Identifying strain-specific associations in colorectal cancer

Colorectal cancer (CRC) is the second most commonly diagnosed malignancy in women and the third in men, and accounts for around 10% of all deaths related to cancer. The progression from healthy intestinal cells, to benign tumors (adenomas), and then to more malignant forms has profound impacts on the composition of the intestinal microbiota. Additionally, the factors influencing this progression are idiopathic but likely involve a combination of genetics, local tumor environment, and extrinsic factors such as diet. Here, we focus on further elucidating the role of the gut microbiome, a large component of the tumor microenvironment, in cancer initiation and progression by considerably expanding on the current largest meta-analysis to include a total of 3,558 samples from 17 public and private studies. Through expanded sample size, increased resolution of the computational tools, and bioinformatic advances we have improved the understanding of the gut ecosystem in CRC. We found several taxa from the Solobacterium group and Clostridia groups enriched in CRC, and several unknown taxa enriched in healthy individuals. However, as has recently been observed with pks+ E. coli, while species-level identification does provide valuable insights; strain-level resolution can often provide the most actionable downstream targets and help to further elucidate the basic biology of the system. Thus, we developed ANPAN, a collection of statistical methods for microbial strain analysis that can identify associations between several different types of microbial genetic variation and host health outcomes (particularly CRC). This collection of methods includes gene-level, phylogenetic, and pathway-level models. When applied to our dataset, the gene model identified 26 transposases or transposable elements associated with CRC status across 16 species, potentially indicating a role for these genes in helping the microbes acquire other genetic elements necessary to adapt to the inflammatory microenvironment of the CRC gut. Meanwhile, the phylogenetic model identifies strong species-wide phylogenetic signals in several species, including species’ typically found to be CRC-associated: Ruminococcus gnavus, Clostridium leptum, Bacteroides fragilis, which could indicate these species have clades with variable CRC risk.