The overall focus of our research group is to study the molecular genetic and epigenetic events associated with cancer development, with the underlying aim of translating this knowledge in to novel diagnostic, prognostic and therapeutic strategies. We employ integrative approaches that include cell-based assays, studies using animal models, analysis of human cancer specimens, next-generation sequencing and bioinformatics to identify (A) the DNA damage and repair pathways that mediate cancer-specific recurrent genomic rearrangements, and (B) the functional consequences of epigenetic and transcriptional deregulation in cancer development. These studies will serve as the basis for early cancer detection and therapeutic targeting. Genomic rearrangements, ETS gene fusions and cancer development Recurrent genomic rearrangements are causally associated with cancer initiation and progression. Rearrangements involving the fusion of androgen regulated genes with ETS family genes are seen in a majority of prostate cancers. Among the ETS gene fusions, the TMPRSS2-ERG fusion is observed in 40 to 60% of prostate cancers. Given the high incidence of prostate cancers, the TMPRSS2-ERG may represent the most prevalent cancer associated gene fusion. However, the factors contributing to the formation and cell type specificities of gene fusions are not clear. Studies by our group and others have demonstrated that androgen signaling and three-dimensional spatial proximity play a role in the formation of TMPRSS2-ERG gene fusions in prostate cancer. As DNA double strand breaks are required for the formation of gene fusions, we are currently investigating the in vivo mechanisms contributing towards these breaks. We recently demonstrated a key role for inflammation in the origins of prostate cancer. Our work suggests that inflammation promotes oxidative stress, leading to the formation of DNA breaks, and thereby resulting in TMPRSS2-ERG gene fusions. We are also investigating the role of specific DNA repair proteins and pathways associated with de novo genomic rearrangements. In parallel, we conduct genetic screens using the CRISPR-Cas9 system to identify molecules that promote or block de novo genomic rearrangements. Epigenetic regulation of gene expression during prostate cancer progression Epigenetic and transcriptional deregulation is a common theme in several cancers. The androgen receptor is a transcription factor that has a role in the normal development of the prostate gland. Paradoxically, androgen receptor is also involved in the development of clinically localized as well as metastatic prostate cancers. More recently, androgen receptor variants have been implicated in the emergence of resistance to targeted therapies. The function of androgen receptor can be influenced by mutations, amplification, alternate splicing and other mechanisms (e.g. molecular cross talk with ETS family proteins, mutations in pioneering transcription factors like FOXA1 etc.). We propose to systematically explore the genome-wide epigenetic and transcriptional alterations mediated by androgen receptor variants, ETS family proteins, chromatin modifiers and pioneering transcription factors by employing methods like ChIP-seq, ChIP-exo and RNA-seq. These studies will provide an epigenetic prism to visualize cancer development. To accomplish these aims, we collaborate extensively with clinicians, bioinformaticians and statisticians. Representative publications: Mani RS, Tomlins SA, Callahan SA, Ghosh A, Nyati MK, Varambally S, Palanisamy N, Chinnaiyan AM. Induced Chromosomal Proximity & Gene Fusions in Prostate Cancer. Science 2009; 326(5957):1230. PMID: 19933109/PMCID: PMC2935583. Mani RS and Chinnaiyan AM. Triggers for genomic rearrangements Nat Rev Genet 2010; 11(12):819-829. PMID: 21045868. Mani RS, Iyer MK, Cao Q, Brenner JC, Wang L, Ghosh A, Cao X, Lonigro RJ, Tomlins SA, Varambally S, Chinnaiyan AM. TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers. Cancer Res 2011; 71(16):5387-5392. PMID: 21676887/PMCID: PMC3156376. Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, Prensner JR, Kim JH, Brenner JC, Jing X, Cao X, Wang R, Li Y, Dahiya A, Wang L, Pandhi M, Lonigro RJ, Wu YM, Tomlins SA, Palanisamy N, Qin Z, Yu J, Maher CA, Varambally S, Chinnaiyan AM. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell 2011; 20(2):187-199. PMID: 21840484/PMCID: PMC3157014. Mani RS. The emerging role of speckle-type POZ protein (SPOP) in cancer development. Drug Discov Today. 2014; 19(9):1498-1502. PMID: 25058385/PMCID: PMC4237012. Mani RS*, MA Amin, Li X, Kalyana-Sundaram S, Veeneman BA, Wang L, Ghosh A, Aslam A, Ramanand SG, Rabquer BJ, Kimura W, Tran M, Cao X, Roychowdhury S, Dhanasekaran SM, Palanisamy N, Sadek HA, Kapur P, Koch AE, and Chinnaiyan AM*. Inflammation induced oxidative stress mediates gene fusion formation in prostate cancer. Cell Rep 2016;17(10):2620-2631. PMID: 27926866/PMCID: PMC5147555 (*corresponding author).