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Original article
Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis
  1. Kosuke Mima1,
  2. Reiko Nishihara1,2,3,4,
  3. Zhi Rong Qian1,
  4. Yin Cao2,3,
  5. Yasutaka Sukawa1,
  6. Jonathan A Nowak5,
  7. Juhong Yang1,6,
  8. Ruoxu Dou1,
  9. Yohei Masugi1,
  10. Mingyang Song2,3,
  11. Aleksandar D Kostic4,7,8,
  12. Marios Giannakis1,7,9,
  13. Susan Bullman1,7,
  14. Danny A Milner5,10,
  15. Hideo Baba11,
  16. Edward L Giovannucci2,3,12,
  17. Levi A Garraway1,7,9,
  18. Gordon J Freeman1,9,
  19. Glenn Dranoff1,9,13,
  20. Wendy S Garrett1,7,10,
  21. Curtis Huttenhower4,7,14,
  22. Matthew Meyerson1,5,7,
  23. Jeffrey A Meyerhardt1,
  24. Andrew T Chan12,15,
  25. Charles S Fuchs1,12,
  26. Shuji Ogino1,3,5
  1. 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
  2. 2Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  3. 3Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  4. 4Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  5. 5Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  6. 6Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
  7. 7Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
  8. 8Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  9. 9Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  10. 10Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  11. 11Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
  12. 12Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  13. 13Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  14. 14Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  15. 15Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Shuji Ogino, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Room M422, Boston, MA 02215 USA; shuji_ogino{at}dfci.harvard.edu

Abstract

Objective Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T cell-mediated immune responses against colorectal tumours. Thus, we hypothesised that the amount of F. nucleatum in colorectal carcinoma might be associated with worse clinical outcome.

Design We used molecular pathological epidemiology database of 1069 rectal and colon cancer cases in the Nurses’ Health Study and the Health Professionals Follow-up Study, and measured F. nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS, BRAF, and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation).

Results Compared with F. nucleatum-negative cases, multivariable HRs (95% CI) for colorectal cancer-specific mortality in F. nucleatum-low cases and F. nucleatum-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively, (p for trend=0.020). The amount of F. nucleatum was associated with MSI-high (multivariable odd ratio (OR), 5.22; 95% CI 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with F. nucleatum only in univariate analyses (p<0.001) but not in multivariate analysis that adjusted for MSI status.

Conclusions The amount of F. nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics.

  • CANCER EPIDEMIOLOGY
  • COLORECTAL CANCER
  • INTESTINAL BACTERIA
  • COLONIC BACTERIA
  • COLONIC MICROFLORA

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Footnotes

  • Contributors KM, RN, ZRQ and YC contributed equally as co first authors. JAM, ATC, CSF and SO contributed equally as co last authors. All authors contributed to review and revision. DAM, ELG, LAG, GJF, GD, WSG, CH MM, JAM, ATC, CSF and SO developed the main concept and designed the study. ATC, CSF and SO wrote grant applications. KM, RN, ZRQ, YC, YS, JY, RD, YM, MS, JAM, ATC, CSF and SO were responsible for collection of tumour tissue, and acquisition of epidemiological, clinical and tumour tissue data, including histopathological and immunohistochemical characteristics. KM, YS, ADK, MG, SB, DAM, WSG, CH, MM, CSF and SO performed data analysis and interpretation. KM, RN and SO drafted the manuscript. JAN, MS, MG, HB, ELG, GJF, GD, WSG, MM, JAM, ATC, CSF and SO contributed to editing and critical revision for important intellectual contents.

  • Funding This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to S E Hankinson; UM1 CA186107 to M J Stampfer; P01 CA55075 and UM1 CA167552 to W C Willett; P50 CA127003 to CSF; R01 CA137178 to ATC; R01 CA151993 and R35 CA197735 to SO; and K07 CA190673 to RN); and by grants from The Paula and Russell Agrusa Fund for Colorectal Cancer Research, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. KM is supported by a fellowship grant from Uehara Memorial Foundation and a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japanese Society for the Promotion of Science.

  • Disclaimer The authors assume full responsibility for analyses and interpretation of these data. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Competing interests ATC previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen and Pfizer. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, Pozen or Pfizer. MM applies a patent on Fusobacterium in colorectal cancer diagnosis, and has ownership interest in and is a consultant and advisory board member for Foundation Medicine.

  • Ethics approval The institutional review boards at the Harvard TH Chan School of Public Health and the Brigham and Women's Hospital (Boston, Massachusetts, USA).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Use of standardised official symbols: We use HUGO (Human Genome Organisation)-approved official symbols for genes and gene products, including APC, BRAF, CACNA1G, CDKN2A, CRABP1, IGF2, KRAS, MLH1, NEUROG1, PIK3CA, RUNX3, SLCO2A1 and SOCS1; all of which are described at www.genenames.org.

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