Abstract
Colorectal cancer is the second leading cause of cancer-related death in the United States and is a primary cause of morbidity and mortality throughout the world. Colorectal cancer development has been linked to differences in colonic bacterial community composition. Viruses are another important component of the colonic microbial community, however they have yet to be studied in colorectal cancer despite their oncogenic potential. We evaluated the colorectal cancer virome (virus community) in stool using a cohort of 90 human subjects with either healthy, adenomatous (precancerous), or cancerous colons. We utilized 16S rRNA gene, whole shotgun metagenomic, and purified virus metagenomic sequencing methods to compare the colorectal cancer virome to the bacterial community. We identified no detectable difference in viral diversity (alpha or beta) between healthy, adenomatous, or cancerous colonic samples, but more sophisticated random forest models identified striking differences in the virome. The majority of the cancer-associated virome consisted of temperate bacteriophages, suggesting that the community was indirectly linked to colorectal cancer by modulating bacterial community structure and function. Our data suggest that the influential phages do not exclusively infect influential bacteria, but rather act through the community as a whole. These results provide foundational evidence that bacteriophage communities are associated with colorectal cancer and likely impact cancer progression by altering the bacterial host communities.
Significance Statement Colorectal cancer is a leading cause of cancer-related death in the United States and worldwide. Its risk and severity have been linked to colonic bacterial community composition. Although viruses have been linked to other cancers and diseases, little is known about colorectal cancer virus communities. We addressed this knowledge gap by identifying differences in colonic virus communities in the stool of colorectal cancer patients and how they compared to bacterial community differences. The results suggested an indirect role for the virome in impacting colorectal cancer by modulating their associated bacterial community. These findings both support a biological role for viruses in colorectal cancer and provide a new understanding of basic colorectal cancer etiology.