Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for characterizing tumor-associated microbiomes. We built and benchmarked a host-subtraction and classification pipeline to identify microbiota in whole-genome sequencing data and applied it to 16,369 high-depth tumor whole genomes from the UK 100,000 Genomes Project. After decontamination, microbial signatures were indistinguishable from the background in most cancer types. However, in orodigestive tumors, we detected multi-kingdom polymicrobial communities, including bacteria, fungi, viruses, archaea, and, in some cases, Trichomonas, a protozoan parasite. These communities varied by tumor site and subtype, with increased microbial colonization of microsatellite-instable and polymerase ε (POLE)/polymerase δ (POLD1)-mutated tumors, supported by a correlation between microbial load and tumor mutation burden observed across orodigestive cancers. This analysis helps to resolve pan-cancer microbial structure and links the tumor microbiome to host phenotype and tumor genomic context.
Keywords: archaea; bacteria; biogeography; cancer; decontamination; fungi; microbiome; multi-kingdom; mutation burden; viruses.
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