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Fusobacterium nucleatum and Clinicopathologic Features of Colorectal Cancer: Results From the ColoCare Study

Published:February 27, 2021DOI:https://doi.org/10.1016/j.clcc.2021.02.007

      Abstract

      Background

      Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood.

      Patients and Methods

      We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naïve CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models.

      Results

      Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival.

      Conclusion

      Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naïve CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.

      Keywords

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      References

        • Bray F
        • Ferlay J
        • Soerjomataram I
        • Siegel RL
        • Torre LA
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Kostic AD
        • Chun E
        • Robertson L
        • et al.
        Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment.
        Cell Host Microbe. 2013; 14: 207-215
        • Brennan CA
        • Garrett WS.
        Fusobacterium nucleatum - symbiont, opportunist and oncobacterium.
        Nat Rev Microbiol. 2019; 17: 156-166
        • Gursoy UK
        • Kononen E
        • Uitto VJ.
        Intracellular replication of fusobacteria requires new actin filament formation of epithelial cells.
        APMIS. 2008; 116: 1063-1070
        • Kostic AD
        • Gevers D
        • Pedamallu CS
        • et al.
        Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.
        Genome Res. 2012; 22: 292-298
        • Castellarin M
        • Warren RL
        • Freeman JD
        • et al.
        Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.
        Genome Res. 2012; 22: 299-306
        • Komiya Y
        • Shimomura Y
        • Higurashi T
        • et al.
        Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity.
        Gut. 2019; 68: 1335-1337
        • Gethings-Behncke C
        • Coleman HG
        • Jordao HWT
        • et al.
        Fusobacterium nucleatum in the colorectum and its association with cancer risk and survival: a systematic review and meta-analysis.
        Cancer Epidemiol Biomarkers Prev. 2020; 29: 539-548
        • Tunsjo HS
        • Gundersen G
        • Rangnes F
        • Noone JC
        • Endres A
        • Bemanian V.
        Detection of Fusobacterium nucleatum in stool and colonic tissues from Norwegian colorectal cancer patients.
        Eur J Clin Microbiol Infect Dis. 2019; 38: 1367-1376
        • Roy S
        • Trinchieri G.
        Microbiota: a key orchestrator of cancer therapy.
        Nat Rev Cancer. 2017; 17: 271-285
        • Ianiro G
        • Tilg H
        • Gasbarrini A.
        Antibiotics as deep modulators of gut microbiota: between good and evil.
        Gut. 2016; 65: 1906-1915
        • Gevers D
        • Kugathasan S
        • Denson LA
        • et al.
        The treatment-naive microbiome in new-onset Crohn's disease.
        Cell Host Microbe. 2014; 15: 382-392
        • Ulrich CM
        • Gigic B
        • Bohm J
        • et al.
        The ColoCare study: a paradigm of transdisciplinary science in colorectal cancer outcomes.
        Cancer Epidemiol Biomarkers Prev. 2019; 28: 591-601
        • Himbert C
        • Ose J
        • Nattenmuller J
        • et al.
        Body fatness, adipose tissue compartments, and biomarkers of inflammation and angiogenesis in colorectal cancer: the ColoCare study.
        Cancer Epidemiol Biomarkers Prev. 2019; 28: 76-82
        • Bacchetti De Gregoris T
        • Aldred N
        • Clare AS
        • Burgess JG.
        Improvement of phylum- and class-specific primers for real-time PCR quantification of bacterial taxa.
        J Microbiol Methods. 2011; 86: 351-356
        • Mima K
        • Cao Y
        • Chan AT
        • et al.
        Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location.
        Clin Transl Gastroenterol. 2016; 7: e200
        • Mima K
        • Nishihara R
        • Qian ZR
