Shanker Kalyana-SundaramUniversity of Michigan | U-M · Department of Pathology
Shanker Kalyana-Sundaram
Ph.D
About
75
Publications
13,778
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12,693
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Introduction
Additional affiliations
April 2004 - present
May 2002 - February 2004
Institute of Bioinformatics
Position
- Senior Research Scientist (Project Leader)
June 2000 - December 2001
DSQ Biotech
Position
- Scientist C (Team Leader)
Education
July 2009 - January 2013
University of Michigan \ Bharathidasan University
Field of study
- Bioinformatics \ Biotechnology
June 1994 - June 1996
Publications
Publications (75)
Introduction: Amplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC) with the most frequent amplified region being 3q26-3q28. It has been described in preinvasive and invasive LUSC and represents one of the most striking molecular differences between LUSC and adenocarcinoma. Many studies e...
Pseudogenes are a class of non-coding genes that are dysfunctional relatives of known functional genes. Often considered as junk DNA, pseudogenes have recently emerged as functional units in the form of non-coding RNA transcripts and micropeptides with regulatory roles in gene expression. Notably, association of some pseudogenes with oncogenes and...
The T cell receptor (TCR), a defining structure of T cells is responsible for the recognition of the antigen-major histocompatibility complex, leading to the initiation of an immune response. The extreme diversity of the TCR repertoire represents a major analytical challenge. Massively parallel high throughput sequencing is commonly deployed to cha...
Pseudogenes are a class of non-coding genes that are dysfunctional relatives of known functional genes. Often considered as junk DNA, pseudogenes have recently emerged as functional units in the form of non-coding RNA transcripts and micropeptides with regulatory roles in gene expression. Notably, association of some pseudogenes with oncogenes and...
Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p...
Amplification of chromosome 6p has been implicated in aggressive behavior in several cancers, but has not been characterized in renal cell carcinoma (RCC). We identified 9 renal tumors with amplification of chromosome 6p including the TFEB gene, 3 by fluorescence in situ hybridization, and 6 from the Cancer Genome Atlas (TCGA) databases. Patients'...
Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However,...
Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC) disease, a lysosomal storage disorder characte...
Genes selectively expressed in posterior lobules of the cerebellar midline.
In situ hybridization images from the Allen Brain Atlas.
(TIF)
HSPB1 over-expression does not rescue accumulation of ubiquitinated proteins or unesterified cholesterol.
Sections of the cerebellar midline were examined from mice at 11 weeks of age. (A) Immunofluorescent staining for calbindin (green) and ubiquitin (red); nuclei were stained by DAPI. (B) Immunofluorescent staining for calbindin (red) and filipin...
HSPB1-3E over-expression rescues Purkinje cell loss in lobule VIII.
7-week-old Npc1 flox/-, Pcp2-Cre mice were injected with AAV2 expressing HSPB1-3E or control vector and then examined at 13 weeks of age. Quantification of Purkinje cell density (A) and soma size (B) in lobule VIII of midline cerebellar sections. Data are mean ± SD, n = 3 mice/grou...
We employed next generation RNA sequencing analysis to reveal dysregulated long non-coding RNAs (lncRNAs) in lung cancer utilizing 461 lung adenocarcinomas (LUAD) and 156 normal lung tissues from 3 separate institutions. We identified 281 lncRNAs with significant differential-expression between LUAD and normal lung tissue. LINC00857, a top deregula...
Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations. Although many gene fusions are found at high frequency in several rare solid cancers, apart from fusions involving the ETS family of transcription factors which ha...
Approximately 30% of all cancers harbor activating mutations in the RAS family of small GTPase proteins, making it one of the most common oncogenic aberrations in humans. Normal RAS proteins (H, K or N-RAS) localize to the inner cell membrane and transduce extracellular growth signals by cycling between an “active” GTP-bound state and “inactive” GD...
Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with T...
Precision/ personalized cancer therapy based on clinical sequencing is premised on the identification of genomic aberrations in actionable therapeutic targets. Protein kinases represent the most accessible therapeutic targets across cancers, albeit only very small subsets of cancers harbor canonical targetable aberrations in kinases. Considering th...
Primary clear-cell adenocarcinoma of the urethra, a rare tumor that histomorphologically resembles clear-cell carcinoma of the female genital tract, occurs predominantly in women and is associated with a relatively poor prognosis. The histogenesis of this rare urethral neoplasm has not been completely resolved, but it is thought to arise from eithe...
Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutati...
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC
Protein kinases represent a most effective class of therapeutic targets in cancer cells, and potent inhibitors of oncogenic kinases including ABL, AKT, ALK, AURKs, BRAF, CDKs, EGFR, ERBB2, FGFRs, KIT, MAPKs, MET, PIK3CA, PLKs, RET, SRC, S6Ks, and VEGFR are in clinical use,...
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 fusions...
Background
Based on their function in cancer micro(mi)RNAs are often grouped as either tumor suppressors or oncogenes. However, miRNAs regulate multiple tumor relevant signaling pathways raising the question whether two oncogenic miRNAs could be functional antagonists by promoting different steps in tumor progression. We recently developed a method...
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 defined distinct “outlier kinases” in i...
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 recurre...
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...
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...
GFML_prototype.XML – XML document describes the prototype of the Gene Fusion Markup Language. It would be good to view in internal explorer or in any XML editor.
GFML_Schema.XSD – Describes the XML Schema Definition (XSD) of Gene Fusion Markup Language, can be viewed in internal explorer or in any XML editor.
