Microbial interactions induce the mutational signature of mismatch repair deficiency in colorectal cancer and associated with EPPK1 mutations

To better understand the impact of microbial interactions on the clonal evolution of colorectal cancer (CRC), we conducted high-resolution profiling of the gut microbiome of 101 treatment-naïve primary CRC patients using nanopore sequencing. We performed an integrated analysis of microbiome and tumor exome data to identify symbiotic microbes that interactively influence the mutational processes and the subsequent clonality of CRC. Our results suggested that Dialister pneumosintes and Fusobacterium animalis were both associated with somatic EPPK1 mutations and promote SBS6 (mismatch repair deficiency, dMMR) activity. Notably, we showed that the symbiotic architecture of Dialister pneumosintes and Fusobacterium animalis undergoes significant changes with the mutational status of EPPK1. In addition, we identified specific metabolic pathways involving key metabolites that potentially mediate microbial interactions in CRC. These findings provide new insights into the interplay between the gut microbiome and the mutation landscape of colorectal cancer, thereby informing the clonal evolution of CRC and new strategies for precision medicine.