Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis
Kosuke Mima, Reiko Nishihara, Zhi Rong Qian, Yin Cao, Yasutaka Sukawa, Jonathan A Nowak, Juhong Yang, Ruoxu Dou, Yohei Masugi, Mingyang Song, Aleksandar D Kostic, Marios Giannakis, Susan Bullman, Danny A Milner, Hideo Baba, Edward L Giovannucci, Levi A Garraway, Gordon J Freeman, Glenn Dranoff, Wendy S Garrett, Curtis Huttenhower, Matthew Meyerson, Jeffrey A Meyerhardt, Andrew T Chan, Charles S Fuchs, Shuji Ogino, Kosuke Mima, Reiko Nishihara, Zhi Rong Qian, Yin Cao, Yasutaka Sukawa, Jonathan A Nowak, Juhong Yang, Ruoxu Dou, Yohei Masugi, Mingyang Song, Aleksandar D Kostic, Marios Giannakis, Susan Bullman, Danny A Milner, Hideo Baba, Edward L Giovannucci, Levi A Garraway, Gordon J Freeman, Glenn Dranoff, Wendy S Garrett, Curtis Huttenhower, Matthew Meyerson, Jeffrey A Meyerhardt, Andrew T Chan, Charles S Fuchs, Shuji Ogino
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.
Keywords: CANCER EPIDEMIOLOGY; COLONIC BACTERIA; COLONIC MICROFLORA; COLORECTAL CANCER; INTESTINAL BACTERIA.
Conflict of interest statement
Dr. Chan previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen Inc, and Pfizer Inc. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, Pozen Inc, or Pfizer Inc. Dr. Meyerson 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. The other authors declare that they have no competing interests.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Source: PubMed