        • et al.
        Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.
        Gut. 2016; 65: 1973-1980
        • Oh HJ
        • Kim JH
        • Bae JM
        • Kim HJ
        • Cho NY
        • Kang GH.
        Prognostic impact of Fusobacterium nucleatum depends on combined tumor location and microsatellite instability status in stage II/III colorectal cancers treated with adjuvant chemotherapy.
        J Pathol Transl Med. 2019; 53: 40-49
        • Ito M
        • Kanno S
        • Nosho K
        • et al.
        Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway.
        Int J Cancer. 2015; 137: 1258-1268
        • Tahara T
        • Yamamoto E
        • Suzuki H
        • et al.
        Fusobacterium in colonic flora and molecular features of colorectal carcinoma.
        Cancer Res. 2014; 74: 1311-1318
        • Gupta VK
        • Paul S
        • Dutta C.
        Geography, ethnicity or subsistence-specific variations in human microbiome composition and diversity.
        Front Microbiol. 2017; 8: 1162
        • McCoy AN
        • Araujo-Perez F
        • Azcarate-Peril A
        • Yeh JJ
        • Sandler RS
        • Keku TO.
        Fusobacterium is associated with colorectal adenomas.
        PLoS One. 2013; 8: e53653
        • Gao R
        • Kong C
        • Huang L
        • et al.
        Mucosa-associated microbiota signature in colorectal cancer.
        Eur J Clin Microbiol Infect Dis. 2017; 36: 2073-2083
        • Serna G
        • Ruiz-Pace F
        • Hernando J
        • et al.
        Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.
        Ann Oncol. 2020; 31: 1366-1375
        • Brenner H
        • Kloor M
        • Pox CP.
        Colorectal cancer.
        Lancet. 2014; 383: 1490-1502
        • Murphy N
        • Ward HA
        • Jenab M
        • et al.
        Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study.
        Clin Gastroenterol Hepatol. 2019; 17 (1323–31.e6)
        • Holowatyj AN
        • Lewis MA
        • Pannier ST
        • et al.
        Clinicopathologic and racial/ethnic differences of colorectal cancer among adolescents and young adults.
        Clin Transl Gastroenterol. 2019; 10: e00059
        • White A
        • Ironmonger L
        • Steele RJC
        • Ormiston-Smith N
        • Crawford C
        • Seims A.
        A review of sex-related differences in colorectal cancer incidence, screening uptake, routes to diagnosis, cancer stage and survival in the UK.
        BMC Cancer. 2018; 18: 906
        • Bogaert J
        • Prenen H.
        Molecular genetics of colorectal cancer.
        Ann Gastroenterol. 2014; 27: 9-14
        • Wirbel J
        • Pyl PT
        • Kartal E
        • et al.
        Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer.
        Nat Med. 2019; 25: 679-689
        • Guo S
        • Li L
        • Xu B
        • et al.
        A simple and novel fecal biomarker for colorectal cancer: ratio of Fusobacterium nucleatum to probiotics populations, based on their antagonistic effect.
        Clin Chem. 2018; 64: 1327-1337
        • Ohigashi S
        • Sudo K
        • Kobayashi D
        • et al.
        Changes of the intestinal microbiota, short chain fatty acids, and fecal pH in patients with colorectal cancer.
        Dig Dis Sci. 2013; 58: 1717-1726
        • Chew J
        • Zilm PS
        • Fuss JM
        • Gully NJ.
        A proteomic investigation of Fusobacterium nucleatum alkaline-induced biofilms.
        BMC Microbiol. 2012; 12: 189
        • Mima K
        • Sukawa Y
        • Nishihara R
        • et al.
        Fusobacterium nucleatum and T cells in colorectal carcinoma.
        JAMA Oncol. 2015; 1: 653-661
        • Liu L
        • Tabung FK
        • Zhang X
        • et al.
        Diets that promote colon inflammation associate with risk of colorectal carcinomas that contain Fusobacterium nucleatum.
        Clin Gastroenterol Hepatol. 2018; 16 (1622–31.e3)
        • Mehta RS
        • Nishihara R
        • Cao Y
        • et al.
        Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue.
        JAMA Oncol. 2017; 3: 921-927