Since Kurzawski et al. described an association between the 3020insC NOD2 single nucleotide polymorphism and the risk of colorectal cancer(CRC) in 2004, reports published in the past several years have controversial results regarding the relationship between the development of CRC and NOD2 gene polymorphisms. To clarify the potential role of NOD2 P286S, R702W, G908R, and 3020insC polymorphisms in CRC patients, we have undertaken a systematic review and meta-analysis of published articles.

The relationship of gastric cancer to the presence of interleukin-8 (IL-8) 251 T/A has been reported with conflicting results.

Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, accounting for nearly 30% of all paediatric cancers and 80% of childhood leukaemias. Polymorphisms in folate-related genes may influence the susceptibility to childhood ALL. This review summarizes the results of 14 studies that focussed on the relationship between folate-related gene polymorphisms and the susceptibility to ALL and that fulfilled certain quality criteria. The total group consisted of 729 children and 1821 adults or non age-defined patients. The results of different studies sometimes contradict each other, for which there are several possible explanations. This includes an influence of the type of population studied, because there was a difference between Asian and European study results. Based on several studies, it is plausible that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with a decreased susceptibility to childhood ALL in non-Asian populations. Polymorphisms in other folate related genes (MTRR, MTR [MS], TYMS [TS], SLC19A1 [RFC1], NNMT, and SHMT1) are less clearly associated with susceptibility to ALL, and the number of included studies on this subject in this review is limited. Further investigations on the relevance of these polymorphisms need to be performed. In general, it is clear that susceptibility to (childhood) ALL is partly related to constitutional differences in folate gene polymorphisms.

The objective of the study was to assess the association between tea consumption and endometrial cancer.

The Glutathione S-transferases (GSTs) play multiple roles in the pathogenesis and treatment of cancer. Studies investigating the association between Glutathione S-transferase M1 (GSTM1) null genotype and gastric cancer risk report conflicting results. The purpose of this study was to quantitatively summarize the evidence for such a relationship.

Published data regarding the association between the apurinic/apyrimidinic endonuclease 1 (APE1) T1349G (Asp148Glu) polymorphism and cancer risk show inconclusive results. To derive a more precise estimation of the relationship, we performed a meta-analysis of 27 published studies that included 12 432 cancer cases and 17 349 controls. We used odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the strength of the associations. The overall results suggested that the variant genotypes were associated with a moderately increased risk of all cancer types (OR = 1.09, 95% CI = 1.01-1.18 for TG versus TT; OR = 1.08, 95% CI = 1.00-1.18 for GG/TG versus TT). In the stratified analyses, the risk remained for studies of colorectal cancer, European populations and population-based studies. Although some modest bias could not be eliminated, this meta-analysis supported that the APE1 T1349G polymorphism is a low-penetrance risk factor for cancer development.

Increasing studies investigating the association between steroid 5-alpha reductase type II gene polymorphism at codon 89 (SRD5A2 V89L) and susceptibility to prostate cancer (PCa) confer inconsistent results. To precisely estimate the relationship with more statistical power, a meta-analysis was performed.

