Fusobacterium in Colonic Flora and Molecular Features of Colorectal Carcinoma

Abstract

Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified over-representation of Fusobacterium in colorectal cancer (CRC) tissues but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fusobacterium status and molecular features in CRCs through quantitative real-time PCR in 149 CRC tissues, 89 adjacent normal appearing mucosae and 72 colonic mucosae from cancer-free individuals. Results were correlated with CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI) and mutations in BRAF, KRAS, TP53, CHD7 and CHD8. Whole exome capture sequencing data were also available in 11 cases. Fusobacterium was detectable in 111/149 (74%) CRC tissues and heavily enriched in 9% (14/149) of the cases. As expected, Fusobacterium was also detected in normal appearing mucosae from both cancer and cancer-free individuals but the amount of bacteria was much lower compared to CRC tissues (a mean of 250-fold lower for Pan-fusobacterium). We found the Fusobacterium-high CRC group (FB-high) to be associated with CIMP positivity (p=0.001), TP53 wild type (p=0.015), hMLH1 methylation positivity (p=0.0028), MSI (p=0.018) and CHD7/8 mutation positivity (p=0.002). Among the 11 cases where whole exome sequencing data was available, two that were FB-high cases also had the highest number of somatic mutations (a mean of 736 per case in FB-high vs. 225 per case in all others). Taken together, our findings show that Fusobacterium enrichment is associated with specific molecular subsets of CRCs, offering support for a pathogenic role in CRC for this gut microbiome component

Gut microbiome compositional and functional differences between tumor and non-tumor adjacent tissues from cohorts from the US and Spain

“…Fusobacterium has been associated with colorectal tumors and adenomas in several recent studies. 27,31,[61][62][63][64][65] In the present study, Fusobacterium was significantly over represented in tumor compared to adjacent tissues in the Spanish cohort, while in the US, this phylum was more abundant in both tissues compared to the Spanish cohort, but enriched specifically in tumors in splenic flexure, sigmoid and rectum. More studies are needed to assess the biological significance of these results, which could be related to the ability of these microorganisms to form and maintain biofilms in specific locations of the large intestine as recently shown.…”

Expression of DNA methyltransferases and target microRNAs in human tissue samples related to sporadic colorectal cancer

“…During the past decade, an emerging notion that the contributions of the TME to carcinogenesis must be considered in the biology of neoplasms (16), revealing an important role of local tissue microenvironment involving in the formation of tumor-associated stroma in tumorigenesis. To date, several studies have found that altered tissue microenvironment has an effect on colorectal carcinogenesis, and epigenetic changes function as a key player in cellular response to the alteration of microenvironment (46)(47)(48), which are consistent with our results revealing the histologically altered morphologies of tissues with different distance to CRC lesions, loss of normal crypts and existence of many ACf in no. 3, however, tissues no.…”

Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer

“…Inter-patient heterogeneity in tumor immunity result from genetic background involved in carcinogenesis, such as mismatch repair gene deficiency and POLE mutation, and personal disease-modifying factors, such as composition of intestinal bacterial flora 15,16) , smoking status and pre-existing disease. These factors of inter-patient heterogeneity were previously evaluated by analyzing therapeutic response data, clustering analysis preceded by DNA microarray analysis, and whole exome sequencing which revealed DNA mutation load found in each patient ( Table 1) .…”