A with ESCC in 269 patients and 269 healthycontrols from Taihangshan Mountain, Henan and Hebei Provinces, the rural area of China which has the highestincidence of esophageal cancer in the world. Thirteen tag SNPs in PLA2G2A and 4 functional SNPs in PTGS2were selected and genotyped using a high-throughput Mass Array genotyping platform. Results: We found amodest increased risk of ESCC in subjects with the PTGS2 rs12042763 AA genotype (OR=1.23; 95% CI, 1.00-3.04) compared with genotype GG. For PLA2G2A, a decreased risk of ESCC was observed in subjects withthe rs11677 CT (OR=0.51, 95%CI, 0.29-0.85) or TT genotype (OR=0.51, 95%CI, 0.17-0.96) or the T carriers(CT+TT) (OR=0.52, 95%CI, 0.31-0.85) when compared with the CC genotype. Also for PLA2G2A, rs2236771C allele carriers were more frequent in the control group (P=0.02). Subjects with the GC (OR=0.55, 95%CI,0.33-0.93) or CC genotype (OR=0.38, 95% CI, 0.16-0.94) or the C carriers (GC+CC) (OR=0.52, 95%CI, 0.32-0.85) showed a negative association with ESCC susceptibility. Conclusions: Our results suggest that PTGS2 andPLA2G2A gene polymorphisms may modify the risk of ESCC development.     

Polymorphisms of the neuronal and inducible nitric oxide synthase genes and the risk of cutaneous melanoma: a case-control study

BACKGROUND: Nitric oxide (NO) is a multifunctional molecule that is produced by both neuronal NO synthase (nNOS) and inducible NO synthase (iNOS), and the expression of nNOS and iNOS is up-regulated in various cancer cells, including cutaneous melanoma (CM). The authors hypothesized that selected functional single-nucleotide polymorphisms (SNPs) in the nNOS and iNOS genes are associated with the risk of CM. METHODS: In a hospital-based case-control study of 602 non-Hispanic white patients with CM and 603 matched, cancer-free controls, the authors genotyped the nNOS -84 guanine-to-adenine (G-->A), nNOS 276 cytosine-to-thymine (C-->T), iNOS Ex16+14C-->T, and iNOS 974G-->T SNPs and assessed their associations with the risk of CM in multivariate logistic regression models. RESULTS: A significantly increased risk of CM was associated with the nNOS -84G-->A (adjusted odds ratio [OR], 1.49; 95% confidence interval [95% CI], 1.05-2.13) and -84AG+AA (OR, 1.48; 95% CI, 1.06-2.06) genotypes compared with the nNOS -84GG genotype, but not with other nNOS or iNOS SNPs. In a combined analysis, an increased risk of CM was associated with the nNOS -84AA+AG/276CT+TT genotype (OR, 1.70; 95% CI, 1.05-2.76) and the nNOS -84AA+AG/276CC genotype (OR, 1.70; 95% CI, 1.08-2.68) compared with the nNOS -84GG/276CT+TT genotypes. No altered risk of CM was associated with iNOS genotypes. In addition, there was statistical evidence of interaction of nNOS SNPs with having moles (P = .002) and sunburns (P = .017). CONCLUSIONS: Genetic variants of nNOS, but not iNOS, may be biomarkers for susceptibility to CM, and the risk of CM associated with sunburns and moles may be modulated by nNOS variant genotypes.     

Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years

The histone protein family member X (H2AFX) is important in maintaining chromatin structure and genetic stability. Genetic variants in H2AFX may alter protein functions and thus cancer risk. In this case-control study, we genotyped four common single nucleotide polymorphisms (i.e., -1654A > G [rs643788], -1420G > A [rs8551], and -1187T > C [rs7759] in the H2AFX promoter region and 1057C > T [rs7350] in the 3' untranslated region (UTR)) in 467 patients with sporadic breast cancer and 488 cancer-free controls. All female subjects were non-Hispanic whites aged T polymorphism. Therefore, we believe that H2AFX promoter polymorphisms may contribute to the etiology of sporadic breast cancer in young non-Hispanic white women. Larger association studies and related functional studies are warranted to confirm these findings.     