Cytosolic glutathione S-transferase comprises multiple isoenzymes; studies have principally examined mu-1 (GSTM1: null/present), theta-1 (GSTT1: null/present) and pi-1 (GSTP1 Ile105Val) gene polymorphisms concerning breast cancer risk. Regarding GSTT1 and GSTP1 polymorphisms, studies remain controversial and no recent meta-analysis has appeared. This meta-analysis aims to examine whether GSTT1 and GSTP1 polymorphisms are associated with breast cancer risk. Separate analyses were performed on Chinese and non-Chinese populations, in an attempt to investigate race-specific effects. Eligible articles were identified by a search of MEDLINE bibliographic database for the period up to August 2009. Regarding GSTT1 null/present genotype, 41 case-control studies were eligible (16,589 breast cancer cases and 19,995 controls); 30 case-control studies were eligible for GSTP1 Ile105Val (16,908 cases and 20,016 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. At the overall analysis, the null GSTT1 genotype was associated with elevated breast cancer risk (pooled OR = 1.114, 95% CI: 1.035-1.199, random effects). However, the association seemed confined to non-Chinese populations (33 studies, pooled OR = 1.128, 95% CI: 1.042-1.221, random effects), given that the association was not significant in the subset of Chinese studies (eight studies, pooled OR = 1.061, 95% CI: 0.875-1.286, random effects). Regarding GSTP1 Ile105Val, no statistically significant associations were detected in non-Chinese populations (25 studies). On the other hand, the GG genotype was associated with increased breast cancer risk in Chinese populations (five studies, pooled OR = 1.297, 95% CI: 1.023-1.645, fixed effects); accordingly, the recessive model yielded statistically significant results (pooled OR = 1.273, 95% CI: 1.006-1.610, fixed effects). In conclusion, polymorphisms of both GSTT1 and GSTP1 genes seem associated with elevated breast cancer risk in a race-specific manner. Given the small number of Chinese studies, the finding on GSTP1 Ile105Val merits further investigation.

Estrogen exposure is a central risk factor in the development of breast cancer. Estrogen receptor alpha (coded by ESR1) is the key mediator of estrogen response in mammary tissue. Genetic changes altering the expression of ESR1 is likely to affect breast cancer susceptibility. Since the identification of several potentially functional polymorphisms in ESR1 (rs2234693, rs9340799, rs1801132, rs3798577, rs2228480), molecular epidemiological studies were conducted in recent years to evaluate the association between polymorphisms and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This current analysis on 10,300 breast cancer cases and 16,620 controls on rs2234693 showed a borderline significant decreased breast cancer risk for CC and CC/CT carriers (CC vs. TT: OR, 0.92, 95% CI, 0.86-0.99; CC/CT vs. TT: OR, 0.95, 95% CI, 0.89-1.00). Variant genotypes of the rs1801132 polymorphism were also associated with a decreased breast cancer risk in a dominant model in 5,649 cases and 6,856 controls (GG/GC vs. CC: OR, 0.92, 95% CI, 0.85-0.99). These results suggest that potentially functional ESR1 polymorphisms may play a low penetrance role in breast cancer susceptibility. SNPs rs9340799, rs3798577, rs2228480, and rs2077647 in ESR1 were not causative SNPs. SNPs rs2747648, rs1062577, and rs3020314 were recommended in further association studies and functional evaluations.

Anaplastic astrocytoma (AA) and its more aggressive counterpart, glioblastoma multiforme (GBM), are the most common intrinsic brain tumors in adults and are almost universally fatal. A deeper understanding of the molecular relationship of these tumor types is necessary to derive insights into the diagnosis, prognosis, and treatment of gliomas. Although genomewide profiling of expression levels with microarrays can be used to identify differentially expressed genes between these tumor types, comparative studies so far have resulted in gene lists that show little overlap.

Polycystic ovary syndrome (PCOS) is a complex but frequently occurring endocrine abnormality. PCOS has become one of the leading causes of oligo-ovulatory infertility among premenopausal women. The definition of PCOS remains unclear because of the heterogeneity of this abnormality, but it is associated with insulin resistance, hyperandrogenism, obesity and dyslipidaemia. The main purpose of this study was to identify possible candidate genes involved in PCOS. Several genomic approaches, including linkage analysis and microarray analysis, have been used to look for candidate PCOS genes. To obtain a clearer view of the mechanism of PCOS, we have compiled data from microarray analyses. An extensive literature search identified seven published microarray analyses that utilized PCOS samples. These were published between the year of 2003 and 2007 and included analyses of ovary tissues as well as whole ovaries and theca cells. Although somewhat different methods were used, all the studies employed cDNA microarrays to compare the gene expression patterns of PCOS patients with those of healthy controls. These analyses identified more than a thousand genes whose expression was altered in PCOS patients. Most of the genes were found to be involved in gene and protein expression, cell signaling and metabolism. We have classified all of the 1081 identified genes as coding for either known or unknown proteins. Cytoscape 2.6.1 was used to build a network of protein and then to analyze it. This protein network consists of 504 protein nodes and 1408 interactions among those proteins. One hypothetical protein in the PCOS network was postulated to be involved in the cell cycle. BiNGO was used to identify the three main ontologies in the protein network: molecular functions, biological processes and cellular components. This gene ontology analysis identified a number of ontologies and genes likely to be involved in the complex mechanism of PCOS. These include the insulin receptor signaling pathway, steroid biosynthesis, and the regulation of gonadotropin secretion among others.

Polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene have been reported as a potential risk factor for the development of oral cancer; however, the overall results are still controversial. In the present study, we therefore performed a meta-analysis of eight case-control studies that examined the association of oral cancer with XRCC1 gene polymorphisms in different populations, including codon 194 (Arg-Trp), 280 (Arg-His) and 399 (Arg-Gln), based on the data identified in Medline of up to June 2008. Literature-based searching was conducted to gather data and both fixed-effects and random-effects model were used to pool the odds ratio (OR). Publication bias and between-study heterogeneity were also evaluated. The eligible studies included 1,326 cases and 3,130 controls. The OR of various comparisons showed that the oral cancer risk was not associated with the selected three XRCC1 polymorphisms (P > 0.05). However, after stratification, significant association was found between the XRCC1 Arg194Trp polymorphism and oral cancer risk among Asians, showing an OR of 1.347 (95% confidence interval (CI): 1.000, 1.814) for allele comparison, 1.378 (95% CI: 1.070, 1.775) for TT homozygotes versus CC homozygotes, and 1.420 (95% CI: 1.041, 1.936) for comparison under the dominant model. Publication bias was not shown around the studies; however, ORs among these three polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and a part of the heterogeneity was from ethnic differences. We suggest that the Arg194Trp polymorphism in the XRCC1 gene may be a biomarker of oral cancer susceptibility among Asian population.

Folate-pathway gene polymorphisms have been implicated in several cancers and investigated inconclusively in relation to prostate cancer. We conducted a systematic review, which identified nine case-control studies (eight included, one excluded). We also included data from four genome-wide association studies and from a case-control study nested within the UK population-based Prostate Testing for Cancer and Treatment study. We investigated by meta-analysis the effects of eight polymorphisms: MTHFR C677T (rs1801133; 12 studies; 10,745 cases; 40,158 controls), MTHFR A1298C (rs1801131; 5 studies; 3,176 cases; 4,829 controls), MTR A2756G (rs1805087; 8 studies; 7,810 cases; 37,543 controls), MTRR A66G (rs1801394; 4 studies; 3,032 cases; 4,515 controls), MTHFD1 G1958A (rs2236225; 6 studies; 7,493 cases; 36,941 controls), SLC19A1/RFC1 G80A (rs1051266; 4 studies; 6,222 cases; 35,821 controls), SHMT1 C1420T (rs1979277; 2 studies; 2,689 cases; 4,110 controls), and FOLH1 T1561C (rs202676; 5 studies; 6,314 cases; 35,190 controls). The majority (10 of 13) of eligible studies had 100% Caucasian subjects; only one study had <90% Caucasian subjects. We found weak evidence of dominant effects of two alleles: MTR 2756A>G [random effects pooled odds ratio, 1.06 (1.00-1.12); P = 0.06 (P = 0.59 for heterogeneity across studies)] and SHMT1 1420C>T [random effects pooled odds ratio, 1.11 (1.00-1.22); P = 0.05 (P = 0.38 for heterogeneity across studies)]. We found no effect of MTHFR 677C>T or any of the other alleles in dominant, recessive or additive models, or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on advanced or localized cancers. Our meta-analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer.

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis.

