TGFBR1*6A is a hypomorphic polymorphic allele of the type I transforming growth factor beta receptor (TGFBR1). TGFBR1*6A is a candidate tumor susceptibility allele that has been associated with an increased incidence of various types of cancer. This study was undertaken to analyze all published case-control studies on TGFBR1*6A and cancer and determine whether TGFBR1*6A is associated with cancer.

Cigarette smoking has inconsistently been associated with an increased risk of colorectal cancer. One of the enzymes responsible for the detoxification of the carcinogenic compounds present in tobacco smoke is glutathione S-transferase-mu (GST-mu). The gene that codes for this enzyme is GSTM1. In this study, we evaluated the associations and interaction between GSTM1 deletion, smoking behaviour and the development of colorectal cancer. We performed a pooled analysis within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). We selected six studies on colorectal cancer, including 1130 cases and 2519 controls, and restricted our analyses to Caucasians because the number of patients from other races was too limited. In addition we performed a meta-analysis including the studies from the GSEC database and other studies identified on MEDLINE on the same subject. The prevalence of the GSTM1 null genotype was within the range reported in other studies: 51.8% of the cases had the GSTM1 null genotype versus 56.6% of the controls. No significant association between the GSTM1 null genotype and colorectal cancer was found (odds ratio 0.92, 95% confidence interval 0.73-1.14). Our results suggest a possible positive association between lack of the GST-mu enzyme and colorectal cancer for non-smoking women (odds ratio 1.47, 95% confidence interval 0.80-2.70). There was no interaction between the effects of smoking and GSTM1 genotype on colorectal cancer risk in men and women (chi2=0.007, p=0.97). Our findings do not support an association between the GSTM1 null genotype and colorectal cancer. In addition, we did not find any modification of the smoking-induced colorectal cancer risk by GSTM1 genotype

With the proliferation of related microarray studies by independent groups, a natural step in the analysis of these gene expression data is to combine the results across these studies. However, this raises a variety of issues in the analysis of such data. In this article, we discuss the statistical issues of combining data from multiple gene expression studies. This leads to more complications than those in standard meta-analyses, including different experimental platforms, duplicate spots and complex data structures. We illustrate these ideas using data from four prostate cancer profiling studies. In addition, we develop a simple approach for assessing differential expression using the LASSO method. A combination of the results and the pathway databases are then used to generate candidate biological pathways for cancer.

Several polymorphisms in the 5alpha-reductase type 2 (SRD5A2) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 9 studies (12 comparisons) with V89L genotyping (2558 prostate cancer cases and 3349 controls), 7 studies (8 comparisons) with A49T genotyping (1594 cases and 2137 controls), and 4 studies with TA repeat genotyping (1109 cases and 1378 controls). The random effects odds ratio (OR) for the L versus V allele was 1.02 [95% confidence interval (CI), 0.94-1.11]. There was no suggestion of an overall effect either in recessive or dominant modeling, and comparison of L/L versus V/V also showed no differential prostate cancer susceptibility (OR, 1.03; 95% CI, 0.83-1.28). The random effects OR for the T versus A allele was 1.56 (95% CI, 0.93-2.62). However, excluding the first published study there was no evidence for any effect (OR, 1.08; 95% CI, 0.72-1.61). Moreover, the T allele had a low prevalence (0%, 1%, and 2% in Asian, African and European controls, respectively). The random effects OR for longer versus short TA alleles was 0.88 (95% CI, 0.74-1.05). Longer TA allele homozygotes were nonsignificantly under-represented among prostate cancer cases (OR, 0.53; 95% CI, 0.26-1.06). We exclude a role for the V89L polymorphism in conferring susceptibility to prostate cancer. The A49T and TA repeat polymorphisms may have a modest effect on prostate cancer susceptibility, but bias and chance findings cannot be excluded; any genuine genetic effects would account only for a small proportion of prostate cancer in the population.

