{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:41:19Z","timestamp":1791438079428,"version":"4.3.3"},"reference-count":39,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Immune checkpoint inhibitors (ICIs) are frontline treatment for advanced Merkel Cell Carcinoma (MCC), regardless of viral status. Frontline ICIs provide durable benefit to only half of patients, highlighting a need for alternative therapies. In this study, the objective is to leverage whole exome sequencing (WES) and transcriptome sequencing (WTS) to distinguish genomic alterations associated with ICI response. Investigate differential genomic alterations between virus-positive (VP) and virus-negative (VN)-MCC to identify novel therapeutic targets. Methods: A total of 95 MCC cases underwent WES and WTS. Utilizing computational pipelines applied to WES, we identified viral status and tumor mutational burden (TMB). RNA-seq data was used to characterize the immune microenvironment. Results: Of 95 MCC cases, 57 (60%) were VP-MCC and 38 (40%) were VN-MCC. Median TMB was higher in VN-MCC (27.5 vs. 1 Muts\/Mb). Mutations in TP53, RB1, NOTCH1, KMTD2, KMT2C, and PIK3CA were primarily found in VN-MCC. MAPK Pathway Activity Score, NK cell infiltration, and the immune checkpoint gene CD276 in VN-MCC tumors were upregulated. No overall survival (OS) difference was identified between VP and VN-MCC, even after ICIs. Conclusions: MCC oncogenesis and treatment response transcend viral status. While mutational analysis confirms previous findings, assessment of the transcriptome and tumor microenvironment suggests alternate therapeutic targets.<\/jats:p>","DOI":"10.3390\/cancers17213508","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:40:48Z","timestamp":1762180848000},"page":"3508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular Characterization of Polyomavirus-Positive and Negative Merkel Cell Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5506-4250","authenticated-orcid":false,"given":"Poorva","family":"Vaidya","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, UC Irvine School of Medicine, Orange, CA 92868, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Wu","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4751-5927","authenticated-orcid":false,"given":"Dave","family":"Bryant","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-5332","authenticated-orcid":false,"given":"Curtis J.","family":"Perry","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology, Yale School of Medicine, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varsha","family":"Prakash","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1607-1386","authenticated-orcid":false,"given":"Emil","family":"Lou","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and Transplantation, Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1689-3275","authenticated-orcid":false,"given":"Theresa","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head & Neck Surgery, University of California, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-9914","authenticated-orcid":false,"given":"Isaac","family":"Brownell","sequence":"additional","affiliation":[{"name":"Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20891, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3395-894X","authenticated-orcid":false,"given":"Sourat","family":"Darabi","sequence":"additional","affiliation":[{"name":"Hoag Family Cancer Institute, Newport Beach, CA 92663, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Dermatology, UC Irvine School of Medicine, Orange, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Abdulla","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo J.","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, UC San Diego School of Medicine, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.1245\/s10434-016-5266-4","article-title":"Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System","volume":"23","author":"Harms","year":"2016","journal-title":"Ann. 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