Tumor microbial biodiversity and microsatellite instability in colorectal cancer

Growing evidence links the gut microbiome to colorectal cancer (CRC) progression, with certain bacterial species enriched in specific molecular tumor subtypes. DNA mismatch repair deficiency in CRC, evidenced by the presence of microsatellite instability (MSI), has been consistently associated with a favorable prognosis, and may be related to certain aspects of the microbiome. Here, we examined the relationship between tumor microbial biodiversity and MSI status.

Diagnostic tumor tissue samples were obtained from the Seattle site of the Colon Cancer Family Registry (SCCFR) and a companion study; both recruited patients diagnosed with incident CRC from 1998 to 2007. MSI status assessment and prokaryotic 16S rRNA gene sequencing was performed on the tumor tissue samples. We used an adaptive test of alpha-diversity (aMiAD) to estimate the association between microbial biodiversity and MSI status. We performed differential abundance analysis with ANCOM-BC to identify enriched genera in tumor tissue, based on dichotomized MSI status. Analyses were adjusted for age, sex, smoking history, and tumor location (N = 632).

The adaptive aMiAD effect estimate was -1.08 (p = 0.29), suggesting that MSI-high tumors had lower estimated alpha-diversity, though this difference was not statistically significant. We identified 20 differentially abundant genera in CRC tumors according to MSI status, with 8 enriched genera and 12 depleted genera in MSI-high tumors. The most strongly enriched genera in MSI-high tumors were Gemella and Lawsonella, while Sporolactobacillaceae and Cloacibacterium were the most strongly depleted. Fusobacterium was enriched in MSI-high tumors only after subsetting the genus to Fusobacterium nucleatum specific sequences.

We did not detect a statistically significant association between the adaptive alpha-diversity measure and MSI status, though individual measures concordantly estimated a depletion of alpha-diversity in the MSI-high tumors. We found evidence of differential abundance of certain genera dependent on MSI status, including several novel associations.