In the current study, the authors present pooled data from studies that investigated p53 protein expression and/or mutation in human epithelial ovarian tumors.

Hormone refractory prostate cancer (PCa) is invariably lethal despite aggressive clinical treatment strategies. Detection strategies are needed to identify aggressive PCa before it becomes widely disseminated. Recently, two studies identified annexin 1 and 7 as potential biomarkers in the development of PCa progression. The annexins are a group of calcium-binding structural proteins that may play a role in the regulation of membrane trafficking, cellular adhesion, and cell signaling. Therefore the goal of this study is to simultaneously characterize the multiple members of the annexin family of genes in advanced PCa. Prostate samples from men with advanced hormone refractory PCa were compared to samples of hormone-naïve PCa and noncancerous prostate tissue. Samples from 15 patients with advanced hormone refractory PCa were used. To examine the annexin family, gene expression profiles from 21 noncancerous prostate tissues, 16 clinically localized PCas, and 20 hormone refractory PCa samples were used. By cDNA microarray analysis, annexins 1, 2, 4, 7, and 11 were significantly decreased in hormone refractory PCa when compared to localized hormone-naïve PCa with 2.2-, 1.5-, 1.3-, 1.4-, and 1.8-fold decreases, respectively (all P values <0.05). Interstudy validation of annexin family transcript expression was performed by meta-analysis of three other published prostate profiling studies. High-density tissue microarrays were used to validate a subset of annexins at the protein level by immunohistochemistry. Tissue microarray analysis revealed a significant decrease in protein expression for annexins 1, 2, 4, 7, and 11 in hormone refractory PCa as compared to localized PCa with 1.68-, 2.46-, 2.52-, and 3.01-fold decreases, respectively (Kruskal Wallis test, all P values P < 0.05). However, no significant differences were detected between the clinically localized PCa and noncancerous prostate tissues. These findings suggest that down-regulation of several members of the annexin family may contribute to PCa tumorigenesis. Annexins 1, 2, 4, 7, and 11 may play a role in tumor progression through distinct mechanisms or, alternatively, they may have redundant tumor suppressor activities. This study also suggests that a meta-analysis of existing gene expression data is useful in confirming findings from individual studies. Finally, down-regulation of several annexin family members may play a role in the development of the lethal PCa phenotype.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.

Myeloperoxidase (MPO) is released from neutrophils in lung tissue in response to exposure to various pulmonary insults, including tobacco smoking. This enzyme is involved in the activation of an intermediate metabolite of benzo(a)pyrene to the highly reactive benzo(a)pyrene diol epoxide. A (-463)G --> A polymorphism in the promoter region of the MPO gene has been identified. The A allele is associated with a decreased transcriptional activity attributable to the disruption of a SP1-binding site. We therefore examined whether carriers of the A allele may be at reduced risk of lung cancer in a case-control study of 150 cases and 172 control individuals, all Caucasian smokers. Relative to subjects with the MPO G/G genotype, a significant decreased risk of lung cancer was found for carriers of the G/A genotype [odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.29-0.88]. A reduction in risk, although not statistically significant, was also observed for subjects with the A/A genotype (OR = 0.84, 95% CI: 0.31-2.32). The lung cancer risk for carriers of one or two copies of the A allele was 0.55 (95% CI: 0.33-0.93). Because of the low prevalence of the A/A genotype, we also performed a meta-analysis of 2686 lung cancer cases and 3325 controls. The summary OR suggested a slight protective effect of the A/A genotype (OR = 0.86, 95% CI: 0.67-1.1), but this finding was strongly influenced by the results of a single large study. The meta-analysis restricted to studies comprising a homogeneous set yielded an OR of 0.68 (95% CI: 0.5-0.93). However, because of the heterogeneity in individual study results, additional large case-control studies are warranted to provide a more definitive conclusion.

The purpose of this study was to determine the incidence of trisomy 18 in women who are <35 years old and who have sonographically detected isolated choroid plexus cyst.

Adenocarcinoma of the esophagus and the gastroesophageal junction is the twentieth most common malignancy in the United States. In developed countries, the incidence of esophageal adenocarcinoma is increasing 5% to 10% per year. Despite the use of endoscopy for earlier detection, mortality from esophageal adenocarcinoma has not declined. Using an evidence-based approach, we review screening methods for esophageal adenocarcinoma, including the use of a symptom questionnaire, identification of patients with a family history of Barrett's esophagus, peroral or transnasal endoscopy, barium swallow, fecal occult blood testing, and brush and balloon cytology. Screening has not been shown to reduce rate of progression of Barrett's esophagus to esophageal cancer. Many treatment options for dysplastic Barrett's esophagus or early carcinoma appear effective, but long-term follow-up data are not available. There is currently insufficient evidence supporting population-based screening for Barrett's esophagus. Several risk factors, including severe reflux symptoms, male sex, and obesity, may identify patients with gastroesophageal reflux disease who are at the greatest risk of the development of cancer.

