I am a researcher specializing in Prostate Cancer, Cancer Genomics, and Molecular Cytogenetics/Molecular Pathology.
My research interests are on the discovery and characterization of gene fusions in cancer and understand their role in carcinogenesis from a translational research perspective. Using genomic technologies such as high-density array comparative genomic hybridization, advanced molecular cytogenetic technologies including FISH, CGH, spectral karyotyping, gene expression microarrays, and next generation sequencing technology, my laboratory investigates the transcriptional and genomic architectures of solid cancer genome. In-depth analysis of genomic amplifications provided an unprecedented view and identified rare gene fusions formed at the boundaries of amplification and deletions. I have also pioneered on the application of next generation sequencing technology for the discovery of new recurrent gene fusions in cancer. The primary goal of this approach is to identify novel gene fusions specific for each cancer type. Further, I am interested in applying the newly developed target capture of all human exons and resequencing approach to identify disease causing gene mutations. In my work, employing the next generation sequencing approach with particular emphasis on RNAseq provided a unique opportunity to interrogate the cancer transcriptome in an unbiased manner to identify novel gene fusions, alternative transcripts, non-coding RNA, SNP’s, micro RNA and expressed pseudogenes not detectable by gene expression microarray analysis. Recently we have discovered a new recurrent gene fusion in a subset of ETS negative prostate cancer. My long term research goals are to conduct advanced research applying the next generation sequencing technology for an integrated analysis using data from RNA and DNA processing, genotyping, chip sequence, gene expression, copy number analysis for variations and rearrangements and methylation analysis to understand the genetic complexity of cancer genome in a comprehensive manner. This work will lead to the identification of novel cancer biomarkers for routine diagnosis and treatment follow up.
Molecular cloning and characterization of recurrent chromosome translocations in leukemia, lymphoma and solid tumors
My research activities during the post-doctoral research associate fellowship at Memorial Sloan-Kettering Cancer Institute centered on molecular cloning and characterization of novel gene fusions in lymphoma and multiple myeloma -IGH/PAX5 (Plasmacytoid lymphoma); IGH/MUC1 (diffuse large B-cell lymphoma); IGH/FGFR2B (Follicular lymphoma); IGH/CHST11 (Chronic lymphocytic leukemia; IGH/IRTA1; IGH/IRTA2 (Multiple myeloma) Oncogene 2004 Sep 9; 23(41):6991-6; Cancer Res 15; 62 (14):4089-94, 2002; Oncogene 20: 7686-7693, 2001; Immunity 14, (3) 277-289, 2001; Blood 95(8): 2666-2671, 2000; Blood 88:4110, 1996
Biomarker discovery through application of Next generation sequencing technology
Identification of molecular markers in solid cancers eluded conventional cytogenetic and molecular methods for several decades. Unbiased comprehensive genomic and transcriptome characterization by high throughput massively parallel sequencing is an emerging approach for biomarker discovery in solid cancers. Our group at the University of Michigan have pioneered the application of next generation sequencing technology for transcriptome sequencing and developed methods for the detection of gene fusions. Recurrent gene fusions involving ETS family genes in more than half of the prostate cancer patients made possible by a novel bioinformatics analytical approach. However, the ETS family genes are challenging to target with small molecule inhibitors due to the lack of enzymatic activity and requirement of interaction with proteins to attain specificity. While screening the ETS negative prostate cancers by transcriptome sequencing we discovered novel recurrent druggable RAF kinase pathway gene fusions. Extended analysis in other solid cancer revealed the RAF gene rearrangements in gastric cancer and melanoma. These RAF gene fusions are targetable with BRAF and MEK inhibitors. This finding is a significant advancement in the identification and treatment of subsets of patient population with RAF family gene rearrangement. [Nature. 2009 Mar 5;458(7234):97-101. Epub 2009 Jan 11; Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12353-8. Epub 2009 Jul 10; Nat Biotechnol. 2009 Nov;27(11):1005-11. Epub 2009 Nov 1; Nat Med. 2010 Jun 6.
Non-coding RNA, pseudogenes as new biomarkers in prostate cancer
Due to the lack of new recurrent genetic aberrations in protein coding genes, my focus was turned to understand the unexplored territory of non-coding RNA’s in prostate cancer. We systematically studied the expression pattern of pseudogenes in prostate cancer along with 12 other epithelial cancers and found tissue and cancer specific expression of pseudogenes (Cell, 2012). I have an NIH R21 grant application funded from April 2014-March 2016 to work on the pseudogene project.
Development of diagnostic reagents based on fluorescence in situ hybridization, immunohistochemistry and RNA in situ hybridization methods for recurrent chromosome translocations and gene amplifications in various cancer types
During my tenure as the founding Director of Research and Development at Cancer Genetics Inc, introduced novel approaches in FISH probe development for the diagnosis of recurrent chromosome translocations in cancer. Research work was supported by three Phase I and one Phase II SBIR grant applications ($2 million) funded by NCI. Filed three patent applications on novel probe development approaches and two of them were granted recently.
