Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.

Lung cancer is the most common neoplastic disease in Eastern and Central Europe. The role of hereditary factors in lung carcinogenesis is not fully understood. Family history (FH) of lung cancer and other tobacco-related cancers might be a strong predictor of the lung cancer risk. We investigated family history of cancer among first-degree relatives of 2,861 patients with lung cancer and 3,118 controls from the Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, and United Kingdom within the IARC Multicenter Case-Control Study. Odds ratios (ORs) and 95% CI were calculated using logistic regression, adjusting for age, gender, study center, education, tobacco smoking, and number of first-degree relatives. In addition, we conducted a meta-analysis of 41 studies on FH of cancer and lung cancer risk. Positive FH of lung cancer increased risk of lung cancer with OR of 1.63 (95%CI: 1.31-2.01), and having two or more affected relatives with lung cancer further increased the risk of lung cancer with OR 3.60 (95%CI: 1.56-8.31). Among subjects aged less than 50, the OR for FH of lung cancer was 2.08 (95%CI: 1.18-3.63). The associations were generally stronger for squamous cell carcinoma and large cell carcinoma subtypes. Heterogeneity in results was not found with respect to smoking status and gender. A significant association was not observed for FH of other smoking-related tumors. The results of meta-analysis were consistent with that of our study with regard to young onset, non-smokers and histology. FH of lung cancer is a predictor of an increased risk of lung cancer, especially in subjects aged less than 50.

A genetic polymorphism at codon 198 in the human glutathione peroxidase 1 gene was reported to be associated with several cancers. However, this relationship remains controversial, especially in breast cancer. For better understanding the effect of GPX1 Pro198Leu polymorphism on breast cancer, a meta-analysis was performed. By searching relevant literatures, a total of six case-control studies, containing 5,509 breast cancer cases and 6,542 healthy controls, were included. The strength of association between GPX1 Pro198Leu polymorphism and breast cancer risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95%CI). And the results strongly suggested that there was no significant association between variant Leu allele and breast cancer susceptibility in overall comparisons in all genetic models [additive model: OR, 1.04; 95% CI, 0.92-1.18; P = 0.555; dominant model: OR, 1.01; 95% CI, 0.94-1.09; P = 0.777; recessive model: OR, 1.04; 95% CI, 0.92-1.18; P = 0.536]. However in subgroup analysis, an elevated risk in African population with variant Leu allele was revealed in additive (OR, 1.91; 95% CI, 1.02-3.58; P = 0.044) and recessive (OR, 2.09; 95% CI, 1.16-3.76; P = 0.014) genetic model. No apparent association between this polymorphism and different menopausal status (premenopausal and postmenopausal) and the other ethnicities (almost Caucasians) was showed. In conclusion, this meta-analysis strongly suggests that GPX1 Pro198Leu polymorphism is not associated with breast cancer risk in Caucasians, and an elevated risk in Africans needs large-scale investigations to confirm.

We have previously identified an oncogenic role of artemin (ARTN), a member of glial cell derived neurotrophic factor family of ligands, in mammary carcinoma. We herein report that ARTN is an estrogen-inducible gene. Meta-analysis of gene expression data sets showed that ARTN expression is positively correlated to estrogen receptor (ER) status in human mammary carcinoma. Furthermore, in patients with ER-positive mammary carcinoma treated with tamoxifen, high ARTN expression is significantly correlated with decreased survival. Forced expression of ARTN in ER-positive human mammary carcinoma cells increased ER transcriptional activity, promoted estrogen-independent growth and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. ARTN-stimulated resistance to tamoxifen and fulvestrant is mediated by increased BCL-2 expression. Conversely, depletion of endogenous ARTN by small-interfering RNA or functional antagonism of ARTN by antibody enhanced the efficacy of antiestrogens. Tamoxifen decreased ARTN expression in tamoxifen-sensitive mammary carcinoma cells whereas ARTN expression was increased in tamoxifen-resistant cells and not affected by tamoxifen treatment. Antibody inhibition of ARTN in tamoxifen-resistant cells improved tamoxifen sensitivity. Functional antagonism of ARTN therefore warrants consideration as an adjuvant therapy to enhance antiestrogen efficacy in ER-positive mammary carcinoma.