The aim was to ascertain whether many hundreds of clinical reports over the last decade are consistent with the prediction of a poorer outcome in cancer patients with p53 abnormalities treated with cytotoxic drugs and radiation.

The increasing availability and maturity of DNA microarray technology has led to an explosion of cancer profiling studies. To extract maximum value from the accumulating mass of publicly available cancer gene expression data, methods are needed to evaluate, integrate, and intervalidate multiple datasets. Here we demonstrate a statistical model for performing meta-analysis of independent microarray datasets. Implementation of this model revealed that four prostate cancer gene expression datasets shared significantly similar results, independent of the method and technology used (i.e., spotted cDNA versus oligonucleotide). This interstudy cross-validation approach generated a cohort of genes that were consistently and significantly dysregulated in prostate cancer. Bioinformatic investigation of these genes revealed a synchronous network of transcriptional regulation in the polyamine and purine biosynthesis pathways. Beyond the specific implications for prostate cancer, this work establishes a much-needed model for the evaluation, cross-validation, and comparison of multiple cancer profiling studies.

Hepatocarcinogenesis is a slow process during which genomic changes progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into hepatocellular carcinoma. During the long preneoplastic stage, in which the liver is often the site of chronic hepatitis, cirrhosis, or both, hepatocyte cycling is accelerated by upregulation of mitogenic pathways, in part through epigenetic mechanisms. This leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomere erosion and telomerase re-expression, sometimes microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and emergence of hepatocellular carcinoma are associated with the accumulation of irreversible structural alterations in genes and chromosomes, but the genomic basis of the malignant phenotype is heterogeneous. The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma. New strategies should enable these variants to be characterized.

To investigate the role of microsomal epoxide hydrolase (mEH) polymorphisms in the aetiology of lung cancer and to assess the interaction between mEH polymorphisms and smoking, we performed a meta-analysis of seven published studies, which included 2078 cases and 3081 controls, and a pooled analysis of eight studies (four published and four unpublished at that time) with a total of 986 cases and 1633 controls. The combined meta-analysis odds ratios (ORs) were 0.98 (95% confidence interval [CI] = 0.72-1.35) for polymorphism at amino acid 113 in exon 3 (His/His versus Tyr/Tyr genotype) and 1.00 (95% CI = 0.71-1.41) for polymorphism at amino acid 139 in exon 4 (Arg/Arg versus His/His genotype). In the pooled analysis, we observed a significant decrease in lung cancer risk (OR = 0.70, 95% CI = 0.51-0.96) for exon 3 His/His genotype after adjustment for age, sex, smoking and centre. The protective effect of exon 3 polymorphism seems stronger for adenocarcinoma of the lung than for other histological types. The OR for high predicted mEH activity, compared with low activity, was 1.54 (95% CI = 0.77-3.07) in the meta analysis and 1.18 (95% CI = 0.92-1.52) in the pooled analysis. We did not find a consistent modification of the carcinogenic effect of smoking according to mEH polymorphism, although the risk of lung cancer decreased among never smokers with high mEH activity and among heavy smokers with the exon 3 His/His genotype. In conclusion, this study suggests a possible effect of mEH polymorphisms at exon 3 in modulating lung cancer. If present, this effect may vary among different populations, possibly because of interaction with genetic or environmental factors.

Much data about genetic imbalances in tumors have been accumulated by comparative genomic hybridization (CGH). In order to distinguish between significantly and coincidentally involved regions in glioma by means of a meta-analysis, we summarized and analyzed the CGH results of 509 cases published in 26 reports between 1992 and 2001. The expansion of all aberrations to the 850-band level impressively visualized distinct patterns in astrocytoma, oligodendroglioma, and ependymoma as well as loci of frequent aberrations. For example, in astrocytoma the frequency of gains culminated at 7p12, 8q24.1, and 12q13-q15 (the loci of EGF-R, C-MYC and CDK4, respectively) and losses at 9p21 (the locus of p15 and p16) and 10q23.3 where PTEN resides. Most chromosomes were variably prone to copy number changes at different scales of aberrations. At the whole chromosome level the analysis showed +7, -10 in astrocytoma and +9, +18 in ependymoma, but +20q, -9p in astrocytoma and +1q, -22q in ependymoma at the p-q arm level. Furthermore, we could confirm the correlation between the average number of copy alterations per patient (average number of copy alterations [ANCA] index) and malignancy for astrocytoma in a refined graduation as well as for oligodendroglioma. As a new parameter, the average number of affected GTG-bands per patient (average number of affected GTG bands [ANAG] index) showed an even more striking correlation with the World Health Organization grade for gains and losses.