Polymorphisms of DNA repair-related genes might modulate cancer predisposition. We performed a systematic review and meta-analysis of the available evidence regarding the relationship between these polymorphisms and the risk of developing cutaneous melanoma. Relevant studies were searched using PubMed, Medline, Embase, Cancerlit, Cochrane and ISI Web of Knowledge databases. Data were gathered according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The model-free approach was adopted to perform the meta-analysis of the retrieved data. We identified 20 original reports that describe the relationship between melanoma risk and the single-nucleotide polymorphisms (SNPs) of 16 genes (cases = 4195). For seven SNPs considered in at least two studies, the findings were heterogeneous. Data were suitable for meta-analysis only in the case of the XPD/ERCC2 SNP rs13181 (cases = 2308, controls = 3698) and demonstrated that the variant C allele is associated with increased melanoma risk (odds ratio = 1.12, 95% confidence interval = 1.03-1.21, P = 0.01; population attributable risk = 9.6%). This is the first meta-analysis suggesting that XPD/ERCC2 might represent a low-penetrance melanoma susceptibility gene. Much work is still to be done before definitive conclusions can be drawn on the role of DNA repair alterations in melanomagenesis since for the other genes involved in this highly complex process, the available information is scarce or null.

A comprehensive and systematic assessment of the current status of candidate-gene association studies for chronic lymphocytic leukemia (CLL) was conducted. Data from 989 candidate-gene association studies (1992-2009) involving 905 distinct genetic variants were analyzed and cataloged in CUMAGAS-CLL, a Web-based information system which allows the retrieval and synthesis of data from candidate-gene association studies on CLL (http://biomath.med.uth.gr). Nine genetic variants (BAX (rs4645878), GSTM1 (null/present), GSTT1 (null/present), IL10 (rs1800896), LTA (rs909253), MTHFR (rs1801131), MTHFR (rs1801133), P2RX7 (rs3751143), and TNF (rs1800629)) were investigated in 4 or more studies, and their results were meta-analyzed. In individual studies, 147 variants showed a significant association with CLL risk under any genetic model. For 53 variants, the association was significant at P < 0.01 with an increased risk greater than 40%. Only 0.3% of studies had statistical power greater than 80%. In meta-analyses, none of the variants showed significant results, and heterogeneity ranged from none to high. Large and rigorous genetic studies (candidate-gene association studies and genome-wide association studies) designed to investigate epistatic and gene-environment interactions may produce more conclusive evidence about the genetic etiology of CLL. CUMAGAS-CLL would be a useful tool for current genomic epidemiology research in the field of CLL.

Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; P(chi2) = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; P(chi2) = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (P(chi2) = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors.

Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptor-positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium.

To study the association of polymorphisms in the genes encoding peroxisome proliferator-activated receptors (PPARs) with the polycystic ovary syndrome (PCOS).

Menopausal hormone therapy (HT) is associated with an increased breast cancer risk among postmenopausal women. In this study, we investigated genetic effect modification of HT associated breast cancer risk in 3,149 postmenopausal breast cancer patients and 5,489 controls from the two German population-based case-control studies MARIE and GENICA. Twenty-eight polymorphisms of 14 candidate genes including two drug and hormone transporter genes (ABCB1/MDR1 and SHBG), four genes involved in cell cycle regulation (BRCA1, P21/CDKN1A, STK15/AURKA and TP53), six cytokine genes (IGFBP3, IL6, TGFB1, TNF, LTA and IGF1), and two cytokine receptor genes (EGFR and ERBB2) were genotyped using validated methods. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and estrogen monotherapy use with regard to breast cancer risk assuming log-additive and co-dominant modes of inheritance. Women homozygous for the major ABCB1_rs2214102_G allele were found to be at a significantly increased breast cancer risk associated with combined estrogen-progestagen therapy [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.12-1.23, P (interaction) = 0.022]. Additionally, risk associated with estrogen monotherapy was modified by BRCA1_rs799917. We observed a trend with increasing minor T alleles leading to the highest risk in homozygous carriers of the minor allele [OR (95% CI) = 1.17 (0.98-1.39), 1.06 (0.98-1.14), and 1.02 (0.94-1.11) for homozygous minor, heterozygous, and homozygous major allele carriers, respectively; P (interaction) = 0.032]. Our results suggest that genetic variants in ABCB1 and BRCA1 may modify the effect of HT on postmenopausal breast cancer risk.