Sporadic adrenocortical tumours are common, but their pathogenesis is poorly elucidated. In this study, we present a meta-analysis and review of gene expression microarray and comparative genome hybridization (CGH) studies performed to date on these tumours, including our own data. Data of whole genome microarray studies from altogether 164 tumours (97 benign, 67 malignant) and 18 normal tissues were reclassified and reanalysed. Significant gene sets and cytogenetic changes from publications without available genomic data were also examined including 269 benign, 215 malignant tumour and 30 normal tissues. In our experimental study, 11 tumour and four normal samples were analysed by parallel mRNA and CGH profiling. Data were examined by an integrative bioinformatics approach (GeneSpring, Gene Set Enrichment Analysis and Ingenuity Pathway Analysis softwares) searching for common gene expression changes and paralleling chromosome aberrations. Both meta-analysis of available mRNA and CGH profiling data and our experimental study revealed three major pathogenetic pathways: (1) cell cycle, (2) retinoic acid signalling (including lipopolysaccharide/Toll like receptor 4 pathway), (3) complement system and antigen presentation. These pathways include novel, previously undescribed pathomechanisms of adrenocortical tumours, and associated gene products may serve as diagnostic markers of malignancy and therapeutic targets.

Vascular endothelial growth factor A (VEGF-A), a major driver of physiological and pathological angiogenesis, plays important roles in the etiology and metastasis of cancers. The +936C>T polymorphism in the 3'-untranslated region of the VEGFA gene has been implicated in cancer risk and is related to VEGF-A protein production; however, published data have been conflicting. To derive a more precise estimation of the relationship, a meta-analysis was performed of 13,293 cancer cases and 12,308 control subjects from 29 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between +936C>T polymorphism and cancer risk. The meta-analysis indicated that individuals with the +936 T had increased risk of oral cancer (OR = 1.39, 95% CI = 1.03-1.88), although no association was found in the contrast of T versus C (OR = 1.00, 95% CI = 0.91-1.10) in the pooled analyses. This meta-analysis supports the idea that VEGFA + 936 T is associated with increased risk of oral cancer. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between VEGFA + 936C>T polymorphism and cancer risk.

A study was carried out to describe associations of MC1R variants and melanoma in a US population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure measures.

In this article, inconsistency of the association of polymorphisms of fibroblast growth factor receptor 2 (FGFR2) with breast cancer is noted. Three commonly studied FGFR2 polymorphisms including rs1219648 (A > G), rs2420946 (C > T), and rs2981582 (C > T) were selected to explore their association with risk of development of breast cancer by meta-analysis of published case-control studies. The results showed that all these three polymorphisms were significantly associated with altered breast cancer risk in any model (co-dominant, dominant, or recessive model) and in stratification based on ethnicity and study design. In the subgroup analyses for postmenopausal women, significantly increased risks were found for rs1219648 and rs2420946 in any model. This meta-analysis suggests that FGFR2 is likely an important genetic marker contributing to susceptibility of breast cancer. We recommend that these single nucleotide polymorphisms to be included in future association studies and functional assays.

Studies investigating the association between interleukin-10 -819 promoter polymorphism and gastric cancer risk report conflicting results. This study aimed to summarize quantitatively the evidence for such a relationship. Two investigators independently searched the Medline (January 1966-January 2009) and Embase (January 1980-January 2009) databases for eligible studies to be included in a meta-analysis. Six case-control studies, which included 681 gastric cancer cases and 1621 control subjects were selected. Combined results for all studies showed that there was no significant difference in genotype distribution (TT, TC or CC) between gastric cancer patients and control subjects. When stratifying for race, results were similar except that Asian patients with gastric cancer had a significantly lower frequency of TT and a higher frequency of TC than Asian control subjects. When stratifying by location and Lauren's classification of gastric cancer, there was no significant difference in genotype distribution between patients with gastric cancer and control subjects. This meta-analysis suggests that the interleukin-10 -819 promoter polymorphism may be associated with gastric cancer in Asians.

