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

Authors

Ivan Borozan; Syed H. Zaidi; Tabitha A. Harrison; Amanda I. Phipps; Jiayin Zheng; Stephen Lee; Quang M. Trinh; Robert S. Steinfelder; Jeremy Adams; Barbara L. Banbury; Sonja I. Berndt; Stefanie Brezina; Daniel D. Buchanan; Susan Bullman; Yin Cao; Alton B. Farris, III; Jane C. Figueiredo; Marios Giannakis; Lawrence E. Heisler; John L. Hopper; Yi Lin; Xuemei Luo; Reiko Nishihara; Elaine R. Mardis; Nickolas Papadopoulos; Conghui Qu; Emma E.G. Reid; Stephen N. Thibodeau; Sophia Harlid; Caroline Y. Um; Li Hsu; Andrea Gsu; Peter T. Campbell; Steven Gallinger; Polly A. Newcomb; Shuji Ogino; Wei Sun; Thomas J. Hudson; Vincent Ferretti; Ulrike Peters

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.