Associations of ERCC4 rs1800067 Polymorphism with Cancer Risk: an Updated Meta-analysis

Background: Results from previous studies concerning the association of ERCC4 rs1800067 polymorphismwith risk of cancer were inconsistent. To explore the exact relation with susceptibility, we conducted the presentmeta-analysis. Materials and Methods: Literature of electronic databases including PubMed, Web of Science,EMBASE, Wanfang and Chinese National Knowledge Infrastructure (CNKI) were systematically searched. ORsand their 95%CIs were used to assess the strength of associations between ERCC4 polymorphism and cancerrisk. Results: There was no significant association between ERCC4 rs1800067 AA or AG genotypes and overallrisk of cancer (AA vs. GG: OR=0.998, 95%CI=0.670-1.486, P=0.992; AG vs. GG: OR=0.970, 95%CI=0.888-1.061, P=0.508). A dominant genetic model also did not demonstrate significant association of (AA+AG)genotype carriers with altered risk of overall cancer (OR=0.985, 95%CI=0.909-1.068, P=0.719). In addition,no significant association was observed between A allele of ERCC4 rs1800067 A/G polymorphism and alteredcancer risk compared with G allele (OR=0.952, 95%CI=0.851-1.063, P=0.381). Subgroup analysis suggestedthat AA genotype carriers were significantly associated with decreased risk of glioma compared with wild-typeGG genotype individuals (OR=0.523, 95%CI=0.275-0.993, P=0.048). For subgroup of lung cancer, A allele ofERCC4 rs1800067 A/G polymorphism was significantly associated with decreased risk of lung cancer comparedwith G allele (OR=0.806, 95%CI=0.697-0.931, P=0.003). Conclusions: This meta-analysis indicated that ERCC4rs1800067 A/G polymorphism might not be associated with risk of overall cancer. However, individuals with theAA genotype were associated with significantly reduced risk of glioma compared with wild-type GG genotype;The A allele was associated with significantly reduced risk of lung cancer compared with G allele. Future largescalestudies performed in multiple populations are warranted to confirm our results.     

Lack of Association between Hsa-Mir-499 rs3746444 Polymorphism and Cancer Risk: Meta-analysis Findings

Epidemiologic findings concerning the association between the hsa-mir-499 rs3746444 A>G polymorphismand cancer risk have yielded mixed results. We aimed to investigate the association by performing a meta-analysisof all available studies. We searched PubMed and EMBASE for studies published up to November 2014, usingodds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of any association. The Benjamini-Hochberg (BH) method was used to correct the p values for multiple comparisons. We included 39 studies,including 14,136 cases and 16,937 controls. The results of overall meta-analysis suggested a borderline associationbetween hsa-mir-499 rs3746444 polymorphism and cancer susceptibility (AG+GG vs. AA: OR=1.15, 95% CI=1.04-1.26, corrected p value=0.04). After removing studies not conforming to Hardy–Weinberg equilibrium(HWE), however, this association disappeared (AG+GG vs AA: OR=1.18, 95% CI=1.03-1.34, corrected pvalue=0.21). When stratified analysis by ethnicity, cancer type or HWE in controls, although some associationsbetween hsa-mir-499 rs3746444 polymorphism and cancer susceptibility were detected, these associations nolonger existed after adjustment using BH method. In conclusion, our meta-analysis suggests that hsa-mir-499rs3746444 A>G polymorphism is not associated with risk of cancer based on current evidence.     

Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population

Using a large-scale case-control study, we examined whether common single-nucleotide polymorphisms (SNPs) within 13 genes involved in the cell cycle pathway are associated with breast cancer risk. Seventy-nine tag SNPs were used to evaluate 240 common SNPs found in the genes: CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKNIB, CDKN2A/CDKN2B, CDKN2C and CDKN2D. These were genotyped in 2270 cases and 2280 controls from the Studies in Epidemiology and Risks of Cancer Heredity (SEARCH) study. Tag SNPs showing evidence of statistically significant differences between cases and controls (P < 0.1) were genotyped in a further 2200 cases and 2280 controls from the same population. This approach found evidence for breast cancer-associated SNPs in four of the cell cycle genes: the cyclin CCNE1 rs997669 had an odds ratio (OR) (GG/AA) of 1.18 [95% confidence interval (95% CI) 1.04-1.34] P = 0.003 and the cyclin-dependent kinase inhibitors-CDKN1A rs3176336: OR (TT/AA) = 1.25 (95% CI 1.11-1.42) P = 0.0026; CDKN1B rs34330: OR (TT/CC) = 1.22 (95% CI 1.02-1.47) P = 0.013 and the region of CDKN2A/2B rs3731239: OR (CC/TT) = 0.90 (95% CI 0.79-1.03) P = 0.013 and rs3218005 OR (GG/AA) = 1.55 (95% CI 1.02-2.37) P = 0.013 (P-values unadjusted for multiple testing). We were able to exclude the D-type cyclins, cyclin-dependent kinases, CDKN2C and CDKN2D from having any significantly associated risk with breast cancer in our study population. The combined effects of the cell cycle genes considered here provide evidence for a significant association with breast cancer risk in a global test (P-heterogeneity = 0.010, P-trend = 0.048). Further large-scale studies are needed to confirm these results.     

