Colorectal cancer mutational profiles correlate with defined microbial communities in the tumor microenvironment

Abstract

Variation in the gut microbiome has been linked to colorectal cancer (CRC), as well as to host genetic variation. However, we do not know whether, in addition to baseline host genetics, somatic mutational profiles in CRC tumors interact with the surrounding tumor microbiome, and if so, whether these changes can be used to understand microbe-host interactions with potential functional biological relevance. Here, we characterized the association between CRC microbial communities and tumor mutations using microbiome profiling and whole-exome sequencing in 44 pairs of tumors and matched normal tissues. We found statistically significant associations between loss-of-function mutations in tumor genes and shifts in the abundances of specific sets of bacterial taxa, suggestive of potential functional interaction. This correlation allows us to statistically predict interactions between loss-of-function tumor mutations in cancer-related genes and pathways, including MAPK and Wnt signaling, solely based on the composition of the microbiome. These results can serve as a starting point for fine-grained exploration of the functional interactions between discrete alterations in tumor DNA and proximal microbial communities in CRC. In addition, these findings can lead to the development of improved microbiome-based CRC screening methods, as well as individualized microbiota-targeting therapies.

Distinct Microbes, Metabolites, and Ecologies Define the Microbiome in Deficient and Proficient Mismatch Repair Colorectal Cancers

“…Interestingly, we also 451 identified several differentially abundant microbes associated with dMMR but not pMMR tumor 452 samples including F. nucleatum, F. periodonticum, and B. fragilis. We further validated these 453 findings in an independent cohort [1], which underscores the importance of including MMR 454 status in future CRC microbiome studies. We additionally characterized the predicted and actual 455 metabolic profiles of dMMR and pMMR individuals in relation to hydrogen sulfide and butyrate 456 production, and we generated a network of predicted interactions within the dMMR and pMMR 457 microbial communities.…”

“…To validate the differentially abundant microbes associated with dMMR status, we investigated 196 data from a recent study that included microbiome profiling in tumor and matched normal tissue 197 samples in 44 CRC patients [1]. We categorized MMR status based on microsatellite instability 198…”

“…The gut microbiota has been linked to colorectal cancer (CRC) in many studies [1][2][3][4][5][6][7], and serves 72 as a very promising target for diagnostic, prophylactic, and therapeutic applications. Yet, despite 73…”

“…Notably, Fusobacterium periodonticum, F. nucleatum, and 335 Bacteroides fragilis-microbes commonly associated with CRC[5, 14, 46-49]-were among the 336 top most differentially abundant microbes in dMMR tumor samples but were not found to be 337 differentially abundant in pMMR tumor samples. 338 339To validate these results, we used publicly available data from tumor and matched normal 340 samples from 44 CRC patients[1]. Our validation analysis showed several overlapping 341 associations of microbial genomes with respect to dMMR and pMMR in tumor and matched 342 normal samples (Additional tumors were found enriched for 343Bacteroides fragilis (p=0.02, FDR p=0.37) and Fusobacterium (p=0.03, FDR p=0.37) while 344 dMMR normal samples were enriched for Dorea (p=0.03, FDR p=0.37) and an 345…”

Interaction Between Host MicroRNAs and the Gut Microbiota in Colorectal Cancer

“…[18][19][20][21][22][23]. This could explain uni-directional host-to-microbiome interaction, especially in CRC, where genetic mutations in host cells are common [24,25]. Interestingly, in a genetic mutation model of intestinal tumors, germ-free animals developed significantly fewer tumors in the small intestine [26].…”