Biomarkers to predict response to therapy in adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are not yet established. In this study, we performed a meta-analysis of earlier genome-wide gene expression studies to identify pathway-based genes that are associated with therapeutic response. The predictive power of these genes was validated by transcript profiling in diagnostic bone marrow samples from Ph+ ALL patients using a quantitative real-time PCR array. Gene expression was correlated with cytogenetic and molecular characteristics, including presence of ABL1 mutations and IKZF1 deletion. A total of 43 de novo Ph+ ALL patients treated uniformly with tyrosine kinase inhibitors combined with chemotherapy were selected to validate 46 identified genes. A 9-gene signature was established to distinguish optimal responders from patients with persistent residual disease and early molecular recurrence. The signature was subsequently validated with 87% predictive accuracy in an independent validation set of patients. When initially optimal responders relapsed, their gene expression patterns also shifted. Optimal responders showed upregulation of genes involved in proliferation and apoptosis pathways, whereas poor responders had higher expression of genes that facilitate tumor cell survival in hypoxic conditions as well as development of drug resistance. This unique 9-gene signature may better enable stratification of patients to proper therapeutic regimens and provides new insights into mechanisms of Ph+ ALL response to therapy.

There is an overwhelming abundance of genetic association studies available in the literature, which can often be collectively difficult to interpret. To address this issue, the Venice interim guidelines were established for determining the credibility of the cumulative evidence. The objective of this report is to evaluate the literature on the association of common glutathione S-transferase (GST) variants (GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphism) and lung cancer, and to assess the credibility of the associations using the newly proposed cumulative evidence guidelines.

The endothelial nitric oxide synthase gene (NOS3) has been proposed as a candidate gene for breast cancer (BC), however, the specific role of variants and haplotypes has not been clarified. We examined the association of two polymorphisms (4b/a and G894T) and their haplotypes in a case-control sample of 306 patients with BC and in 131 healthy females. In addition, a meta-analysis of studies investigating association between NOS3 polymorphisms and BC was conducted. The single locus analysis for the two polymorphisms revealed an association only for the 4b/a polymorphism, but adjustment for age diminished this association (odds ratio (OR) (95% confidence interval)=0.98 (0.34-2.81)). The analysis of haplotypes showed an association for two haplotypes involving the 894T allele (bT and aT) (P<0.05). The meta-analysis for both polymorphisms produced nonsignificant associations without significant heterogeneity. A positive association was detected for the promoter T786C polymorphism (pooled OR=1.51 (1.07-2.12)), but this comparison was based on few studies. The available evidence from our study and the meta-analysis cannot support a major contributory role of these common NOS3 polymorphisms in BC, although future larger studies may help in drawing safer conclusions about the genetics of BC.

Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

This paper summarizes the results of a National Cancer Institute (NCI) sponsored Phase III clinical trial led by the North Central Cancer Treatment Group (NCCTG) that enrolled patients with metastatic colorectal cancer (MCRC) on combination chemotherapy regimens in the late 1990s through 2003. The study changed clinical practice in the US and led to a new Food and Drug Agency (FDA) indication for the drug oxaliplatin. The time was opportune in the management of MCRC, when, after 50 years of using the single active agent 5-Fluorouracil (5-FU), two new cytotoxic agents, irinotecan and oxaliplatin, were found to be active in MCRC. Patients were randomized to receive two of those three agents in each arm of the trial. Over 500 of the >1700 enrolled patients permitted their germline DNA and plasma samples to be banked. Consequently this is one of the largest cancer populations available for pharmacogenetic studies and for the study of other biomarkers. Data derived from N9741 led to publications related to treatment of MCRC and trial methodology, used pooled meta-analyses and helped to pioneer the field of pharmacogenetics. This review highlights some of those observations. Initiated in 1997, the trial has spawned 26 published or in press papers and 39 abstracts.

Genome-wide and replication association studies (GWAs) have identified multiple loci at which common variants modestly influence the risk of developing prostate cancer (PCa). To enhance the power to identify loci associated with PCa, we constructed a meta-analysis of GWAs on PCa.

Colorectal signet-ring cell carcinoma (SRCC) is rare, and very little detailed information on the molecular biology of the disease is available.

It has been proven that close relation was existed between XPD polymorphism G312A and lung cancer risk. However, some of the results are not consistent. The aim of this study is to explore the impact of DNA repair gene XPD polymorphism G312A on lung cancer risk.

The relationship between myeloperoxidase G-463A genetic polymorphisms and lung cancer susceptibility has been studied extensively. However, the outcomes are not consistent. The aim of this study is to evaluate the relationship between myeloperoxidase genetic polymorphisms and lung cancer susceptibility by meta analysis.

Sulfotransferase (SULT) plays an important role in the formation of estrogen which is usually conferred as a risk factor for breast cancer. Polymorphism of the SULT1A1 may be closely associated with breast cancer. However, studies on the association between polymorphism and breast cancer have yielded inconsistent results. We performed a meta-analysis including ethnic subgroup and menopausal statue subgroup to investigate the association of SULT1A1 Arg213His polymorphism with breast cancer.

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved.

Both ETV6-RUNX1 (TEL-AML1) fusion and hyperdiploidy (>50 chromosomes) in transformed lymphoblasts are favorable genetic features in childhood acute lymphoblastic leukemia (ALL).