Further, I have been working on developing new diagnostic methods for screening prostate cancer markers. In this regard we developed RNA in situ hybridization based methods and for the first time we showed the tissue level expression of PCA3 (non-coding RNA) and correlated with urine PCA3 and TMPRSS2-ERG (Modern Pathology, 2013) in prostate cancer. My industry collaborations with Ventana Medical Systems resulted in the development of automated dual color immunohistochemistry procedures for simultaneous detection of ERG-PTEN and ERG-SPINK1 in prostate cancer and showed concomitant expression of ERG/SPINK1 in the same or in two independent tumor foci (Modern Pathology, 2013). This work was extended to screen carriers of HOXB13 mutations and found increased incidence of SPINK1 overexpression in HOXB13 mutation carriers (Am J Surg Pathol 2014). Due to the lack of specific antibodies, tissue level expression of ETV1, ETV4 and ETV5 in prostate cancer is not known. Using RNA in situ hybridization method we showed the heterogeneous expression of ETV1and also found that a subset of ETV1 positive cases harbor ERG rearrangement in independent foci. Given the multifocal nature of prostate cancer and specific role of ETV1 under PTEN deletion background induce invasive adenocarcinoma; observation of such dual ETS rearrangement in prostate cancer may identify a new molecular subset of prostate cancer (AIMM 2014 – IN PRESS)
Application of new high throughput technologies in genome research for the discovery of gene fusions in cancer
Gene identification signature-paired end di tag (GIS-PET), high resolution array comparative genomic hybridization (a-CGH) and next generation sequencing technologies (NextGen – RNAseq, ChIPSeq, DNAseq) (Illumina single read and paired end sequencing) for transcriptome and genome analysis. Using GIS-PET and high density array CGH identified novel gene fusions in MCF7 breast cancer cell line (Genome Research, 2007 17: 828-838). Further, with the aim to characterize the unbalanced copy number changes in solid tumors, applied the high-density oligonucleotide based array comparative genomic hybridization (244K Agilent) and discovered novel gene fusions in breast cancer. An international patent application is under review on this novel approach: My current research work during the past two years at Michigan Center for Translational pathology is centered on gene fusion discovery and transcriptome characterization of solid tumors using next generation sequencing technology with particular emphasis on prostate cancer and metastatic melanoma. Our initial proof of concept work on the application of next generation sequencing technology for the discovery gene fusion resulted in a publication in Nature, PNAS and Nat Biotechnology.
My major accomplishments in prostate cancer research include the discovery of recurrent RAF gene fusions in ETS negative prostate cancer, development of new approaches for the molecular profiling of prostate cancer which lead to the identification of new subset of prostate cancer with dual ERG/SPINK1 rearrangements and dual ETS rearrangements with ERG and ETV1 rearrangements in two independent tumor foci and identification of pseudogenes as a new class of prostate cancer biomarker.
American Association for Cancer Research
Development of Prostate Cancer Personalized Medicine
Elucidation of Tumor Heterogeneity in Prostate Cancer by Combined Immunohistochemistry and Novel RNA in Situ Hybridization
High Resolution Analysis of Genomic Imbalances in the Cancer Genome
National Cancer Institute at the National Institutes of Health
Member of the Josephine Ford Cancer Institute Urological Oncology Research Program
Key Terms: Cancer Genomics, Molecular Cytogenetics, Next Generation Sequencing, Prostate Cancer, and RNA in situ hybridization
Awards and Honors
1983 First prize for Merit in M.Sc., Zoology (1983) Kongunadu Arts and Science College, University of Madras
1985-1987 Junior Research Fellowship (JRF) Award
1987-1990 Senior Research Fellowship (SRF) Award, Council of Scientific and Industrial Research, New Delhi, India
2000-2003 Small Business Innovative Research (SBIR) Grant Awards, funded by National Cancer Institute, National Institutes of Health (Phase I: 3; Phase II: 1)
2006 Agilent Technologies University Relations Grant Award
2008 Best Reviewer Award – Singapore Medical Journal
2009 Melanoma Research Alliance Development Award
2009 Agilent Technologies University Relations Grant Award
2010-2012 Career Development Award, University of Michigan Comprehensive Cancer Center Prostate Cancer SPORE
2011 Who’s Who in America-Marquis – 2011, 65th Edition (pub.2010)
2011 Recognition of Professional Development Award, University of Michigan, Department of Pathology “REWARD” – Employee Recognition Program
2013 Recognition of Professional Development Award, University of Michigan, Department of Pathology “REWARD” – Employee Recognition Program
2015 Member, Josephine Ford Cancer Institute (JFCI), Henry Ford Health System, Detroit, MI
2015 Member, Karmanos Cancer Institute, Wayne State University, Detroit, MI