Although a number of genetic studies have attempted to link transforming growth factor beta 1 gene (TGFB1) -509 C>T polymorphism to breast cancer, the results were often irreproducible. We therefore aimed to meta-analyze all available case-control studies from the English-published literature to explore the association of this polymorphism with breast cancer. A total of 6 studies with 9 populations involving 10,197 patients and 13,382 controls were identified as of February 20, 2010. A random-effects model was performed irrespective of the between-study heterogeneity. Study quality was assessed in duplicate. The frequencies of TGFB1 -509 T allele in patients and controls ranged from 21.72 to 51.74%, and 24.53 to 52.40%, respectively. The presence of -509 T allele conferred a nonsignificant protective effect on breast cancer [odds ratio (OR) = 0.99; 95% confidence interval (CI) 0.93-1.05; P = 0.72]. This lack of association persisted under co-dominant, dominant, and recessive models. However, exclusion of the initial study significantly strengthened the magnitude of this protective effect. For example, under the dominant assumption, carriers of -509 T allele had a moderate reduced risk for breast cancer compared with the -509 CC homozygous (OR = 0.94; 95% CI 0.88-1.00; P = 0.04). Subgroup analyses by study designs and geographic areas did not substantially affect the present associations. No publication biases were observed by the fail-safe number. Taken together, our results demonstrated that TGFB1 -509 T allele was associated with a reduced risk to develop breast cancer and this allele appeared to act in an additive mode.

Polymorphisms in the elaC homolog-2 (ELAC2)/HPC2 gene have been hypothesized to alter the risk of prostate cancer. However, the results of the related published studies remained conflicting. We performed a meta-analysis of 18 studies evaluating the association between ELAC2 Ser217Leu and Ala541Thr polymorphisms and prostate cancer risk. Overall, ELAC2 Leu217 allele was associated with increased prostate cancer risk as compared with the Ser217 allele (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.03-1.24, P=0.019 for heterogeneity), as well as in the heterozygote comparison (OR=1.21, 95% CI: 1.07-1.36, P=0.034 for heterogeneity) and the dominant genetic model (OR=1.20, 95% CI: 1.07-1.35, P=0.025 for heterogeneity). Furthermore, the ELAC2 Thr541 allele was associated with increased prostate cancer risk as compared with the Ala541 allele (OR=1.22, 95% CI: 1.00-0.48, P=0.131 for heterogeneity). In the stratified analyses for Ser217Leu polymorphism, there was significantly increased prostate cancer risk in Asian and Caucasian populations, and studies using sporadic and familial prostate cancer cases. Similar result was found in the Asian population in the stratified analyses for Ala541Thr polymorphism. This meta-analysis showed evidence that ELAC2 Ser217Leu and Ala541Thr polymorphisms were associated with prostate cancer risk, and might be low-penetrance susceptibility markers of prostate cancer.

Predicting pituitary tumor behavior remains a challenge, since the prognostic value of identified pathological markers has not yet been evaluated. Genome-wide transcriptome analyses allow the identification of molecular markers to highlight global changes in gene expression and enable the discovery of signaling pathways within complex biological networks. While several transcriptome studies comparing normal with tumoral pituitary as a whole or with respect to subtype have given interesting data concerning pituitary pathogenesis, none have considered pituitary tumor prognosis. Only one study to date, focusing on the pathological classification and progression of prolactin tumors, has identified some molecular markers with diagnostic and prognostic value. We reviewed data in the literature on human pituitary tumor transcriptome and conducted a meta-analysis on the expression of genes involved in cell growth, proliferation and the cell cycle. Based on our expertise, we evaluate the interests and the limitations of using this approach with human pituitary tumors.

Acute myeloid leukemia (AML) is a heterogeneous disease with an overall poor prognosis. Gene expression profiling studies of patients with AML has provided key insights into disease pathogenesis while exposing potential diagnostic and prognostic markers and therapeutic targets. A systematic comparison of the large body of gene expression profiling studies in AML has the potential to test the extensibility of conclusions based on single studies and provide further insights into AML.

