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. 2022 Jan;31(1):210-220.
doi: 10.1158/1055-9965.EPI-21-0463. Epub 2021 Nov 4.

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

Ivan Borozan #  1 , Syed H Zaidi #  1 , Tabitha A Harrison  2 , Amanda I Phipps  2 , Jiayin Zheng  2 , Stephen Lee  1 , Quang M Trinh  1 , Robert S Steinfelder  2 , Jeremy Adams  1 , Barbara L Banbury  2 , Sonja I Berndt  3 , Stefanie Brezina  4 , Daniel D Buchanan  5   6   7   8 , Susan Bullman  9 , Yin Cao  10   11 , Alton B Farris 3rd  12 , Jane C Figueiredo  13 , Marios Giannakis  14   15 , Lawrence E Heisler  1 , John L Hopper  6 , Yi Lin  2 , Xuemei Luo  1 , Reiko Nishihara  16   17   18 , Elaine R Mardis  19 , Nickolas Papadopoulos  20 , Conghui Qu  2 , Emma E G Reid  1 , Stephen N Thibodeau  21 , Sophia Harlid  22 , Caroline Y Um  23 , Li Hsu  2   24 , Andrea Gsur  4 , Peter T Campbell  23 , Steven Gallinger  1   25   26 , Polly A Newcomb  2   27 , Shuji Ogino  14   17   28   29   30 , Wei Sun  2 , Thomas J Hudson  1 , Vincent Ferretti  31   32 , Ulrike Peters  33   27
Affiliations

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

Ivan Borozan et al. Cancer Epidemiol Biomarkers Prev. 2022 Jan.

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.

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Conflict of interest statement

Conflict of interests:

Daniel Buchanan served as a consultant on the Tumour Agnostic (dMMR) Advisory Board of Merck Sharp and Dohme in 2017 and 2018 for Pembrolizumab. Reiko Nishihara’s current employer is Pfizer, Inc. Her contribution to this work was prior to employment at Pfizer, Inc. M. Giannakis receives research funding from Bristol-Myers Squibb and Merck. Nickolas Papadopoulos is a co-founder of, holds equity in, and is a consultant to Thrive Earlier Detection and Personal Genome Diagnostics. He is on the Thrive Earlier Detection Board of Directors and is a consultant to and holds equity in NeoPhore. Sysmex, Qiagen, Invitae, Personal Genome Diagnostics, PapGene, Thrive Earlier Detection, Horizon Discovery, Thermo FIsher, and other companies, have licensed previously described technologies from Johns Hopkins University. Nickolas Papadopoulos is an inventor on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors, as well as to Johns Hopkins University. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict-of-interest policies.

Figures

Figure 1.
Figure 1.. F nucleatum DNA abundance detected in 1994 colorectal cancer tumors.
F nucleatum DNA abundance in units of parts per million (ppm) detected in 206 colorectal tumor DNA samples with minimum abundance ≥ 0.5 ppm. The F nucleatum subspecies are shown in different colors.
Figure 2.
Figure 2.. Percent of sequencing reads mapping to Fusobacterium species and subspecies.
A total of 206 colorectal cancer tumors positive for F nucleatum were used in the plots.
Figure 3.
Figure 3.. Adjusted survival curves for colorectal cancer-specific survival based on Cox models.
(A) According to the presence of F nucleatum DNA in colorectal cancer tissues adjusted for sex, age at diagnosis, tumor site, hypermutation status, tumor burden, mutations in POLE, TP53, and ERBB3 and MSI. (B) According to the presence of F nucleatum DNA in colorectal cancer tissues adjusted for sex, age at diagnosis, tumor site, hypermutation status, tumor burden, mutations in POLE, TP53, and ERBB3, MSI, and tumor stage. (C) According to the presence of F nucleatum subspecies DNA in colorectal cancer tissues adjusted for sex, age at diagnosis, tumor site, hypermutation status, tumor burden, mutations in POLE, TP53, and ERBB3, and MSI. (D) According to the presence of F nucleatum subspecies DNA in colorectal cancer tissues adjusted for sex, age at diagnosis, tumor site, hypermutation status, tumor burden, mutations in POLE, TP53, and ERBB3, MSI, and tumor stage. P-values resulting from the multivariate analyses are shown on the plots. Pointwise confidence intervals are based on 1000 bootstrapping samples.
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Comment in

  • Selected Articles from This Issue.
    [No authors listed] [No authors listed] Cancer Epidemiol Biomarkers Prev. 2022 Jan;31(1):1. doi: 10.1158/1055-9965.EPI-31-1-HI. Cancer Epidemiol Biomarkers Prev. 2022. PMID: 35017191 No abstract available.

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