Search

Purpose: Inconsistency of reported associations between the C1420T polymorphism in the cytosolic serine hydroxymethyltransferase (SHMT1) gene and colorectal cancer (CRC) prompted us to undertake a meta-analysis., Methods: We conducted searches of published literature in MEDLINE through PubMed up to April 2012. Individual data on 5,043 cases and 6,311 controls from 15 published case-control studies were evaluated. Meta-analyses were performed on the compiled dataset., Results: In the overall analysis, association was lacking between the C1420T polymorphism and CRC risk (odds ratio [OR] 0.96-1.04, p = 0.47-0.77), materially unchanged when reanalyzed without the Hardy-Weinberg equilibrium-deviating studies (OR 1.03-1.09, p = 0.22-0.55) or subjected to outlier treatment (OR 0.89-0.99, p = 0.10-0.8). In the ethnic subgroups, Europeans were susceptible (OR 1.11-1.17, p = 0.13-0.48) and Americans, slightly protected (OR 0.86-0.87, p = 0.49-0.61). The increased risk effects, however, became null following outlier treatment (OR 0.95-1.06). Test for interaction between decreased risk associations in the low-folate subgroup (OR 0.60-0.85, p = 0.009-0.03) with the susceptible effects in the high-folate category (OR 1.14-1.22, p = 0.19-0.32) was significant (p interaction = 0.004)., Conclusions: Overall summary estimates imply no associations but suggest geography-specific effects of the SHMT1 polymorphism that render Europeans susceptible, but not Americans. Folate status appears to show an inverse association of this polymorphism with CRC.

Inconsistency of reported associations between the Pro919Ser polymorphism in the BRCA1 interacting protein 1 (BRIP1) gene and breast cancer prompted us to undertake a meta-analysis. Although investigated by fewer studies, we have also studied the risk associated with the two additional BRIP1 polymorphisms, C47G and G64A, and breast cancer riskWe conducted searches of the published literature in MEDLINE through PubMed up to October 2012. Individual data on 5,122 cases and 5,735 controls from eight published case-control studies were evaluated for the Pro919Ser polymorphism. Accordingly, C47G and G64A polymorphisms were studied in 1,539 cases and 1,183 controls, and 667 and 782, respectively.In the overall analysis, association was lacking between the Pro919Ser polymorphism and breast cancer risk (odds ratio [OR] 0.98-1.02), materially unchanged when confined to subjects of European ancestry (OR 0.96-1.03) or even in the high-powered studies (OR 0.97-1.03). In the menopausal subgroups, premenopausal women followed the null pattern (OR 0.94-0.98) for the Pro and Ser allele contrasts, but not for the Pro-Ser genotype comparison where significant increased risk was observed (OR 1.39, P = 0.002). The postmenopausal women (>50 years) exhibited a range of pooled effects from protection (OR 0.83, P = 0.11) in the Pro-Ser genotype to slightly increased risk (OR 1.12-1.16, P = 0.28-0.42) in the Pro and Ser allele comparisons. The G64A polymorphism effects were essentially null (OR 0.90-0.98), but C47G was found to confer non-significantly increased risk under all genetic models (OR 1.27-1.40).Upon conclusion, overall summary estimates imply no associations but suggest susceptibility among carriers of the C47G polymorphism and Pro-Ser genotype in premenopausal women. The premenopausal findings and variable outcomes in postmenopausal women require more studies for confirmation.

