577P Systematically assessing the intratissue microbiota in 937 patients with colorectal cancer

Dysbiosis of the fecal microbiota has been closely related to colorectal cancer (CRC) and has increasingly proven to be associated with CRC prognosis. However, a significant knowledge gap still exists regarding intestinal tissue-resident microbes and their associations with host genetic alterations, gene expressions and prognosis in CRC. We undertook a comprehensive analysis of the tissue-resident microbes in CRC patients from the U-CAN cohort, a large prospective longitudinal study of adult cancer patients in Sweden, using treatment-naïve whole-genome (average 53x coverage) and whole-transcriptome sequencing data of tumors (n=937) and their adjacent normal tissues (n=475). In total, 301 genera and 420 species were identified as common tissue-resident taxa. We showed for the first-time distinct enrichment patterns of tissue-resident microbiome in the right- and left-sided colons. Importantly, these patterns were highly consistent between tumor and normal tissues, with right-sided colons enriched with Clostridium spp and left-sided colons enriched with Akkermansia muciniphila and Bifidobacterium spp. We identified 94 tumor-enriched bacteria, and 38 were significantly associated with host hypermutation (HM) status. Previously known CRC-enriched bacteria, such as Fusobacterium groups and Campylobacter, were more prevalent in right-sided and HM tumors, and strongly correlated with mutations in host drivers and DNA damage repair genes. CRC driver genes that correlated with identified intratissue bacteria including CASP8, TP53 and SMAD2, with CASP8 significantly associated with multiple CRC-enriched taxa in all and in HM samples. Finally, risk scores derived from tumor or normal-resident taxa could both predict CRC prognosis and significantly improve the prognosis performance of the consensus molecular subtypes (CMS). Our study provides new insights into the interactions between tumor-enriched microbiota with CRC and identifies potential bacteria markers that could improve the accuracy of CRC prognosis prediction. These findings can guide future efforts to exploit the performance of intratissue bacteria on CRC prognosis prediction.