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Grant Details

Grant Number: 5R33CA120726-03 Interpret this number
Primary Investigator: Moore, Patrick
Organization: University Of Pittsburgh At Pittsburgh
Project Title: Emerging Technologies Applied to the Discovery of Human Tumor Viruses
Fiscal Year: 2009


Abstract

DESCRIPTION (provided by applicant): Infection contributes to ~20% of human cancers worldwide. The list of known carcinogenic infectious agents, however, is surprisingly short and no new human tumor viruses have been discovered over the past decade. Current tumor virus discovery methods are not comprehensive and are likely to miss discovery of new families of agents. Negative studies using these techniques do not rule out the presence of a tumor virus and may miss a previously unknown agent. We propose modifying long Serial Analysis of Gene Expression (SAGE) as an unbiased means for virus discovery using in silica digital transcript subtraction (DTS). We show here a practical method to perform transcriptome-wide in silico subtraction of short transcript tags, allowing discrimination between human and nonhuman sequences. Once a candidate tumor virus sequence is found, it can be used as a start point for viral genome walking and characterization. To demonstrate the feasibility of this method, we performed pilot studies of DTS on a tumor cell line infected with latent KSHV virus. DTS rapidly and uniquely identified 5 KSHV transcripts de novo comprising 0.44% of the total cell transcriptome. The technique was quantitatively reproduced by spiking KSHV-infected cell line RNA into uninfected human tumor tissue RNA. We also identified practical cut-off levels that distinguish most human polymorphisms from viral SAGE tags using DTS. Finally, we performed pilot DTS on 3 squamous cell conjunctival carcinoma (SCCC) tumors, an immunodeficiency-related malignancy. In silico subtraction of 108,000 SAGE tags generated 46 candidate sequences, including 12 high probability tags that are being evaluated as possible SCCC agent sequences. We show that this technique is surprisingly immune to RNA degradation so that it can be used on rare or archival materials in which partial RNA degradation has occurred. We seek phase II R33 funding to perform DTS on 4 SCCC samples, extending our pilot studies into a full analysis of SCCC at the 5-10 transcripts per million level. This will allow us to either identify or exclude a likely tumor virus causing this immunodeficiency-related cancer. This also completes development of DTS technology, allowing us to fully optimize its performance for application to other suspected infectious tumors ASSESSMENT:



