Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma

ABSTRACT Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genome...

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Autores principales:	Gabriel J. Starrett, Christina Marcelus, Paul G. Cantalupo, Joshua P. Katz, Jingwei Cheng, Keiko Akagi, Manisha Thakuria, Guilherme Rabinowits, Linda C. Wang, David E. Symer, James M. Pipas, Reuben S. Harris, James A. DeCaprio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/897076653c5b47418a7b045c9bff2e0e
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spelling	oai:doaj.org-article:897076653c5b47418a7b045c9bff2e0e2021-11-15T15:51:07ZMerkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma10.1128/mBio.02079-162150-7511https://doaj.org/article/897076653c5b47418a7b045c9bff2e0e2017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02079-16https://doaj.org/toc/2150-7511ABSTRACT Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations. IMPORTANCE A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors.Gabriel J. StarrettChristina MarcelusPaul G. CantalupoJoshua P. KatzJingwei ChengKeiko AkagiManisha ThakuriaGuilherme RabinowitsLinda C. WangDavid E. SymerJames M. PipasReuben S. HarrisJames A. DeCaprioAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Gabriel J. Starrett Christina Marcelus Paul G. Cantalupo Joshua P. Katz Jingwei Cheng Keiko Akagi Manisha Thakuria Guilherme Rabinowits Linda C. Wang David E. Symer James M. Pipas Reuben S. Harris James A. DeCaprio Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma
description	ABSTRACT Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations. IMPORTANCE A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors.
format	article
author	Gabriel J. Starrett Christina Marcelus Paul G. Cantalupo Joshua P. Katz Jingwei Cheng Keiko Akagi Manisha Thakuria Guilherme Rabinowits Linda C. Wang David E. Symer James M. Pipas Reuben S. Harris James A. DeCaprio
author_facet	Gabriel J. Starrett Christina Marcelus Paul G. Cantalupo Joshua P. Katz Jingwei Cheng Keiko Akagi Manisha Thakuria Guilherme Rabinowits Linda C. Wang David E. Symer James M. Pipas Reuben S. Harris James A. DeCaprio
author_sort	Gabriel J. Starrett
title	Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma
title_short	Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma
title_full	Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma
title_fullStr	Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma
title_full_unstemmed	Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma
title_sort	merkel cell polyomavirus exhibits dominant control of the tumor genome and transcriptome in virus-associated merkel cell carcinoma
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/897076653c5b47418a7b045c9bff2e0e
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Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma

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