Shanker Kalyana-Sundaram

Publications (28) View all

• Source

  Available from: Nickolay A Khazanov

  Article: Identification of Targetable FGFR Gene Fusions in Diverse Cancers.

  Yi-Mi Wu, Fengyun Su, Shanker Kalyana-Sundaram, Nick Khazanov, Bushra Ateeq, Xuhong Cao, Robert J Lonigro, Pankaj Vats, Rui Wang, Su-Fang Lin, [......], Seth Sadis, Sameek Roychowdhury, Maha Hussain, Felix Y Feng, Mark M Zalupski, Moshe Talpaz, Kenneth J Pienta, Daniel R Rhodes, Dan R Robinson, Arul M Chinnaiyan
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  ABSTRACT: Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2 including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR gene fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.
  Cancer discovery. 04/2013;
• Source

  Available from: Chandan Kumar-Sinha

  Article: Outlier Kinase Expression by RNA Sequencing as Targets for Precision Therapy

  Vishal Kothari, Iris Wei, Sunita Shankar, Shanker Kalyana-Sundaram, Lidong Wang, Linda W. Ma, Pankaj Vats, Catherine S. Grasso, Dan R. Robinson, Yi-Mi Wu, Xuhong Cao, Diane M. Simeone, Arul M. Chinnaiyan, and Chandan Kumar-Sinha
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  ABSTRACT: Protein kinases represent the most effective class of therapeutic targets in cancer; therefore, determination of kinase aberrations is a major focus of cancer genomic studies. Here, we analyzed transcriptome sequencing data from a compendium of 482 cancer and benign samples from 25 different tissue types, and defi ned distinct "outlier kinases" in individual breast and pancreatic cancer samples, based on highest levels of absolute and differential expression. Frequent outlier kinases in breast cancer included therapeutic targets like ERBB2 and FGFR4 , distinct from MET , AKT2 , and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specifi c depend-encies in various cell lines, as tested by siRNA knockdown and/or pharmacologic inhibition. Outlier expression of polo-like kinases was observed in a subset of KRAS -dependent pancreatic cancer cell lines, and conferred increased sensitivity to the pan-PLK inhibitor BI-6727. Our results suggest that outlier kinases represent effective precision therapeutic targets that are readily identifi able through RNA sequencing of tumors. SIGNIFICANCE: Various breast and pancreatic cancer cell lines display sensitivity to knockdown or pharmacologic inhibition of sample-specifi c outlier kinases identifi ed by high-throughput transcrip-tome sequencing. Outlier kinases represent personalized therapeutic targets that could improve
  Cancer Discovery 02/2013;
• Article: Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

  Thirunavukkarasu Velusamy, Nallasivam Palanisamy, Shanker Kalyana-Sundaram, Anagh Anant Sahasrabuddhe, Christopher A. Maher, Daniel R. Robinson, David W. Bahler, Timothy T. Cornell, Thomas E. Wilson, Megan S. Lim, Arul M. Chinnaiyan, and Kojo S. J. Elenitoba-Johnson
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  ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.
  Proceedings of the National Academy of Sciences 02/2013; · 9.68 Impact Factor
• Article: Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing.

  Dan R Robinson, Yi-Mi Wu, Shanker Kalyana-Sundaram, Xuhong Cao, Robert J Lonigro, Yun-Shao Sung, Chun-Liang Chen, Lei Zhang, Rui Wang, Fengyun Su, [......], Sameek Roychowdhury, Javed Siddiqui, Kenneth J Pienta, Lakshmi P Kunju, Moshe Talpaz, Juan Miguel Mosquera, Samuel Singer, Scott M Schuetze, Cristina R Antonescu, Arul M Chinnaiyan
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  ABSTRACT: A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.
  Nature Genetics 01/2013; · 35.53 Impact Factor
• Article: Gene Fusion Markup Language: a prototype for exchanging gene fusion data.

  Shanker Kalyana-Sundaram, Achiraman Shanmugam, Arul M Chinnaiyan
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  ABSTRACT: BACKGROUND: An avalanche of next generation sequencing (NGS) studies has generated an unprecedented amount of genomic structural variation data. These studies have also identified many novel gene fusion candidates with more detailed resolution than previously achieved. However, in the excitement and necessity of publishing the observations from this recently developed cutting-edge technology, no community standardization approach has arisen to organize and represent the data with the essential attributes in an interchangeable manner. As transcriptome studies have been widely used for gene fusion discoveries, the current non-standard mode of data representation could potentially impede data accessibility, critical analyses, and further discoveries in the near future. RESULTS: Here we propose a prototype, Gene Fusion Markup Language (GFML) as an initiative to provide a standard format for organizing and representing the significant features of gene fusion data. GFML will offer the advantage of representing the data in a machine-readable format to enable data exchange, automated analysis interpretation, and independent verification. As this database-independent exchange initiative evolves it will further facilitate the formation of related databases, repositories, and analysis tools. The GFML prototype is made available at http://code.google.com/p/gfml-prototype/ CONCLUSION: The Gene Fusion Markup Language (GFML) presented here could facilitate the development of a standard format for organizing, integrating and representing the significant features of gene fusion data in an inter-operable and query-able fashion that will enable biologically intuitive access to gene fusion findings and expedite functional characterization. A similar model is envisaged for other NGS data analyses.
  BMC Bioinformatics 10/2012; 13(1):269. · 2.75 Impact Factor