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Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.
Gut. 2016 12; 65(12):1973-1980.Gut

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.

Authors+Show Affiliations

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Collaborative 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.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26311717

Citation

Mima, Kosuke, et al. "Fusobacterium Nucleatum in Colorectal Carcinoma Tissue and Patient Prognosis." Gut, vol. 65, no. 12, 2016, pp. 1973-1980.
Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 2016;65(12):1973-1980.
Mima, K., Nishihara, R., Qian, Z. R., Cao, Y., Sukawa, Y., Nowak, J. A., Yang, J., Dou, R., Masugi, Y., Song, M., Kostic, A. D., Giannakis, M., Bullman, S., Milner, D. A., Baba, H., Giovannucci, E. L., Garraway, L. A., Freeman, G. J., Dranoff, G., ... Ogino, S. (2016). Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut, 65(12), 1973-1980. https://doi.org/10.1136/gutjnl-2015-310101
Mima K, et al. Fusobacterium Nucleatum in Colorectal Carcinoma Tissue and Patient Prognosis. Gut. 2016;65(12):1973-1980. PubMed PMID: 26311717.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. AU - Mima,Kosuke, AU - Nishihara,Reiko, AU - Qian,Zhi Rong, AU - Cao,Yin, AU - Sukawa,Yasutaka, AU - Nowak,Jonathan A, AU - Yang,Juhong, AU - Dou,Ruoxu, AU - Masugi,Yohei, AU - Song,Mingyang, AU - Kostic,Aleksandar D, AU - Giannakis,Marios, AU - Bullman,Susan, AU - Milner,Danny A, AU - Baba,Hideo, AU - Giovannucci,Edward L, AU - Garraway,Levi A, AU - Freeman,Gordon J, AU - Dranoff,Glenn, AU - Garrett,Wendy S, AU - Huttenhower,Curtis, AU - Meyerson,Matthew, AU - Meyerhardt,Jeffrey A, AU - Chan,Andrew T, AU - Fuchs,Charles S, AU - Ogino,Shuji, Y1 - 2015/08/26/ PY - 2015/06/02/received PY - 2015/07/27/revised PY - 2015/08/08/accepted PY - 2015/8/28/pubmed PY - 2017/8/2/medline PY - 2015/8/28/entrez KW - CANCER EPIDEMIOLOGY KW - COLONIC BACTERIA KW - COLONIC MICROFLORA KW - COLORECTAL CANCER KW - INTESTINAL BACTERIA SP - 1973 EP - 1980 JF - Gut JO - Gut VL - 65 IS - 12 N2 - 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. SN - 1468-3288 UR - https://www.unboundmedicine.com/medline/citation/26311717/Fusobacterium_nucleatum_in_colorectal_carcinoma_tissue_and_patient_prognosis_ L2 - https://gut.bmj.com/lookup/pmidlookup?view=long&amp;pmid=26311717 DB - PRIME DP - Unbound Medicine ER -