The Val762Ala polymorphism poly [ADP-ribose] polymerase 1 (PARP1) gene [ADPRT (adenosine diphosphate ribosyltransferase) gene] affects enzymatic activity, which modulates cancer susceptibility among human populations. Individual data on 13,745 cases and 16,947 controls from 28 published case-control studies were re-evaluated. Odds ratios (OR) were estimated for ethnic group, cancer type, smoking joint effects and studies confined to the Hardy-Weinberg equilibrium. We applied subgroup, sensitivity and outlier analyses as well as the Bonferroni correction for multiple testing. The results show strong evidence that the variant (C) allele confers significant increased risk in the Chinese (OR 1.20-1.44, P < 0.0001-0.002), exacerbated by smoking (OR 1.66-2.53, P < 0.0001) and joint interaction with XRCC1 Arg399Gln (OR 1.39, P < 0.0001) as well as adjustment for tumor type (gastric carcinoma ORs 1.39-2.01, P < 0.0001). These significant effects were unaltered following conservative correction for multiple tests. By contrast, this procedure erased the protective significance in Caucasians, but not in two American subgroups, (i) those in the brain tumor category (0.77-0.79, P < 0.0001) and (ii) smokers in the dominant model (OR 0.86, P < 0.0001). These differential findings between the two ethnicities maybe correlated with significantly (P < 0.0001) greater allele frequency of the variant allele (C) among the Chinese compared to Caucasians. Our racial and tissue-specific summary estimates imply consideration of the Val762Ala polymorphism as candidate gene marker for screening cancer patients' best suited for PARP inhibitor therapy.

Background: Breast cancer susceptibility may be modulated partly through polymorphisms in oxidative enzymes, one of which is myeloperoxidase (MPO). Association of the low transcription activity variant allele A in the G463A polymorphism has been investigated for its association with breast cancer risk, considering the modifying effects of menopausal status and antioxidant intake levels of cases and controls., Methodology/principal Findings: To obtain a more precise estimate of association using the odds ratio (OR), we performed a meta-analysis of 2,975 cases and 3,427 controls from three published articles of Caucasian populations living in the United States. Heterogeneity among studies was tested and sensitivity analysis was applied. The lower transcriptional activity AA genotype of MPO in the pre-menopausal population showed significantly reduced risk (OR 0.56-0.57, p = 0.03) in contrast to their post-menopausal counterparts which showed non-significant increased risk (OR 1.14; p = 0.34-0.36). High intake of antioxidants (OR 0.67-0.86, p = 0.04-0.05) and carotenoids (OR 0.68-0.86, p = 0.03-0.05) conferred significant protection in the women. Stratified by menopausal status, this effect was observed in pre-menopausal women especially those whose antioxidant intake was high (OR 0.42-0.69, p = 0.04). In post-menopausal women, effect of low intake elicited susceptibility (OR 1.19-1.67, p = 0.07-0.17) to breast cancer., Conclusions/significance: Based on a homogeneous Caucasian population, the MPO G463A polymorphism places post-menopausal women at risk for breast cancer, where this effect is modified by diet.

The excision repair cross-complementing group 2 gene (ERCC2) plays a key role in DNA repair. Several polymorphisms in the ERCC2 gene have been described, including the commonly occurring Lys751Gln and Asp312Asn polymorphisms. Studies investigating the association of these polymorphisms with breast cancer risk produced controversial results. To evaluate these associations presented in diverse populations, we have conducted a meta-analysis based on 40 studies from 33 publications in PubMed which included analyses of Lys751Gln (14,545 cases, 15,352 controls) and Asp312Asn polymorphisms (16,254 cases, 14,006 controls). Overall findings of both polymorphisms have implicated null effects (OR = 1.01-1.03) when the analyses were limited to the statistically powerful (≥80%) studies. Although modestly increased statistically significant breast cancer risk was detected in the underpowered studies (≤80%), removal of outliers resulted in null associations. Ethnic stratification showed non-significant and relatively null associations for both polymorphisms with breast cancer risk for the overall Caucasians as well as North American and the European sub-populations. Although statistically increased and decreased risks were observed for the homogenous populations of African-Americans (Lys751Gln, OR 1.25, 95% CI 1.03-1.53, P = 0.03) and Asians (Asp312Asn, ORs: 0.53-0.55, P values: 0.02-0.03), respectively, this may be the result of small sample size. Analyses of the homogeneous adduct studies, with relatively large sample size, exhibited increased risk for Lys751Gln (OR 1.20, 95% CI (1.02-1.41), P = 0.03) and Asp312Asn (OR 1.17 95% CI 1.02-1.34, P = 0.03) under the dominant genetic model. In conclusion, our results suggest null associations of both polymorphisms in the overall and the Caucasian subgroups, although some effects can be suggested for relatively smaller minority studies. Increased risk effect was more visible when the adduct studies are considered, suggesting the role of these polymorphisms in the presence of exposure to DNA damaging agents.