Cytochrome P450 1A1 plays a major role in the bioactivation of a number of tobacco procarcinogens. Much interest has focused on a polymorphism in exon 7 of the CYP1A1 gene which has been associated with a more inducible form of the enzyme. However, past results of its association with lung cancer have been inconsistent, especially in Caucasians. We carried out a pooled analysis of the data submitted to the Genetic Susceptibility to Environmental Carcinogens (GSEC) database to further investigate this association and, especially, to examine the modifying effects of smoking status and race.

To examine the risk of lung cancer associated with the codon 72, intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case-control studies was undertaken. The principle outcome measure was the odds ratio (OR) for the risk of lung cancer using homozygosity of the 'wild-type allele' as the reference group. Data from 13 studies detailing the relationship between lung cancer and the codon 72 polymorphism of TP53 and three studies examining the intron 3 and 6 polymorphisms of TP53 were analysed. The ORs of lung cancer associated with the Pro-Pro and Pro-carrier genotypes of codon 72 were 1.18 [95% confidence interval (CI) 0.99-1.41] and 1.02 (95% CI 0.86-1.20), respectively. The ORs of lung cancer associated with homozygous and variant allele carrier genotypes of the intron 6 (MspI RFLP) polymorphism were 1.13 (95% CI 0.55-2.27) and 1.30 (95% CI 0.75-2.26) and of the intron 3 (16 bp duplication) polymorphism were 1.50 (95% CI 0.76-2.97) and 1.11 (95% CI 0.53-2.35), respectively. Although polymorphic variations in TP53 represent attractive candidate susceptibility alleles for lung cancer the results from this analysis provide little support for this hypothesis. Additional well-designed studies based on sample sizes commensurate with the detection of small genotypic risks may allow a more definitive conclusion.

The role of the anti-apoptotic protein Bcl-2 in lung cancer remains controversial. In order to clarify its impact on survival in small and non-small cell lung cancer (NSCLC), we performed a systematic review of the literature. Trials were selected for further analysis if they provided an independent assessment of Bcl-2 in lung cancer and reported analysis of survival data according to Bcl-2 status. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a quality scale designed by the European Lung Cancer Working Party (including study design, laboratory methods and analysis). Of 28 studies, 11 identified Bcl-2 expression as a favourable prognostic factor and three linked it with poor prognosis; 14 trials were not significant. No differences in scoring measurement were detected between the studies, except that significantly higher scores were found in the trials with the largest sample sizes. Assessments of methodology and of laboratory technique were made independently of the conclusion of the trials. A total of 25 trials, comprising 3370 patients, provided sufficient information for the meta-analysis. The studies were categorised according to histology, disease stage and laboratory technique. The combined hazard ratio (HR) suggested that a positive Bcl-2 status has a favourable impact on survival: 0.70 (95% confidence interval 0.57-0.86) in seven studies on stages I-II NSCLC; 0.50 (0.39-0.65) in eight studies on surgically resected NSCLC; 0.91 (0.76-1.10) in six studies on any stage NSCLC; 0.57 (0.41-0.78) in five studies on squamous cell cancer; 0.75 (0.61-0.93) and 0.71 (0.61-0.83) respectively for five studies detecting Bcl-2 by immunohistochemistry with Ab clone 100 and for 13 studies assessing Bcl-2 with Ab clone 124; 0.92 (0.73-1.16) for four studies on small cell lung cancer; 1.26 (0.58-2.72) for three studies on neuroendocrine tumours. In NSCLC, Bcl-2 expression was associated with a better prognosis. The data on Bcl-2 expression in small cell lung cancer were insufficient to assess its prognostic value.

The ELAC2 gene has been proposed to be a prostate cancer susceptibility gene and is being referred to as HPC2, in part because three case-control studies suggested that two common polymorphisms (Ser217Leu and Ala541Thr) are associated with risk. However, four subsequent larger studies have not confirmed this association. In five of the seven total studies, subject selection was influenced by prostate-specific antigen (PSA) levels. We examined the association and possible effect of subject selection in a larger study and a meta-analysis.

