Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis

Abstract

Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer–specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer–specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer–specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07–3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer–specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer–specific mortality and specific somatic mutated genes. Impact: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

Identification and characterization of four bacteriome- and mycobiome-derived subtypes in tumour and adjacent mucosa tissue of colorectal cancer patients

“…The microbial subtypes were associated with distinct prognosis and clinical patient phenotypes such as staging, tumour location, history, lymphovascular invasion and TP53 status. Interestingly, we did not observe an association between the microbial subtypes with microsatellite instability, CMS-[39] and CRIS-[40] subtypes, despite observing such a relationship with individual families, particularly Bacteroidaceae and Fusobacteriaceae, as previously reported [11,33,42]. These findings further underscore the orthogonal value of microbial fingerprinting in addition to transcriptomic-based subtyping and more conventional stratification signatures and clinical markers.…”

“…On-tumour tissue was enriched with Fusobacteria , Proteobacteria , Basidyomicota and depleted of Bacteroidetes , Firmicutes , Ascomycota compared with adjacent off-tumour mucosa. Abundance of Fusobacteria , largely from the Fusobacteriaceae family and Fusobacterium nucleatum species, have been implicated in the aetiology [12,31,41], clinical phenotype [11,33,34,42] such as tumour location, microsatellite instability, assignment to transcriptome-based molecular subtyping, clinico-pathological features, therapy response [32,43] and, ultimately, clinical outcome [11,33,44]. This study identified a depletion of Firmicutes, driven by Clostridia, but not Bacilli, and Bacteroidetes, driven by Bacteroidia, but not Flavobacteriia, corroborating findings in the CRC settings [45].…”

“…Fusobacterium_nucleatum associated with distinct molecular characteristics and patients prognosis in CRC tumours [1,[10][11][12][13][31][32][33][34].…”

The cancer chemotherapeutic 5-fluorouracil is a potent inhibitor of Fusobacterium nucleatum and its activity is modified by the intratumoral microbiota

“…nucleatum ( Fnn ), animalis ( Fna ), polymorphum ( Fnp ), vincentii/fusiforme ( Fnv ) 24,25 . Fna is the most prevalent subspecies found in CRC in epidemiological studies 26,27 , and we therefore sampled Fna at a higher frequency (10/14 isolates tested). We confirmed that 5-FU is a potent growth inhibitor of CRC Fn isolates representing all four subspecies, suggesting that 5-FU sensitivity is a core feature of Fn species (Figure 2B).…”

Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science

“…CRC containing F. nucleatum is characterised by proximal tumour localisation, BRAF mutation, high-level microsatellite instability, high-level CpG island methylator phenotype,27–29 decreased CD3 + CD4 + CD45RO (PTPRC) + cells30 and increased tumour-associated macrophages 31. Specifically, F. nucleatum subspecies animalis may play a role in most of these associations 32…”