Smoking is a known risk factor for bladder cancer. The product of the GSTM1 gene, glutathione S-transferase M1 (GSTM1), is involved in the detoxification of polycyclic aromatic hydrocarbons found in tobacco smoke; a homozygous deletion of this gene in approximately 50% of Caucasians and Asians results in a lack of GSTM1 enzyme activity. Most studies examining the relation between bladder cancer and GSTM1 have reported an increased risk associated with a lack of GSTM1 activity. The authors performed meta- and pooled analyses of published and unpublished, case-control, genotype-based studies that examined this association (17 studies, 2,149 cases, 3,646 controls) and excluded studies conducted in populations with a high prevalence of exposure to known bladder cancer risk factors other than tobacco smoke. Using random effects models in the meta-analysis, the authors obtained a summary odds ratio of 1.44 (95% confidence interval (CI): 1.23, 1.68) for GSTM1 null status with all studies included. Results from studies with at least 100 cases and 100 controls produced a summary odds ratio of 1.42 (95% CI: 1.26, 1.60). Pooled analyses using original data sets from 10 studies (1,496 cases and 1,444 controls) and adjusting for age, sex, and race produced similar results. There was no evidence of multiplicative interaction between the GSTM1 null genotype and ever smoking in relation to bladder cancer, although there was a suggestion of additive interaction (additive interaction = 0.45, 95% CI: -0.03, 0.93). These results indicate that, among populations studied to date, GSTM1 null status is associated with a modest increase in the risk of bladder cancer.

Meta-analytic methods were used to determine the impact of genetic counselling on women with a family history of breast cancer. Published studies with prospective designs and randomized controlled trials were included in the review, and the psychological outcomes assessed were generalized psychological distress, generalized anxiety, depression, and breast cancer anxiety. Other outcomes investigated were the accuracy of perceived risk of developing breast cancer, breast cancer genetics knowledge and breast cancer screening uptake. A meta-analysis was performed to estimate effect size, where sufficient data were available. A total of 12 studies, most of which measured several outcomes, met at least one of the inclusion criteria. A sufficiently large number of studies were available to assess the magnitude of effects on three outcomes: generalized psychological distress, generalized anxiety and accuracy of perceived risk of developing breast cancer. The quantitative synthesis showed that genetic counselling leads to statistically significant decreases in generalized anxiety, with an average weighted effect sizes of r = - 0.17 (p<0.01). In contrast, the reduction in psychological distress exhibited a trend towards statistical significance only, with r = -0.074 (p = 0.052). The impact of genetic counselling on the accuracy of perceived risk was associated with an effect size of r = 0.56 (p<0.01). Thus in this meta-analysis, we demonstrated the efficacy of genetic counselling in meeting two of its objectives: reducing women's anxiety levels and improving the accuracy of their perceived risk. This review highlighted that most research so far focused on generalized distress and anxiety and accuracy of perceived risk, to the exclusion of other, perhaps equally important, types of outcomes. Future studies are likely to lead to more comprehensive assessments if additional emotional, cognitive and behavioural outcomes are included in the assessment.

The literature relating to human leucocyte antigens (HLA) and nasopharyngeal carcinoma (NPC) identifies conflicting ranges of possible allelic associations. We aimed to clarify this by conducting a systematic review to identify and quantify associations present across all of the available studies. A literature search was performed and, subsequently, a meta-analysis was performed on 13 published studies using both fixed-effects and random-effects models when appropriate. Evidence for positive associations between NPC and the HLA alleles A2, B14 and B46 (P = 1.57 x 10-5, 1.13 x 10-3 and 6.38 x 10-5 respectively) were found, and negative associations were identified for the alleles A11, B13 and B22 (P = 5.42 x 10-3, 0.017 and 0.009). Whereas an association between HLA-B13 or B22 and NPC has not been noted previously, the results for HLA-A2, A11, B14 and B46 are in accordance with published studies. There is evidence that specific allele subtypes or combinations of alleles may carry particular risk for NPC.

