Supplementary Figure S1 from UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas
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posted on 2023-03-30, 23:31 authored by Stephen Q. Wong, Kelly Waldeck, Ismael A. Vergara, Jan Schröder, Jason Madore, James S. Wilmott, Andrew J. Colebatch, Ricardo De Paoli-Iseppi, Jason Li, Richard Lupat, Timothy Semple, Gisela Mir Arnau, Andrew Fellowes, J. Helen Leonard, George Hruby, Graham J. Mann, John F. Thompson, Carleen Cullinane, Meredith Johnston, Mark Shackleton, Shahneen Sandhu, David D.L. Bowtell, Ricky W. Johnstone, Stephen B. Fox, Grant A. McArthur, Anthony T. Papenfuss, Richard A. Scolyer, Anthony J. Gill, Rodney J. Hicks, Richard W. TothillFocal copy number alterations proximal to viral integrations in V+MCC.
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ARTICLE 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. Cancer Res; 75(24); 5228–34. ©2015 AACR.Usage metrics
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