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This study aimed to compare the clinical and molecular features of four viral\u2010associated cancers: stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and cervical squamous cell carcinoma (CESC). Patients were categorized based on viral infection status, as provided in the clinical data, into virus\u2010associated and non\u2010virus\u2010associated groups, followed by a comprehensive comparison of clinical and molecular features. Our analysis disclosed that viral infections confer unique clinical and molecular signatures to their associated tumors. Specifically, human papillomavirus\u2010associated (HPV+) HNSC and hepatitis B virus\u2010associated (HBV+) LIHC patients were predominantly male, younger, and exhibited better clinical prognoses. Virus\u2010associated tumors displayed enhanced immune microenvironments and high DNA damage response scores, while non\u2010virus\u2010associated tumors were enriched in stromal signatures. HPV+\u2009HNSC and Epstein\u2010Barr virus\u2010associated (EBV+) STAD showed similarities across multi\u2010omics features, including better responses to immunotherapy, lower <jats:italic>TP53<\/jats:italic> mutation rates, tumor mutation burden (TMB), and copy number alteration (CNA). Conversely, HBV+, Hepatitis C virus\u2010associated (HCV+) LIHCs and HPV+\u2009CESC were more genomically unstable due to high <jats:italic>TP53<\/jats:italic> mutation rates, TMB, and CNA. At the protein level, <jats:italic>Caspase\u20107<\/jats:italic> and <jats:italic>Syk<\/jats:italic> were upregulated in HPV+\u2009HNSC and EBV+\u2009STAD, and positively correlated with the enrichment levels of CD8\u2009+\u2009T cell, PD\u2010L1, and cytolytic activity. Patient stratification based on infection status has significant clinical implications, particularly for patient prognosis and drug response.<\/jats:p>","DOI":"10.1002\/jmv.70239","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T10:33:02Z","timestamp":1739961182000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comprehensive Analysis of Clinical and Molecular Features in Cancer Patients Associated With Major Human Oncoviruses"],"prefix":"10.1002","volume":"97","author":[{"given":"Ahmed Osman","family":"Mohamed","sequence":"first","affiliation":[{"name":"Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing China"},{"name":"Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing China"},{"name":"Big Data Research Institute China Pharmaceutical 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