Citations

Abstract Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients. Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells. Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells. Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801–11. ©2011 AACR.

Adenosine monophosphate–activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.

Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.

AbstractElevated serum levels of the soluble form of IL-2 receptor α (sIL-2Rα) have been correlated with a poor prognosis in a variety of different types of cancers. However, its biologic relevance remains unclear and controversial. In patients with follicular B-cell non-Hodgkin lymphoma (FL), we observed that serum sIL-2Rα levels were elevated compared with controls and that elevated sIL-2Rα levels before treatment were associated with a poor outcome. To explore the mechanism by which sIL-2Rα may contribute to a poor prognosis in FL, we determined the effects of sIL-2Rα on IL-2 signaling and found that the sIL-2Rα–IL-2 complex promoted T-cell differentiation toward to inhibitory Treg cells rather than TH1 or TH17 cells. Shed by activated T cells that express membrane-bound IL-2Rα, sIL-2Rα further enhanced IL-2–mediated phosphorylation of Stat5 thereby significantly up-regulating Foxp3 expression in CD4+ T cells. We found that CD4+ T cells treated with either IL-2 or sIL-2Rα–IL-2 complex, but not with sIL-2Rα alone, inhibited the function of CD8+ T cells. Taken together, these results indicate that sIL-2Rα actually plays an active biologic role in FL by binding IL-2 and promoting IL-2 signaling rather than depleting IL-2 and blocking its function.

Abstract Purpose: Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non–small cell lung cancer (NSCLC) treated with chemotherapy. Experimental Design: A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups. Results: A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20–1.77 and HR = 1.25; 95% CI = 1.05–1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11–1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50–0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38–0.77; HR = 0.67; 95% CI = 0.52–0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30–2.80; HR = 1.83; 95% CI = 1.27–2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis. Conclusion: Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations. Clin Cancer Res; 17(11); 3830–40. ©2011 AACR.

Abstract Motivation: Fusion transcripts can be created as a result of genome rearrangement in cancer. Some of them play important roles in carcinogenesis, and can serve as diagnostic and therapeutic targets. With more and more cancer genomes being sequenced by next-generation sequencing technologies, we believe an efficient tool for reliably identifying fusion transcripts will be desirable for many groups. Results: We designed and implemented an open-source software tool, called FusionHunter, which reliably identifies fusion transcripts from transcriptional analysis of paired-end RNA-seq. We show that FusionHunter can accurately detect fusions that were previously confirmed by RT-PCR in a publicly available dataset. The purpose of FusionHunter is to identify potential fusions with high sensitivity and specificity and to guide further functional validation in the laboratory. Availability: http://bioen-compbio.bioen.illinois.edu/FusionHunter/. Contact: jianma@illinois.edu Supplementary information: Supplementary data are available at Bioinformatics online.

The genome sequence of a lycophyte hints at ancient evolutionary transitions.

Background— Preoperative factors associated with increased mortality and worse outcome after tricuspid valve replacement in patients with severe tricuspid regurgitation are poorly understood. Methods and Results— We retrospectively analyzed 189 patients (37% men; age, 67.5±11.3 years) who underwent tricuspid valve replacement for severe tricuspid regurgitation. Operative mortality rate was 10%, and was associated with intra-aortic balloon pump (odds ratio, 3.2; 95% confidence interval, 1.9 to 5.6; P <0.0001) or the presence of severe symptoms (New York Heart Association class IV relative to classes II and/or III) at the time of surgery (1.7; 95% confidence interval, 1.05 to 2.8; P =0.02). At the end of follow-up (29.3±27.1 months), 70 patients (37%) died, 6 (3%) needed tricuspid reoperation, and 41 (21.7%) were readmitted for heart failure. Seventy-eight patients (41.3%) were free from cardiovascular events (death, tricuspid reoperation, or heart failure admissions). The only echocardiographic parameter independently associated with adverse outcomes was a decrease in the right index of myocardial performance ratio. All-cause mortality was independently associated with a higher Charlson index (hazard ratio, 1.18; 95% confidence interval, 1.01 to 1.36; P =0.03), shorter right index of myocardial performance ratio (0.91; 95% confidence interval, 0.87 to 0.96; P =0.005), and preoperative New York Heart Association IV class (1.71; 95% confidence interval, 1.3 to 2.2; P <0.0001). In 68 patients with isolated tricuspid valve replacement, the associations between short right index of myocardial performance ratio, high Charlson index, New York Heart Association class IV, and increased mortality remained significant. Conclusions— Tricuspid valve replacement for severe tricuspid regurgitation can be performed with an acceptable operative mortality if patients undergo surgery before the onset of advanced heart failure symptoms. Late mortality is associated with a high preoperative Charlson index, short right index of myocardial performance ratio, and advanced New York Heart Association class.