The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR cis-regulation has been extensively studied in prostate cancer, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited. In this paper, we propose a novel framework to profile long-range chromatin interactions associated with AR and its collaborative transcription factor, erythroblast transformation-specific related gene (ERG), using chromatin interaction analysis by paired-end tag (ChIA-PET). We identified ERG-associated long-range chromatin interactions as a cooperative component in the AR-associated chromatin interactome, acting in concert to achieve coordinated regulation of a subset of AR target genes. Through multifaceted functional data analysis, we found that AR-ERG interaction hub regions are characterized by distinct functional signatures, including bidirectional transcription and cotranscription factor binding. In addition, cancer-associated long noncoding RNAs were found to be connected near protein-coding genes through AR-ERG looping. Finally, we found strong enrichment of prostate cancer genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) at AR-ERG co-binding sites participating in chromatin interactions and gene regulation, suggesting GWAS target genes identified from chromatin looping data provide more biologically relevant findings than using the nearest gene approach. Taken together, our results revealed an AR-ERG-centric higher-order chromatin structure that drives coordinated gene expression in prostate cancer progression and the identification of potential target genes for therapeutic intervention.

Pathogen detection by microarray

New design and optimization of pathogen detection microarrays is shown to allow robust and accurate detection of a range of pathogens. The customized microarray platform includes a method for reducing PCR bias during DNA amplification.

Melanoma is one of the most aggressive human cancers. The worldwide incidence rate of melanoma has increased during the last decade but with few FDA approved therapeutic options. Patients with lymph node metastasis can show highly variable clinical outcomes, from several years disease free survival after excision of the primary lesion to extremely aggressive metastatic disease; while patients with distant metastasis show poor clinical outcome. Outstanding outcomes using target therapies such as B-RAF V600E inhibitor (Vemurafenib) bring hope for possibility of melanoma cure. Alternatively, since melanoma acquires resistance to Vemurafenib, the necessity of searching for other candidates and simultaneously targeting several pathways for long-term survival is inevitable. Better understanding of the genomic signatures of melanoma progression and maintenance provides new opportunities for developing novel therapeutic targets for successful management of this fatal disease. In this study, we aim to reveal the complex patterns of distinct molecular aberrations and mechanisms underlying the progression and maintenance of melanoma using high-throughput sequencing approaches. Our hypothesis is that there are genetic changes in melanoma which suggest the survival of the distant metastasis; these genetic changes include activated oncogenes and suppressed tumor suppressor genes correlated with melanoma progression and maintenance. As a proof of principal we initiated this study with a poor prognosis melanoma patient; a 46 year old man diagnosed with lymph node metastasis and treated with T-cell vaccination (TCV), who showed the tumor distant metastasis to lung, 14.8 months after complete lymph node dissection. The availability of primary cell lines established from both lymph node and lung metastatic tissues represents a major advantage for the functional validation of individual candidate genes which may serve as novel targets for cancer therapy. Integration of copy number with structural variation data showed a great selection for cell lines generation (derived from lymph node and lung tumors) and we observed that this selection was for a similar clone embedded in lymph node and lung metastatic tumors. With this data, we hypothesized that common sets of events which cut across all samples in this case identify the core sets of putative oncogenes and tumor suppressor genes which drive this patient's cancer cells. The correlation of these genes with the cancer phenotype will be addressed. Citation Format: Faranak Ghazi Sherbaf, Charlie LEE Wah Heng, Xing Yi Woo, Denis Bertrand, Koichiro Inaki, Kelly Chong Chong, Donald Morton, Sharon Huang, Dave Hoon, Edison Liu. Genomic signatures of melanoma progression and maintenance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2001. doi:10.1158/1538-7445.AM2013-2001