Abstract Fusobacterium nucleatum is an opportunistic bacterial pathogen and oncogenic microbe. To systematically investigate Fusobacterium-host interactions in colorectal cancers (CRCs), using host sequencing data, we developed a multi-omics PAThogen CHaracterization tool (PATCH) allowing for gene-level annotations. In 1,020 CRC transcriptomes and 28 genomes from The Cancer Genome Atlas (TCGA), we detected 9 Fusobacterium species and genes encoding 2,346 proteins, including carcinogenic virulence factors, oxidative stress chaperones, and immune response modulators. Fusobacterium was absent in tumor-adjacent normal tissue, however showed variable intra-tumor heterogeneity. PATCH-defined Fusobacterium-positive CRCs confirmed known and revealed novel perturbations in several host DNA damage responses (DDR) mechanisms, including deficiencies in telomere maintenance pathways, elevated cytosolic DNA/RNA sensing signaling, and mutations in genes involved in multiple oncogenic-related pathways. Moreover, PATCH uncovered Fusobacterium’s DNA integrated into the coding regions of tumor suppressor genes in the cancer genome and in non- coding regions significantly enriched in close proximity to Long Interspersed Elements (LINE-1), suggesting a potential rationale for LINE-1 hypomethylation in Fusobacterium-positive CRCs. Collectively, our analytical approaches have delineated Fusobacterium’s multimodal contribution to disrupting genomic stability, which ultimately could facilitate tailored treatment options targeting several DDR pathways in Fusobacterium-positive CRC. Citation Format: Radhika Kataria, Jelmar Quist, Sunjae Lee, Anargyros Megalios, Elinor Sawyer, Thomas Hardiman, Chang Liu, Katherine Kelly, Theo Portlock, Saeed Shoaie, Anita Grigoriadis. Multiomics analyses reveal multimodal Fusobacterium DNA damage perturbations in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6212.