The G870A polymorphism in the CCND1 gene may influence cancer risk. However, data from published studies with individual low statistical power have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and cancer, we considered all available studies in a meta-analysis. Sixty studies were combined representing data for 18,411 cases and 22,209 controls. In our meta-analysis, we investigated overall sample and two ethnic populations (Caucasians and Asians) as well as nine cancer subtypes. Individuals who are homozygous for A allele (AA) were found to be associated with significantly increased cancer risk in overall sample [odds ratio (OR), 1.23; 95% confidence interval (95% CI), 1.13-1.33; P

Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome-based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the genetic and drug response data of the NCI60 cell lines to discover potential candidate genetic variants associated with variable response to chemotherapy. As an example we have applied this strategy to discover single genetic markers and haplotypes from candidate genes previously implicated in the pharmacobiology of gemcitabine. Single-marker association analyses have implicated the association of four SNPs within the gene loci of CDC5L, EPC2, POLS, and PARP1. We have also investigated the combined effect of SNPs using haplotype-based analysis. Accordingly, we have shown modest association of haplotypes in six genes, whereas the most significant associations included a haplotype of the POLS gene. The hypothesis-generating tool presented in this study can be applied to drugs profiled in the NCI60 cell line screen and provides an effective means for the identification of genes associated with drug response. The results obtained using this novel methodology can be used to better design the clinical trials for effective study of the chemotherapeutic agents and thus provide a basis for individualized chemotherapy., (Copyright 2008 Wiley-Liss, Inc.)

Proteins destined for secretion or membrane compartments possess signal peptides for insertion into the membrane. The signal peptide is therefore critical for localization and function of cell surface receptors and ligands that mediate cell-cell communication. About 4% of all human proteins listed in UniProt database have signal peptide domains in their N terminals. A comprehensive literature survey was performed to retrieve functional and disease associated genetic variants in the signal peptide domains of human proteins. In 21 human proteins we have identified 26 disease associated mutations within their signal peptide domains, 14 mutations of which have been experimentally shown to impair the signal peptide function and thus influence protein transportation. We took advantage of SignalP 3.0 predictions to characterize the signal peptide prediction score differences between the mutant and the wild-type alleles of each mutation, as well as 189 previously uncharacterized single nucleotide polymorphisms (SNPs) found to be located in the signal peptide domains of 165 human proteins. Comparisons of signal peptide prediction outcomes of mutations and SNPs, have implicated SNPs potentially impacting the signal peptide function, and thus the cellular localization of the human proteins. The majority of the top candidate proteins represented membrane and secreted proteins that are associated with molecular transport, cell signaling and cell to cell interaction processes of the cell. This is the first study that systematically characterizes genetic variation occurring in the signal peptides of all human proteins. This study represents a useful strategy for prioritization of SNPs occurring within the signal peptide domains of human proteins. Functional evaluation of candidates identified herein may reveal effects on major cellular processes including immune cell function, cell recognition and adhesion, and signal transduction., ((c) 2007 Wiley-Liss, Inc.)

Background: Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription., Methods: In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins., Results: Here, we have shown that the high enzymatic activity genotype of CCND1High (AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0-1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01-1.84)]. The heterozygous COMTMedium (MetVal) and the high enzymatic activity of COMTHigh (ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07-1.68)] and [OR: 1.4, 95%CI (1.07-1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMTHigh (ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73-1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: 2.22, 95%CI (1.49-3.28)] and Finland [OR: 1.73, 95%CI (1.08-2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity., Conclusion: Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.

The recent availability of the sequenced and annotated DNA sequences of chromosomes 21 and 22 has initiated the next phase in the human genome project: the application of this resource. One facet of these data is that they provide a list of ordered genes along the chromosome that can be capitalized upon to determine gene position effects. Specifically, the physical position and distribution of genes along the chromosomes may be related to gene expression in specific organs or organ systems. In this report we index the subset of genes constituting the human "cardiovascular genome" on chromosomes 21q and 22q as well as report the identification of several "cardiovascular gene" clusters. These gene clusters are suggestive of a higher order of tissue-specific gene regulation at the chromosomal level., (Copyright 2001 Academic Press.)