Glutathione S-transferases (GSTs) catalyse reactions between glutathione and lipophilic compounds with electrophilic centres, leading to neutralisation of toxic compounds, xenobiotics and products of oxidative stress. Controversy exists about whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, GSTP1 Ile105Val and GSTA1 *A/*B) represent risk factors for colorectal cancer. This meta-analysis aims to examine the associations between the above-mentioned polymorphisms and colorectal cancer risk. Forty-four studies were eligible for GSTM1 (11,998 colorectal cancer cases, 17,552 controls), 34 studies for GSTT1 (8596 cases, 13,589 controls), 19 studies for GSTP1 (5421 cases, 7671 controls) and four studies for GSTA1 polymorphism (1648 cases, 2039 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Separate analyses were conducted on Caucasian and Chinese populations. Where appropriate, sensitivity analysis concerning the deviation of genotype frequencies in controls from the Hardy-Weinberg equilibrium was performed. GSTM1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR=1.150, 95% confidence interval (CI): 1.060-1.248, random effects); no significant association was detected for Chinese subjects (pooled OR=1.025, 95% CI: 0.903-1.163, fixed effects). Similarly, GSTT1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR=1.312, 95% CI: 1.119-1.538, random effects); the association in Chinese subjects was not significant (pooled OR=1.068, 95% CI: 0.788-1.449, random effects). Concerning GSTP1 Ile105Val no significant associations were demonstrated in either race. GSTA1 *A/*B polymorphism was not associated with colorectal cancer risk. GSTM1 and GSTT1 null genotypes confer additional risk for colorectal cancer in Caucasian populations.

Numerous studies have investigated the risk of cancer associated with the polymorphism of epidermal growth factor (EGF) 61A>G, but the results have been inconsistent. We performed this meta-analysis to drive a more precise estimation of association between this polymorphism and risk of cancer.

Breast cancer is one of the most common malignant tumors worldwide. Endothelial nitric oxide synthase (eNOS) plays a key role in breast cancer development. The associations between the two eNOS polymorphisms (E298D rs1799983, -786T>C rs2070744) and breast cancer risk are inconclusive. A meta-analysis was performed in this study. By searching Medline, ISI Web of Knowledge, ScienceDirect, EBSCO, CNKI, and SinoMed database, six case-control studies were collected for the eNOS E298D polymorphism (3,038 cases and 2,508 controls) and three case-control studies were eligible for the eNOS -786T>C polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between the two eNOS polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Overall, significantly decreased risk was observed for E298D (for EE vs. DD: OR = 0.74, 95% CI = 0.59-0.94; for ED vs. DD: OR = 0.78, 95% CI = 0.61-0.98; for dominant model: OR = 0.77, 95% CI = 0.61-0.96) and -786T > C (for TT vs. CC: OR = 0.60, 95% CI = 0.42-0.86; for dominant model: OR = 0.66, 95% CI = 0.47-0.94). In the subgroup analysis by ethnicity, significant decreased risks were found for E298D (for EE vs. DD: OR = 0.75, 95% CI = 0.56-0.99) and -786T>C (for TT vs. CC: OR = 0.53, 95% CI = 0.35-0.81; for dominant model: OR = 0.61, 95% CI = 0.41-0.91; for recessive model: OR = 0.70, 95% CI = 0.55-0.91) among Caucasians; significant decreased risks were observed for E298D (for ED vs. DD: OR = 0.12, 95% CI = 0.02-0.96; for dominant model: OR = 0.13, 95% CI = 0.02-1.00) among Asians. In conclusion, this meta-analysis suggests that both eNOS E298D and -786T>C polymorphisms are associated with reduced breast cancer risk.

Published data on the association between Xeroderma Pigmentosum complementation group D (XPD) Lys751Gln polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of 30 studies including 14,283 cases and 14,426 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with XPD 751Gln allele when all studies were pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR = 1.13, 95% CI = 1.02-1.25; Gln/Gln vs. Lys/Lys: OR = 1.21, 95% CI = 1.06-1.38; dominant model: OR = 1.16, 95% CI = 1.05-1.29; and recessive model: OR = 1.14, 95% CI = 1.02-1.27). In the subgroup analysis by ethnicity, borderline significantly increased risks were found for Caucasians (Lys/Gln vs. Lys/Lys: OR = 1.09, 95% CI = 0.98-1.22; dominant model: OR = 1.10, 95% CI = 0.99-1.22) and significantly increased risks were found for Africans in dominant model (OR = 1.10, 95% CI = 1.04-1.15). When stratified by study design, statistically significantly elevated risk was found in population-based studies (Lys/Gln vs. Lys/Lys: OR = 1.10, 95% CI = 1.01-1.20; Gln/Gln vs. Lys/Lys: OR = 1.15, 95% CI = 1.01-1.31; dominant model: OR = 1.12, 95% CI = 1.03-1.23). In conclusion, this meta-analysis suggests that the XPD 751Gln allele is a low-penetrant risk factor for developing breast cancer.