To identify published studies quantifying familial prostate cancer risks in relatives of prostate cancer cases and, by meta-analysis, obtain more precise estimates of familial risk according to the family history.

DNA mismatch repair deficiency is observed in about 15% of human colorectal, gastric, and endometrial tumors and in lower frequencies in a minority of other tumors thereby causing insertion/deletion mutations at short repetitive sequences, recognized as microsatellite instability (MSI). Evolution of tumors, including those with MSI, is a continuous process of mutation and selection favoring neoplastic growth. Mutations in microsatellite-bearing genes that promote tumor cell growth in general (Real Common Target genes) are assumed to be the driving force during MSI carcinogenesis. Thus, microsatellite mutations in these genes should occur more frequently than mutations in microsatellite genes without contribution to malignancy (ByStander genes). So far, only a few Real Common Target genes have been identified by functional studies. Thus, comprehensive analysis of microsatellite mutations will provide important clues to the understanding of MSI-driven carcinogenesis. Here, we evaluated published mutation frequencies on 194 repeat tracts in 137 genes in MSI-H colorectal, endometrial, and gastric carcinomas and propose a statistical model that aims to identify Real Common Target genes. According to our model nine genes including BAX and TGFbetaRII were identified as Real Common Targets in colorectal cancer, one gene in gastric cancer, and three genes in endometrial cancer. Microsatellite mutations in five additional genes seem to be counterselected in gastrointestinal tumors. Overall, the general applicability, the capacity to unlimited data analysis, the inclusion of mutation data generated by different groups on different sets of tumors make this model a useful tool for predicting Real Common Target genes with specificity for MSI-H tumors of different organs, guiding subsequent functional studies to the most likely targets among numerous microsatellite harboring genes.

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

Although narrative reviews have concluded that there is strong support for familial clustering of prostate carcinoma, the association has never systematically been quantified in reviews. The purpose of this meta-analysis was to summarize and quantify the recurrence risk ratio with emphasis on the degree of relation, the specific relationship of the family member, the number of affected family members, and the age at diagnosis.

A T-to-C polymorphism in the 5' promoter region of the CYP17 gene that encodes the cytochrome P450c17alpha has been implicated as a risk factor for prostate cancer, but individual studies have been inconclusive or controversial. Therefore we performed a meta-analysis of 10 studies (12 comparisons) with CYP17 genotyping on 2404 patients with prostate cancer and 2755 controls. Overall, the random effects odds ratio (OR) for the A2 (C) versus A1 (T) allele was 1.08 [95% confidence interval (CI), 0.95-1.22], with some between-study heterogeneity (P = 0.04). There was no suggestion of an overall effect either in recessive or dominant modeling of A2 effects, and the comparison of A2/A2 versus A1/A1 also showed no differential susceptibility to prostate cancer (OR, 1.15; 95% CI, 0.91-1.46). No effect of A2 was seen in subjects of European descent (7 comparisons, OR, 1.04; 95% CI, 0.92-1.18, no significant between-study heterogeneity) or Asian descent (2 comparisons, OR, 1.06; 95% CI, 0.66-1.71; P = 0.02 for heterogeneity), whereas A2 increased susceptibility to prostate cancer in subjects of African descent (3 comparisons, OR, 1.56; 95% CI, 1.07-2.28; no between-study heterogeneity). Smaller studies unilaterally showed more prominent genetic effects for A2 than larger studies (P = 0.038). The meta-analysis suggests that the CYP17 polymorphism is unlikely to increase considerably the risk of sporadic prostate cancer on a wide population basis, especially in subjects of European descent. Previously reported associations may reflect publication bias, although it is also possible that the polymorphism may be important in subjects of African descent.

The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter.

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.