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Srinivasan Yegnasubramanian

Srinivasan Yegnasubramanian

Department Affiliation: Primary: Oncology
Degree: M.D., Ph.D., Johns Hopkins University
Rank: Associate Professor
Telephone Number: 410-502-3425
Fax Number: 410-502-9817
E-mail address: syegnasu@jhmi.edu 
Johns Hopkins Hospital Address: Sidney Kimmel Comprehensive Cancer Center, CRB 2, Room 145, 1550 Orleans Street, Baltimore, MD  21231
 

Understanding and exploiting alterations in the cancer genome and epigenome for development of biomarkers and therapeutics

I direct a Laboratory of Cancer Molecular Genetics and Epigenetics at the Sidney Kimmel Comprehensive Cancer Center (SKCCC), and am also the Director of the SKCCC Next Generation Sequencing Center.  My research is focused on understanding the complex interplay between genetic and epigenetic alterations in carcinogenesis and disease progression, and to exploit this understanding in developing novel biomarkers for diagnosis and risk stratification as well as in identifying targets for therapeutic intervention.  Along this theme, my laboratory has charted three broad categories of investigation:

1)    Understanding the complex interplay of genetic and epigenetic processes in establishing and maintaining the neoplastic phenotype

It is now clear that cancer initiation and progression occurs through the acquisition of somatic genome alterations at both the genetic and epigenetic levels. Interestingly, genetic and epigenetic processes are often seen to cooperate to establish and maintain the neoplastic phenotype in cancer cells. While much recent effort has focused on understanding the inherited and somatic genome alterations occurring in human cancer, it is becoming clear that this is an incomplete picture without the simultaneous and integrated understanding of epigenetic alterations. A major limitation has been the lack of robust, cost-effective, quantitative and integrative technologies for the assessment of epigenetic processes alongside the genetic processes.

My lab has developed and optimized a novel suite of technologies that harness the power of microarrays and next generation sequencing for integrated, cost-effective, and quantitative measurement of genetic and epigenetic alterations. We are currently applying these technologies to understand the cooperation of genetic alterations, such as mutations, deletions, amplifications, and rearrangements, with epigenetic alterations, such as DNA methylation changes, in carcinogenesis and disease progression. These analyses have helped identify novel tumor suppressor and metastasis suppressor genes that we are currently functionally characterizing using gain- and loss-of-function experiments. In addition to providing insights into cancer biology, these analyses have helped to nominate several DNA based biomarkers for cancer detection, risk stratification, and prediction of treatment response.

2)    Targeting epigenetic alterations for cancer therapy

Epigenetic gene silencing ubiquitously accompanies the development of cancer; reactivation of silenced genes has emerged as a rational treatment strategy. Unfortunately, epigenetic drugs have only had limited success as single agent therapies for human cancers including prostate cancer, and there has been a somewhat haphazard approach to empirically identify drug combinations that may synergize with epigenetic drugs.  In a collaboration with Bill Nelson’s laboratory, we have developed a novel, rational, approach to identification of effective drug combinations with epigenetic drugs that can induce synthetic lethality of cancer cells.

3)    Role of genome organization and TOP2B in androgen signaling, transcription, and genomic instability

Androgen receptor (AR) signaling is critical to the pathogenesis of prostate cancer and AR is a critical therapeutic target in prostate cancer. Androgen receptor (AR) signaling involves a complex and coordinated series of events that include binding of androgen hormones by the receptor, binding of the liganded receptor complex to diverse sites on the genome, and dynamic reorganization of the genome to facilitate efficient target gene expression.  My lab has recently shown that topoisomerase II beta (TOP2B) is co-recruited with AR to target sites where it often carries out its catalytic cleavage, and that its recruitment and catalytic activity are required for efficient AR target gene expression. We have also shown that androgen stimulation promotes co-recruitment of AR and TOP2B to sites of recurrent rearrangement breakpoints in prostate cancer, triggering recombinogenic TOP2B-mediated double strand breaks. These data suggest that androgen signaling and associated intrinsic transcriptional programs require TOP2B, and also that such processes can be corrupted, leading to TOP2B-mediated genomic breaks that may ultimately nucleate genomic rearrangements in prostate and other cancers. TOP2B mediated DNA breaks are also evident in other induced transcriptional programs, including those governed by ER, RAR, insulin signaling, and others.