Multigene assays have been developed and validated to determine the prognosis of breast cancer. In this study, we assessed the additional predictive value of the 70-gene MammaPrint signature for chemotherapy (CT) benefit in addition to endocrine therapy (ET) from pooled study series. For 541 patients who received either ET (n = 315) or ET + CT (n = 226), breast cancer-specific survival (BCSS) and distant disease-free survival (DDFS) at 5 years were assessed separately for the 70-gene high and low risk groups. The 70-gene signature classified 252 patients (47%) as low risk and 289 (53%) as high risk. Within the 70-gene low risk group, BCSS was 97% for the ET group and 99% for the ET + CT group at 5 years with a non-significant univariate hazard ratio (HR) of 0.58 (95% CI 0.07-4.98; P = 0.62). In the 70-gene high risk group, BCSS was 81% (ET group) and 94% (ET + CT group) at 5 years with a significant HR of 0.21 (95% CI 0.07-0.59; P < 0.01). DDFS was 93% (ET) versus 99% (ET + CT), respectively, in the 70-gene low risk group, HR 0.26 (95% CI 0.03-2.02; P = 0.20). In the high risk group DDFS was 76 versus 88%, HR of 0.35 (95% CI 0.17-0.71; P < 0.01). Results were similar in multivariate analysis, showing significant survival benefit by adding CT in the 70-gene high risk group. A significant and clinically meaningful benefit was observed by adding chemotherapy to endocrine treatment in 70-gene high risk patients. This benefit was not significant in low risk patients, who were at such low risk for recurrence and cancer-related death, that adding CT does not appear to be clinically meaningful.

Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports.

Polymorphisms within interleukin-1 (IL1) and tumor necrosis factor alpha (TNFA) gene clusters are associated with an increased risk of gastric cancer. However, their role in gastric precancerous lesions remains poorly understood. Our objective was to perform a meta-analysis of studies addressing the association between IL1B-511, IL1RN variable number of tandem repeat, and TNFA-308 gene polymorphisms and gastric precancerous lesions, including original data from Portugal and Mozambique. Published studies on the association between these cytokine gene polymorphisms and gastric precancerous lesions were identified by systematic review, and estimates of the association were combined using random-effects meta-analysis taking into account new data obtained from Portuguese volunteer shipyard workers (n = 215) and Mozambican dyspeptic patients (n = 96) who underwent endoscopic and pathologic evaluation following the same protocol. Odds ratio (OR) estimates for intestinal metaplasia were 2.83 [95% confidence interval (95% CI), 1.15-6.96] for the IL1RN*22 genotype, 1.86 (95% CI, 1.03-3.36) for IL1B-511 T carriers, and 0.59 (95% CI, 0.12-3.04) for the TNFA-308*AA genotype in the Portuguese sample. All Mozambican subjects with intestinal metaplasia were T carriers for IL1B-511 and none had the 2 allele for IL1RN. In meta-analysis, IL1RN*22 genotype was associated with an increased risk of gastric precancerous lesions (22 versus LL: OR, 2.27; 95% CI, 1.40-3.70; I(2) = 26.4%; 12 studies). No such association was found for the IL1B-511 (TT versus CC: OR, 1.34; 95% CI, 0.87-2.07; I(2) = 65.7%; 13 studies) or TNFA-308 genotypes (AA versus GG: OR, 0.93; 95% CI, 0.35-2.43; I(2) = 0.0%; 7 studies). The IL1RN*22 genotype seems to consistently increase the risk of gastric precancerous lesions, supporting a role for this polymorphism in the early stages of gastric carcinogenesis.