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Potential viral pathogens were systematically investigated in the whole-genome and transcriptome sequencing of 2384 donors across Pan-Cancer Analysis of Whole Genomes using a consensus approach integrating three independent pathogen detection pipelines. Viruses were detected in 485 genomic and 70 transcriptome data sets. Besides confirming the prevalence of known tumor associated viruses such as EBV, HBV and several HPV types, numerous novel features were discovered. A strong association was observed between HPV infection and the APOBEC mutational signatures, suggesting the role of impaired mechanism of antiviral cellular defense as a driving force in the development of cervical, bladder and head neck carcinoma. Viral integration into the host genome was observed for HBV, HPV16, HPV18 and AAV2 and associated with a local increase in copy number variations. The recurrent viral integrations at the TERT promoter were coupled to high telomerase expression uncovering a further mechanism to activate this tumor driving process. Most importantly, our systematic analysis revealed a novel association between mastadenovirus and several tumor entities. In renal cancer, mastadenovirus presence was significantly exclusive with well-known driver mutations in kidney cancer and defined a patient subgroup with better survival. Independent from mastadenovirus presence, high levels of endogenous retrovirus ERV1 expression is linked to worse survival outcome in kidney cancer.

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