Association Between the hsa-mir-27a Variant and Breast Cancer Risk: a Meta-analysis

Introduction: Although a number of studies were published in the past several years on associations betweenhsa-mir-27a and cancer risk, the findings remain conflicting rather than conclusive. To derive a more precise effecton the association between SNP hsa-mir-27a rs895819 and breast cancer risk, we conducted a meta-analysis forthe first time. Materials and Methods: Through retrieval from PubMed for the period up to August 2012, a totalof four studies were identified with 3,287 cases and 4,298 controls for SNP hsa-mir-27a rs895819.We calculatedsummary odds ratio (ORs) and corresponding 95% confidence intervals (CIs) using a fixed effects model (whenthe heterogeneity was absent, P>0.10). Otherwise, the random-effects model was used. Results: We found thathsa-mir-27a rs895819 polymorphism also did not reveal any relationship with breast cancer susceptibility (AGversus AA: OR = 0.98; 95%CI, 0.73-1.32; GG versus AA: OR = 0.86; 95% CI, 0.72-1.03; AG/GG versus AA:OR = 0.92; 95% CI, 0.74-1.14), while significantly decreased risk was found among Europeans in AG versus AAand AG/GG versus AA models tested (AG versus AA: OR = 0.83; 95%CI, 0.72-0.97; GG versus AA: OR = 0.86;95% CI, 0.71-1.05; AG/GG versus AA: OR = 0.84; 95% CI, 0.75-0.94). Conclusion: These findings suggest thathsa-mir-27a rs895819 polymorphism may play an important role in breast cancer development.     

Association Between the Pre-mir-218 Polymorphism and Cancer Risk in the Chinese Population: a Meta-Analysis

Background: Several recent studies have explored associations between pre-mir-218 polymorphism(rs11134527) and cancer risk. However, published data are still inconclusive. To obtain a more precise estimationof the relationship in the Chinese population, we carried out a meta-analysis for the first time. Materials andMethods: Through retrieval from the PubMed, Medline, Embase, Web of Science databases, China NationalKnowledge Infrastructure and the Chinese BioMedical Literature Database, a total of four studies wereanalyzed with 3,561 cases and 3,628 controls for SNP pre-mir-218 rs11134527. We calculated odds ratios (ORs)and 95% confidence intervals (95%CIs) to explore the strength of associations. Results: The results showedthat the rs11134527 polymorphism was associated with decreased cancer risk in GG versus AA and GG versusAA+AG models tested ( GG vs AA: OR=0.82, 95%CI: 0.71-0.94; GG vs AA+AG: OR=0.84, 95%CI: 0.74-0.96),and significantly decreased cervical cancer risk was observed in GG versus AA and GG versus AA+AG models(GG vs AA: OR=0.79, 95%CI: 0.66-0.94; GG vs AA+AG: OR=0.80, 95%CI: 0.68-0.94). However, no significantassociation between the rs11134527polymorphism and hepatocellular carcinoma risk was observed in allcomparison models tested (AG vs AA: OR=0.94, 95%CI: 0.79-1.11; GG vs AA: OR=0.88, 95%CI: 0.70-1.10;GG+AG vs AA: OR=0.92, 95%CI: 0.79-1.08; GG vs AA+AG: OR=0.91, 95%CI: 0.75-1.11). Conclusion: Thefindings suggest that pre-miR-218 rs11134527 polymorphism may have some relation to cancer development inChinese. However, well-designed studies with larger sample size and more detailed data are needed to confirmthese conclusions.     

MicroRNA-124 rs531564 Polymorphism and Cancer Risk: A Meta-analysis

Several studies reported there was a polymorphism (rs531564 C > G) in miR-124 gene. To investigate the MiR-124 rs531564 polymorphism and cancer risk. We conducted a literature search of the Medline, Embase and Wangfang Medicine databases to identify all relevant studies for this meta-analysis. We determined that the miR-124 rs531564 polymorphism was significantly associated with decreased risks of cancers in the allelic model (G vs C, OR=0.71, 95% CI=0.53-0.94, P=0.02), homozygote model (GG vs CC, OR=0.42, 95% CI=0.26-0.66, P=0.0002), dominant model (GG/GC vs CC, OR=0.71, 95% CI=0.51-0.98, P=0.04) and recessive model (GG vs GC/CC, OR=0.43, 95% CI=0.27-0.69, P=0.0004). In an analysis stratified by cervical cancer group, significant associations were observed in the allelic model (G vs C, OR=0.46, 95% CI=0.32-0.66, P<0.0001), and dominant model (GG/GC vs CC, OR=0.45, 95% CI=0.3-0.66, P<0.0001). Subgroup analysis also revealed a decreased risk for esophageal squamous cell carcinoma in the homozygote model (GG vs CC, OR=0.45, 95% CI=0.27-0.75, P=0.002) and recessive model (GG vs GC/CC, OR=0.46, 95% CI=0.28-0.75, P=0.002). This meta-analysis suggests that the miR-124 rs531564 C > G polymorphism is an important risk factor for cancers among the Chinese population.