Identifying strain-specific functional genes with colorectal cancer

Colorectal cancer (CRC) most often occurs sporadically (as compared to genetic forms of the disease) and is one of the leading causes of cancer-related death worldwide. Environmental factors contribute substantially to CRC risk and development, particularly the intestinal microbiota. Recent meta-analyses of gut microbial profiles in CRC have identified multiple taxa (including Fusobacterium) reproducibly associated with late-stage cancers across populations. However, neither the causal mechanisms nor corresponding microbial strains and small molecule products have been pinpointed for CRC, particularly among subsets of non-Fusobacterium clades newly associated with the disease. We leveraged stool metagenomic profiles from 352 CRC patients, 143 with pre-cancerous adenomas, and 312 healthy controls from seven recent CRC microbiome studies in combination with our integrated metagenomic and metatranscriptomic data from the Integrative Human Microbiome Project, Nurses’ Health Study, and Health Professionals Follow-Up Study. Within CRC-associated species, we assessed strain specific gene carriage and sub- species phylogenetic enrichments via gene- and variant-based culture-independent profiling. The former identified gene families carried significantly more or less frequently by individual strains during disease, and the latter called out subclades with significant phylogenetic associations with carcinogenesis. In some cases, these genes and nucleotide variants also corresponded with transcriptional changes. This study adds further evidence to the hypothesis that strain-level genomic variation in gut microbes may be a major driver in the initiation or development of colorectal cancer.