GFML_common.XSD – Describes the common reusable elements of Gene Fusion Markup Language, can be viewed in internal explorer or in any XML editor.
GFML_prototype_instance.XML – Demonstrate the Gene Fusion Markup Language prototype with illustration, can be viewed in internal explorer or in any XML editor.
Application of high-throughput transcriptome sequencing has spurred highly sensitive detection and discovery of gene fusions in cancer, but distinguishing potentially oncogenic fusions from random, "passenger" aberrations has proven challenging. Here we examine a distinctive group of gene fusions that involve genes present in the loci of chromosoma...
Using a series of detailed experiments, Zhang and colleagues establish that the prostate cancer RNA chimera SLC45A3-ELK4 is generated by cis-splicing between the 2 adjacent genes and does not involve DNA rearrangements or trans-splicing. The chimera expression is induced by androgen treatment likely by overcoming the read-through block imposed by t...
Pseudogene transcripts can provide a novel tier of gene regulation through generation of endogenous siRNAs or miRNA-binding sites. Characterization of pseudogene expression, however, has remained confined to anecdotal observations due to analytical challenges posed by the extremely close sequence similarity with their counterpart coding genes. Here...
Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were el...
Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identifie...
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL
Targeted cancer therapy, which takes into account the intrinsic molecular heterogeneity of individual cases, is the ultimate goal of cancer genomics research. Despite intrinsic genetic complexity and heterogeneity, a few genes exert an overarching influence on the growth and...
Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in select prostate tissues and cell lines using MethylPlex-next-generation sequencing (M-NGS). Hidden Markov model-based next-generation sequence analysis identified ∼68,000 methylated re...
Rap1GAP is a critical tumor suppressor gene that is downregulated in multiple aggressive cancers, such as head and neck squamous cell carcinoma, melanoma and pancreatic cancer. However, the mechanistic basis of rap1GAP downregulation in cancers is poorly understood. By employing an integrative approach, we demonstrate polycomb-mediated repression o...
In cancer, the genome undergoes global DNA methylation changes, which contributes to disease progression. We mapped the global DNA methylation patterns in prostate tissues and cells (n=19) from fifty nanograms of genomic DNA. The methylated regions enriched by Methylplex technology, were subjected -Next Generation Sequencing (M-NGS). A total of 28...
In the paper published by Jentzmik et al. [1], the authors address the importance of urine-derived sarcosine based on public interest in our report [2], which describes elevated levels of the metabolite in urine of biopsy-proven prostate cancer (PCa) patients. We found especially elevated sarcosine levels in tumor specimens from patients with metas...
More detailed information on methods and additional Tables and Figures.
Protein-DNA interaction constitutes a basic mechanism for the genetic regulation of target gene expression. Deciphering this mechanism has been a daunting task due to the difficulty in characterizing protein-bound DNA on a large scale. A powerful technique has recently emerged that couples chromatin immunoprecipitation (ChIP) with next-generation s...
Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been...
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of biomarkers of cancer invasion and disease aggressiveness. Although alterations in gene expression have been extensively quantified du...
Recurrent gene fusions are a prevalent class of mutations arising from the juxtaposition of 2 distinct regions, which can generate novel functional transcripts that could serve as valuable therapeutic targets in cancer. Therefore, we aim to establish a sensitive, high-throughput methodology to comprehensively catalog functional gene fusions in canc...
Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations. To identify additional opportunities for targeted therapy, we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3,200 microarray experiments. In addition t...
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profil...
Recurrent gene fusions, typically associated with hematological malignancies and rare bone and soft tissue tumors1, have been recently described in common solid tumors2–9. Here we employ an integrative analysis of high-throughput long and short read transcriptome sequencing of cancer cells to discover novel gene fusions. As a proof of concept we su...
Supplementary Information is linked to the online version of this paper at www.nature.com/nature.
There is considerable evidence for an association between prostate cancer development and inflammation, which results in autoantibody generation against tumor proteins. This immune system-driven amplification of the autoantibody response to intracellular antigens can serve as a sensitive tool to detect low abundance serum proteomic tumor markers fo...
Global molecular profiling of cancers has shown broad utility in delineating pathways and processes underlying disease, in predicting prognosis and response to therapy, and in suggesting novel treatments. To gain further insights from such data, we have integrated and analyzed a comprehensive collection of "molecular concepts" representing > 2500 c...
DNA microarrays have been widely applied to cancer transcriptome analysis; however, the majority of such data are not easily accessible or comparable. Furthermore, several important analytic approaches have been applied to microarray analysis; however, their application is often limited. To overcome these limitations, we have developed Oncomine, a...
Despite efforts to profile prostate cancer, the genetic alterations and biological processes that correlate with the observed histological progression are unclear. Using laser-capture microdissection to isolate 101 cell populations, we have profiled prostate cancer progression from benign epithelium to metastatic disease. By analyzing expression si...
A catalog of all human protein-protein interactions would provide scientists with a framework to study protein deregulation in complex diseases such as cancer. Here we demonstrate that a probabilistic analysis integrating model organism interactome data, protein domain data, genome-wide gene expression data and functional annotation data predicts n...
DNA microarrays have been widely applied to cancer transcriptome analysis. The Oncomine database contains a large collection of such data, as well as hundreds of derived gene-expression signatures. We studied the regulatory mechanisms responsible for gene deregulation in these cancer signatures by searching for the coordinate regulation of genes wi...