Abstract 6530: A comprehensive genomic analysis elucidates the microbial landscape of cancer

Abstract There is growing evidence that microorganisms are an important component of the tumor microenvironment. However, conflicting reports regarding the cancer microbiome have left the extent of microbial presence across cancer types unclear, highlighting the need for more accurate methods of profiling of tumor-associated microorganisms. Leveraging the new human genome T2T-CHM13, we developed a new host-subtraction and decontamination pipeline for accurately profiling tumor-associated microorganisms in tumor sequencing data and benchmarked it on simulated and real-world datasets. We used this pipeline to perform a pan-cancer analysis of new high-depth whole-genome tumor sequencing data from The Cancer Genome Atlas (n = 8,840) and the UK 100,000 Genomes Project (n = 15,223). Our analysis revealed that in both cohorts, most cancer types do not harbor a detectable microbiome. However, we identified polymicrobial communities in association with nearly all oral, esophageal, gastric, and colorectal cancers, each of which harbored cancer-type specific microbiomes. Within cancer types, microbial communities differed by anatomical site and tumor subtype. Notably, we observed increased bacterial colonization in microsatellite-instable (MSI) cancers of the upper and lower gastrointestinal tract, and a correlation between bacterial colonization and tumor mutational burden in a pattern that persisted after controlling for MSI status. This trend was driven by a specific community of pathogens including Fusobacterium animalis, and was linked to a tumor-specific immune signature using patient-matched RNA-sequencing. Finally, we demonstrate that complete microbial genomes can be assembled from bulk tumor sequencing data, allowing phylogenetic and functional analysis of tumor-resident microorganisms. Together, our analysis helps clarify the microbial landscape of cancer and highlights its potential clinical importance in gastrointestinal malignancies. Citation Format: Anders B. Dohlman, Robin Mjelle, Henry Wood, Iris Lee, Kevin Jiang, Ethan Shurberg, Alaina Shumate, Blake Sanders, Guanxi Qiao, Jodi Hirshman, Andrew Cherniack, Phil Quirke, Matthew Meyerson. A comprehensive genomic analysis elucidates the microbial landscape of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6530.