Published studies on the association between the vascular endothelial growth factor (VEGF) gene 936 C/T polymorphism and breast cancer risk are inconclusive, and a meta-analysis is required to verify the association. Nine studies, including a total of 4,973 cases and 5,035 controls, were subjected to meta-analysis. When all eligible subjects were pooled for meta-analysis, the CT + TT genotypes were not associated with a significant decrease in breast cancer risk (odds ratio = 0.87; 95% confidence interval 0.75-1.02; P = 0.087). We also categorized by ethnicity (Caucasian, Asian, or mixed) for subgroup analysis, however, according to this subgroup analysis, we found no significant association between the CT and TT versus CC genotype with breast cancer risk reduction in any of the subgroups. We conclude that the VEGF gene 936 C/T polymorphism does not affect breast cancer risk.

Published data on the association between XPD Lys751Gln and Asp312Asn gene polymorphism and lung cancer risk are inconclusive.

Renal cell carcinomas (RCCs) in children and adolescents are much rarer than in adults. In this age group, Xp11.2 translocation RCCs were the most common subtype of pediatric RCCs. Information regarding the clinical behavior of pediatric RCCs remains controversial because of their relatively rare incidence. The authors aimed to perform a systematic review and meta-analysis to better define the biological features of pediatric RCCs.

Emerging evidence has shown that miRNAs participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) which located in the pre-miRNA may affect the processing and then influence the expression of mature miRNA. Previous studies yielded conflicting results as to the association of two common polymorphisms in pre-miRNAs (i.e. hsa-miR-146 rs2910164 and hsa-miR-196a2 rs11614913) with breast cancer. To derive a more precise effect on the association between these polymorphisms and breast cancer risk, we conducted a meta-analysis. Through retrieving PubMed for the period up to May 2010, a total of four studies were identified with 3,007 cases and 3,718 controls for has-miR-146a rs2910164 polymorphism and with 3,287 cases and 4,298 controls for hsa-miR-196a2 rs11614913 polymorphism. We found that individuals carrying CC genotype of has-miR-196a2 rs11614913 polymorphism was associated with an increased breast cancer risk in homozygote comparison (OR = 1.30; 95% CI, 1.01-1.68), and dominant model (OR = 1.11; 95% CI, 1.01-1.23). However, no significant association between has-miR-146a rs2910164 polymorphism and breast cancer risk was observed in all comparison models tested. These findings suggest that has-miR-196a2 rs11614913 polymorphism may play crucial roles in breast cancer development.

Growing evidence suggests that RAD51 plays a pivotal role in the repair of DNA double-strand breaks and the maintenance of genomic stability. A single nucleotide polymorphism, 135G/C, has been identified in the 5' untranslated region of the RAD51 gene and has been shown to influence gene transcription activity. Previous studies yielded conflicting results as to the association of 135G/C polymorphism with breast cancer. We aimed to assess the effect of 135G/C of RAD51 on breast cancer susceptibility with the use of a meta-analysis. We performed a meta-analysis of 21 published case-control studies up to April 2010. We found that the CC genotype was associated with a significantly increased risk of breast cancer when compared with the GG, CG, and CG/GG genotypes. Subgroup analyses showed that individuals carrying the CC genotype were associated with an elevated tumor risk in European populations and in sporadic breast cancer. After stratified analyses according to manuscript quality, the CC genotype was associated with a significantly increased risk of breast cancer compared with the CG genotype in studies of both higher and lower quality. However, significantly elevated risk was found in studies of higher quality, but not in studies of lower quality when homozygote and a recessive comparison model were tested. This meta-analysis indicates that RAD51 135G/C polymorphism may be identified as a susceptibility locus for breast cancer.

Fibroblast growth factor receptor 4 (FGFR4), belonging to the receptor tyrosine kinase family, is involved in cancer initiation and progression. The FGFR4 Gly388Arg polymorphism in the transmembrane domain of the receptor was shown to contribute to genetic susceptibility to cancer but the results were inconsistent. We performed a meta-analysis using 12 eligible case-control studies with a total of 4892 patients and 3663 controls to summarise the data on the association between the FGFR4 Gly388Arg polymorphism and cancer risks. The overall odds ratio (OR) with a 95% confidence interval (CI) showed statistical association between the FGFR4 Gly388Arg polymorphism and cancer risks under homozygote comparison, allele contrast and the recessive genetic model. In the subgroup analysis by ethnicity, statistically significantly increased cancer risks were found among Asians for homozygote comparison (OR = 1.43, 95% CI = 1.13-1.80, P(heterogeneity)=0.24), allele contrast (OR = 1.16, 95% CI = 1.04-1.29, P(heterogeneity) = 0.25) and the recessive genetic model (OR = 1.47, 95% CI = 1.19-1.81, P(heterogeneity) = 0.15). In the subgroup analysis for different tumour types, Arg(388) allele had an effect of increasing the risks of breast (homozygote comparison OR = 1.57, 95% CI = 1.04-2.37, P(heterogeneity) = 0.83 and the recessive model OR = 1.51, 95% CI = 1.02-2.24, P(heterogeneity) = 0.80) and prostate cancer (Gly/Arg versus Gly/Gly: OR = 1.16, 95% CI = 1.02-1.32, P(heterogeneity)=0.74; Arg versus Gly: OR = 1.17, 95% CI = 1.07-1.29, P(heterogeneity) = 0.18 and the dominant model: OR = 1.20, 95% CI = 1.06-1.35, P(heterogeneity) = 0.89). Our meta-analysis suggests that the FGFR4 Gly388Arg polymorphism most likely contributes to susceptibility to cancer, especially in Asians. Besides, the Arg(388) allele might be associated with increased risks of breast and prostate cancer.