In this study, we review a variety of genetic polymorphisms that may have an etiologic role in prostate cancer. We include associations identified in molecular epidemiology studies and the consistency of findings reported to date. Suggestions for further research are also offered. For the purposes of this review, we identified relevant articles through a MEDLINE search for the period of January 1987 through March 2001. The searches were limited to articles published in English. Medical subject headings were used to scan titles, abstracts, and subject headings in the databases using the keywords "prostate neoplasms," "genetics," and "polymorphisms."

Inter-individual differences in susceptibility to breast cancer are partially mediated through the levels of endogenous and exogenous steroid hormones. The CYP17 gene encodes P450c17alpha, an enzyme that is involved in the metabolism of steroid hormones. Increased endogenous steroid hormone levels have been associated with a MspA1 polymorphism in the 5'-promoter region of the CYP17 gene. The CYP17 MspA1 polymorphism has been postulated as being associated with the risk of developing breast cancer. However, the association between the CYP17 MspA1 polymorphism and breast cancer risk has been controversial in the literature. To re-examine this controversy, we have undertaken a meta-analysis of 15 case-control studies, which included a total of 4227 breast cancer cases and 4730 individual controls. The odds ratio (OR) was used to evaluate the risk of breast cancer for each study, using homozygosity of the wild-type allele as the control group. Statistical analysis showed no evidence of heterogeneity within the studies. The pooled ORs of breast cancer associated with the combined variant (A1/A2 + A2/A2) and the homozygous genotype (A2/A2) were 0.98 (95% CI 0.89-1.07) and 1.05 (95% CI 0.87-1.21), respectively. Similarly, the pooled ORs of advanced breast cancer associated with the combined variant and the homozygous genotype were 0.96 (95% CI 0.77-1.20) and 0.88 (95% CI 0.55-1.41), respectively. A pooling of the studies was also conducted for the various ethnic groups, but failed to show an association of CYP17 MspA1 polymorphism with breast cancer risk in the different ethnic groups. In addition, our results show that a possible protective effect for breast cancer risk of a later age at menarche was mainly limited to women with the A1 homozygous genotype. The OR for age at menarche (> or = 13) was 0.87 (95% CI 0.62-1.17). Our results suggest that CYP17 MspA1 polymorphism may be at best a weak modifier of breast cancer risk but is not a significant independent risk factor.

The role of p53, as a prognostic factor for survival in lung cancer, is controversial and the purpose of the present systematic review of the literature is to determine this effect. Published studies were identified with the objective to aggregate the available survival results after a methodological assessment using a scale specifically designed by the European Lung Cancer Working Party (ELCWP). To be eligible, a study had to deal with p53 assessment in lung cancer (primary site) only, and to provide a survival comparison according to the p53 status. Among the 74 eligible papers, 30 identified p53 abnormalities as a univariate statistically significant poor prognostic factor and 56 provided sufficient data to allow survival results aggregation. There was no significant difference between the trials that either showed or did not show a prognostic effect of p53 according to the methodological score or to the laboratory technique used. The studies were categorized by histology, disease stage, treatment and laboratory technique. Combined hazard ratios suggested that an abnormal p53 status had an unfavourable impact on survival: in any stage nonsmall cell lung cancer (NSCLC) the mean (95% confidence interval) was 1.44 (1.20-1.72) (number of studies included in the subgroup was 11), 1.50 (1.32-1.70) in stages I-II NSCLC (n=19), 1.68 (1.23-2.29) in stages I-IIIB NSCLC (n=5), 1.68 (1.30-2.18) in stages III-IV NSCLC (n=9), 1.48 (1.29-1.70) in surgically resected NSCLC (n=20), 1.37 (1.02-1.85) in squamous cell carcinoma (n=9), 2.24 (1.70-2.95) in adenocarcinoma (n=9), 1.57 (1.28-1.91) for a positive immunohistochemistry with antibody 1801 (n=8), 1.25 (1.09-1.43) for a positive immunohistochemistry with antibody DO-7 (n=16), and 1.65 (1.35-2.00) for an abnormal molecular biology test (n=13). Data were insufficient to determine the prognostic value of p53 in small cell lung cancer. In each subgroup of nonsmall cell lung cancer, p53 abnormal status was shown to be associated with a poorer survival prognosis.

The aim of this study was to identify published studies quantifying familial colorectal cancer (CRC) risks in first-degree relatives of CRC and colorectal adenoma (CRA) cases and, through a meta-analysis, obtain more precise estimates of familial risk according to the nature of the family history and type of neoplasm.

Increasingly, studies of the relationship between common genetic variants and colorectal tumor risk are being proposed. To assess the evidence that any of these confers a risk, a systematic review and meta-analysis of published studies was undertaken.