title: 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 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.
  
  
  
  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.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Starrett
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Marcelus
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Cantalupo
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Katz
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.|Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Thakuria
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Rabinowits
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.|Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Symer
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA rsh@umn.edu james_decaprio@dfci.harvard.edu.|Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA rsh@umn.edu james_decaprio@dfci.harvard.edu.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James A
authors.identifier: 0000-0002-0896-167X
authors.initials: JA
authors.lastname: DeCaprio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis; D015266:Carcinoma, Merkel Cell / Q000473:pathology* / Q000821:virology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D059965:Merkel cell polyomavirus / Q000472:pathogenicity*; D008875:Middle Aged; D016662:Virus Integration