title: UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas.
abstract: Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell-infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Stephen Q
authors.initials: SQ
authors.lastname: Wong
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Waldeck
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Ismael A
authors.initials: IA
authors.lastname: Vergara
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Walter Eliza Hall Institute, Melbourne, Victoria, Australia. Department of Computing and Information Systems, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Schröder
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Madore
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Colebatch
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Ricardo
authors.initials: R
authors.lastname: De Paoli-Iseppi
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Lupat
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Semple
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Gisela Mir
authors.initials: GM
authors.lastname: Arnau
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Fellowes
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: J Helen
authors.initials: JH
authors.lastname: Leonard
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Hruby
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: Johnston
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Shahneen
authors.initials: S
authors.lastname: Sandhu
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Walter Eliza Hall Institute, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Papenfuss
authors.affiliation: Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Cancer Diagnosis and Pathology Research Group Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia. richard.tothill@petermac.org.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
mesh_terms: D015153:Blotting, Western; D015266:Carcinoma, Merkel Cell / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects*; D004252:DNA Mutational Analysis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D059965:Merkel cell polyomavirus; D009154:Mutation; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics*; D059467:Transcriptome; D014466:Ultraviolet Rays / Q000009:adverse effects*