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1.  Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial 
Purpose
Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA SNPs and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here.
Patients and Methods
E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. Fluorescence in situ hybridization to assess gene amplification status for VEGFA was performed on paraffin embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was performed.
Results
ER+ or PR+ tumors were less likely to have VEGFA amplification compared with ER/PR-tumors (p=0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; p=0.013) in univariate analysis with a trend for worse OS in multivariate analysis (p=0.08). There was a significant interaction between VEGFA amplification, hormone-receptor status, and study arm. Patients with VEGFA amplification and triple negative breast cancers (TNBCs) or HER2 amplification had inferior OS (p=0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior PFS (p=0.010) and OS (p=0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant.
Conclusion
VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab.
doi:10.1158/1078-0432.CCR-12-3029
PMCID: PMC3594423  PMID: 23340303
Breast cancer; VEGF amplification; bevacizumab
2.  New aQTL SNPs for the CYP2D6 Identified by a Novel Mediation Analysis of Genome-Wide SNP Arrays, Gene Expression Arrays, and CYP2D6 Activity 
BioMed Research International  2013;2013:493019.
Background. The genome-wide association studies (GWAS) have been successful during the last few years. A key challenge is that the interpretation of the results is not straightforward, especially for transacting SNPs. Integration of transcriptome data into GWAS may provide clues elucidating the mechanisms by which a genetic variant leads to a disease. Methods. Here, we developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTL) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. Results. 389,573 and 1,214,416 SNP-transcript-CYP2D6 activity trios are found strongly associated (P < 10−5, FDR = 16.6% and 11.7%) for two different genotype platforms, namely, Affymetrix and Illumina, respectively. The majority of eQTLs are trans-SNPs. A single polymorphism leads to widespread downstream changes in the expression of distant genes by affecting major regulators or transcription factors (TFs), which would be visible as an eQTL hotspot and can lead to large and consistent biological effects. Overlapped eQTL hotspots with the mediators lead to the discovery of 64 TFs. Conclusions. Our mediation analysis is a powerful approach in identifying the trans-QTL-phenotype associations. It improves our understanding of the functional genetic variations for the liver metabolism mechanisms.
doi:10.1155/2013/493019
PMCID: PMC3819829  PMID: 24232670
3.  A modulator based regulatory network for ERα signaling pathway 
BMC Genomics  2012;13(Suppl 6):S6.
Background
Estrogens control multiple functions of hormone-responsive breast cancer cells. They regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. ERα requires distinct co-regulator or modulators for efficient transcriptional regulation, and they form a regulatory network. Knowing this regulatory network will enable systematic study of the effect of ERα on breast cancer.
Methods
To investigate the regulatory network of ERα and discover novel modulators of ERα functions, we proposed an analytical method based on a linear regression model to identify translational modulators and their network relationships. In the network analysis, a group of specific modulator and target genes were selected according to the functionality of modulator and the ERα binding. Network formed from targets genes with ERα binding was called ERα genomic regulatory network; while network formed from targets genes without ERα binding was called ERα non-genomic regulatory network. Considering the active or repressive function of ERα, active or repressive function of a modulator, and agonist or antagonist effect of a modulator on ERα, the ERα/modulator/target relationships were categorized into 27 classes.
Results
Using the gene expression data and ERα Chip-seq data from the MCF-7 cell line, the ERα genomic/non-genomic regulatory networks were built by merging ERα/ modulator/target triplets (TF, M, T), where TF refers to the ERα, M refers to the modulator, and T refers to the target. Comparing these two networks, ERα non-genomic network has lower FDR than the genomic network. In order to validate these two networks, the same network analysis was performed in the gene expression data from the ZR-75.1 cell. The network overlap analysis between two cancer cells showed 1% overlap for the ERα genomic regulatory network, but 4% overlap for the non-genomic regulatory network.
Conclusions
We proposed a novel approach to infer the ERα/modulator/target relationships, and construct the genomic/non-genomic regulatory networks in two cancer cells. We found that the non-genomic regulatory network is more reliable than the genomic regulatory network.
doi:10.1186/1471-2164-13-S6-S6
PMCID: PMC3481450  PMID: 23134758

Results 1-3 (3)