Based on these data, we hypothesize that TOP2B may be involved in relieving topological constraints during genomic reorganization during induction of transcriptional programs. Furthermore, we hypothesize that the need to re-establish this genomic reorganization after every cell division may make proliferating cancer cells more prone to developing TOP2B-mediated double strand breaks that may contribute to genomic instability and cell-type specific rearrangements. Additionally, we envision that it may be possible to exploit these transcription-associated TOP2B mediated double strand breaks as an Achilles heel for cancer therapy. In ongoing work, we are interested in examining these hypotheses further.

Representative Publications:

  • Yegnasubramanian, S., Wu, Z., Haffner, M.C., Esopi, D., Aryee, M.J., Badrinath, R., He, T.L., Morgan, J.D., Carvalho, B., Zheng, Q., De Marzo, A.M., Irizarry, R.A., Nelson, W.G.  Chromosome-wide mapping of DNA methylation patterns in normal and malignant prostate cells reveals pervasive methylation of gene-associated and conserved intergenic sequences. BMC Genomics Jun 13;2:313, 2011.  Pub Med Reference     
  • Haffner, M.C., De Marzo, A.M., Meeker, A.K., Nelson, W.G., Yegnasubramanian, S. Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin Cancer Res. Jun 15;17(12):3858-3864, 2011.  Pub Med Reference     

  • Haffner, M.C., Aryee, M.J., Toubaji, A., Esopi, D.M., Albadine, R., Gurel, B., Isaacs, W.B., Bova, G.S., Liu, W., Xu, J., Meeker, A.K., Netto, G., De Marzo, A.M., Nelson, W.G., Yegnasubramanian, S. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. Aug; 42(8):668-675, 2010. Pub Med Reference  

  • Nelson, W.G., De Marzo, A.M., Yegnasubramanian, S. Epigenetic alterations in human prostate cancers. Endocrinology Sep;150(9):3991-4002, 2009. Pub Med Reference  

  • Liu, W., Laitinen, S., Khan, S., Vihinen, M., Kowalski, J., Yu, G., Chen, L., Ewing, C.M., Eisenberger, M.A., Carducci, M.A., Nelson, W.G., Yegnasubramanian, S., Luo, J., Wang, Y., Xu, J., Isaacs, W.B., Visakorpi, T., Bova, G.S. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med. May;15(5):559-565, 2009.  Pub Med Reference  

  • Yegnasubramanian, S., Haffner, M.C., Zhang, Y., Gurel, B., Cornish, T.C., Wu, Z., Irizarry, R.A., Morgan, J., Hicks, J., DeWeese, T.L., Isaacs, W.B., Bova, G.S., De Marzo, A.M., Nelson, W.G. DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer Res. Nov 1;68(21):8954-8967, 2008.  Pub Med Reference
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  • Yegnasubramanian. S., Lin, X., Haffner, M.C., DeMarzo, A.M., Nelson, W.G. Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. Nucleic Acids Res. Feb 9;34(3):e19, 2006.  Pub Med Reference
  • Yegnasubramanian, S., Kowalski, J., Gonzalgo, M.L., Zahurak, M., Piantadosi, S., Walsh, P.C., Bova, G.S., De Marzo, A.M., Isaacs, W.B., Nelson, W.G.  Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res.  Mar 15;64(6):1975-1986, 2004.  Pub Med Reference  


Other graduate programs in which Dr. Yegnasubramanian participates:

Pathobiology

 
 
 
 
 
 

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