Publications

Characterization of a Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Cell Line CVG-1.
Authors: Velásquez C. , Amako Y. , Harold A. , Toptan T. , Chang Y. , Shuda M. .
Source: Frontiers in microbiology, 2018; 9, p. 713.
EPub date: 2018-04-11.
PMID: 29696010
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Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting.
Authors: Kwun H.J. , Wendzicki J.A. , Shuda Y. , Moore P.S. , Chang Y. .
Source: Oncogene, 2017-12-07; 36(49), p. 6784-6792.
EPub date: 2017-08-28.
PMID: 28846109
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Protein-mediated viral latency is a novel mechanism for Merkel cell polyomavirus persistence.
Authors: Kwun H.J. , Chang Y. , Moore P.S. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2017-05-16; 114(20), p. E4040-E4047.
EPub date: 2017-05-01.
PMID: 28461484
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Restricted protein phosphatase 2A targeting by Merkel cell polyomavirus small T antigen.
Authors: Kwun H.J. , Shuda M. , Camacho C.J. , Gamper A.M. , Thant M. , Chang Y. , Moore P.S. .
Source: Journal of virology, 2015 Apr; 89(8), p. 4191-200.
EPub date: 2015-01-28.
PMID: 25631078
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Human DNA tumor viruses generate alternative reading frame proteins through repeat sequence recoding.
Authors: Kwun H.J. , Toptan T. , Ramos da Silva S. , Atkins J.F. , Moore P.S. , Chang Y. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2014-10-14; 111(41), p. E4342-9.
EPub date: 2014-09-30.
PMID: 25271323
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Merkel cell polyomavirus-positive Merkel cell carcinoma requires viral small T-antigen for cell proliferation.
Authors: Shuda M. , Chang Y. , Moore P.S. .
Source: The Journal of investigative dermatology, 2014 May; 134(5), p. 1479-1481.
EPub date: 2013-11-12.
PMID: 24217011
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The T antigen locus of Merkel cell polyomavirus downregulates human Toll-like receptor 9 expression.
Authors: Shahzad N. , Shuda M. , Gheit T. , Kwun H.J. , Cornet I. , Saidj D. , Zannetti C. , Hasan U. , Chang Y. , Moore P.S. , et al. .
Source: Journal of virology, 2013 Dec; 87(23), p. 13009-19.
EPub date: 2013-09-25.
PMID: 24067965
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Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7.
Authors: Kwun H.J. , Shuda M. , Feng H. , Camacho C.J. , Moore P.S. , Chang Y. .
Source: Cell host & microbe, 2013-08-14; 14(2), p. 125-35.
PMID: 23954152
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Multicolor microRNA FISH effectively differentiates tumor types.
Authors: Renwick N. , Cekan P. , Masry P.A. , McGeary S.E. , Miller J.B. , Hafner M. , Li Z. , Mihailovic A. , Morozov P. , Brown M. , et al. .
Source: The Journal of clinical investigation, 2013 Jun; 123(6), p. 2694-702.
PMID: 23728175
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Complex alternative cytoplasmic protein isoforms of the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 generated through noncanonical translation initiation.
Authors: Toptan T. , Fonseca L. , Kwun H.J. , Chang Y. , Moore P.S. .
Source: Journal of virology, 2013 Mar; 87(5), p. 2744-55.
EPub date: 2012-12-19.
PMID: 23255808
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Characterization of an early passage Merkel cell polyomavirus-positive Merkel cell carcinoma cell line, MS-1, and its growth in NOD scid gamma mice.
Authors: Guastafierro A. , Feng H. , Thant M. , Kirkwood J.M. , Chang Y. , Moore P.S. , Shuda M. .
Source: Journal of virological methods, 2013 Jan; 187(1), p. 6-14.
EPub date: 2012-10-18.
PMID: 23085629
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Lack of integrin β5 in Merkel cell carcinomas and derived cell lines is frequently associated with Merkel cell polyomavirus positivity.
Authors: Akgül B. , Zigrino P. , Hufbauer M. , Liu X. , Moore P.S. , Mauch C. , Pfister H. .
Source: Journal of dermatological science, 2012 Jul; 67(1), p. 66-8.
EPub date: 2012-03-30.
PMID: 22503669
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Survivin is a therapeutic target in Merkel cell carcinoma.
Authors: Arora R. , Shuda M. , Guastafierro A. , Feng H. , Toptan T. , Tolstov Y. , Normolle D. , Vollmer L.L. , Vogt A. , Dömling A. , et al. .
Source: Science translational medicine, 2012-05-09; 4(133), p. 133ra56.
PMID: 22572880
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Merkel cell carcinoma: a virus-induced human cancer.
Authors: Chang Y. , Moore P.S. .
Source: Annual review of pathology, 2012; 7, p. 123-44.
EPub date: 2011-09-13.
PMID: 21942528
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Coupled transcriptome and proteome analysis of human lymphotropic tumor viruses: insights on the detection and discovery of viral genes.
Authors: Dresang L.R. , Teuton J.R. , Feng H. , Jacobs J.M. , Camp D.G. , Purvine S.O. , Gritsenko M.A. , Li Z. , Smith R.D. , Sugden B. , et al. .
Source: BMC genomics, 2011-12-20; 12, p. 625.
EPub date: 2011-12-20.
PMID: 22185355
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Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator.
Authors: Shuda M. , Kwun H.J. , Feng H. , Chang Y. , Moore P.S. .
Source: The Journal of clinical investigation, 2011 Sep; 121(9), p. 3623-34.
EPub date: 2011-08-15.
PMID: 21841310
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Asymptomatic primary Merkel cell polyomavirus infection among adults.
Authors: Tolstov Y.L. , Knauer A. , Chen J.G. , Kensler T.W. , Kingsley L.A. , Moore P.S. , Chang Y. .
Source: Emerging infectious diseases, 2011 Aug; 17(8), p. 1371-80.
PMID: 21801612
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Asymmetric assembly of Merkel cell polyomavirus large T-antigen origin binding domains at the viral origin.
Authors: Harrison C.J. , Meinke G. , Kwun H.J. , Rogalin H. , Phelan P.J. , Bullock P.A. , Chang Y. , Moore P.S. , Bohm A. .
Source: Journal of molecular biology, 2011-06-17; 409(4), p. 529-42.
EPub date: 2011-04-09.
PMID: 21501625
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Merkel cell polyomavirus large T antigen disrupts lysosome clustering by translocating human Vam6p from the cytoplasm to the nucleus.
Authors: Liu X. , Hein J. , Richardson S.C. , Basse P.H. , Toptan T. , Moore P.S. , Gjoerup O.V. , Chang Y. .
Source: The Journal of biological chemistry, 2011-05-13; 286(19), p. 17079-90.
EPub date: 2011-03-16.
PMID: 21454559
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Cellular and viral factors regulating Merkel cell polyomavirus replication.
Authors: Feng H. , Kwun H.J. , Liu X. , Gjoerup O. , Stolz D.B. , Chang Y. , Moore P.S. .
Source: PloS one, 2011; 6(7), p. e22468.
EPub date: 2011-07-22.
PMID: 21799863
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Why do viruses cause cancer? Highlights of the first century of human tumour virology.
Authors: Moore P.S. , Chang Y. .
Source: Nature reviews. Cancer, 2010 Dec; 10(12), p. 878-89.
EPub date: 2010-11-24.
PMID: 21102637
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Lack of evidence for basal or squamous cell carcinoma infection with Merkel cell polyomavirus in immunocompetent patients with Merkel cell carcinoma.
Authors: Reisinger D.M. , Shiffer J.D. , Cognetta A.B. , Chang Y. , Moore P.S. .
Source: Journal of the American Academy of Dermatology, 2010 Sep; 63(3), p. 400-3.
EPub date: 2010-06-26.
PMID: 20584559
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Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens.
Authors: Houben R. , Shuda M. , Weinkam R. , Schrama D. , Feng H. , Chang Y. , Moore P.S. , Becker J.C. .
Source: Journal of virology, 2010 Jul; 84(14), p. 7064-72.
EPub date: 2010-05-05.
PMID: 20444890
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Lack of evidence for direct involvement of Merkel cell polyomavirus (MCV) in chronic lymphocytic leukemia (CLL).
Authors: Tolstov Y.L. , Arora R. , Scudiere S.C. , Busam K. , Chaudhary P.M. , Chang Y. , Moore P.S. .
Source: Blood, 2010-06-10; 115(23), p. 4973-4.
PMID: 20538816
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Update on human polyomaviruses and cancer.
Authors: Gjoerup O. , Chang Y. .
Source: Advances in cancer research, 2010; 106, p. 1-51.
PMID: 20399955
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The minimum replication origin of merkel cell polyomavirus has a unique large T-antigen loading architecture and requires small T-antigen expression for optimal replication.
Authors: Kwun H.J. , Guastafierro A. , Shuda M. , Meinke G. , Bohm A. , Moore P.S. , Chang Y. .
Source: Journal of virology, 2009 Dec; 83(23), p. 12118-28.
EPub date: 2009-09-16.
PMID: 19759150
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Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays.
Authors: Tolstov Y.L. , Pastrana D.V. , Feng H. , Becker J.C. , Jenkins F.J. , Moschos S. , Chang Y. , Buck C.B. , Moore P.S. .
Source: International journal of cancer, 2009-09-15; 125(6), p. 1250-6.
PMID: 19499548
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Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors.
Authors: Shuda M. , Arora R. , Kwun H.J. , Feng H. , Sarid R. , Fernández-Figueras M.T. , Tolstov Y. , Gjoerup O. , Mansukhani M.M. , Swerdlow S.H. , et al. .
Source: International journal of cancer, 2009-09-15; 125(6), p. 1243-9.
PMID: 19499546
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Quantitation of human seroresponsiveness to Merkel cell polyomavirus.
Authors: Pastrana D.V. , Tolstov Y.L. , Becker J.C. , Moore P.S. , Chang Y. , Buck C.B. .
Source: PLoS pathogens, 2009 Sep; 5(9), p. e1000578.
EPub date: 2009-09-11.
PMID: 19750217
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Clonal integration of a polyomavirus in human Merkel cell carcinoma.
Authors: Feng H. , Shuda M. , Chang Y. , Moore P.S. .
Source: Science (New York, N.Y.), 2008-02-22; 319(5866), p. 1096-100.
EPub date: 2008-01-17.
PMID: 18202256
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