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Nat Med. 2019 Apr;25(4):667-678. doi: 10.1038/s41591-019-0405-7. Epub 2019 Apr 1.

Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation.

Author information

1
Department CIBIO, University of Trento, Trento, Italy.
2
Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, Brazil.
3
Medical Genomics Laboratory, CIPE/A.C. Camargo Cancer Center, São Paulo, Brazil.
4
European Institute of Oncology, Milan, Italy.
5
Italian Institute for Genomic Medicine, Turin, Italy.
6
Department of Surgical and Medical Sciences, University of Catanzaro, Catanzaro, Italy.
7
Department of Colorectal Surgery, Clinica S. Rita, Vercelli, Italy.
8
Department of Computer Science, University of Turin, Turin, Italy.
9
School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
10
Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.
11
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
12
Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
13
Department of Cancer Genome Informatics, Osaka University, Osaka, Japan.
14
PRESTO, Japan Science and Technology Agency, Saitama, Japan.
15
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
16
Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
17
Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
18
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
19
German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
20
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
21
Faculty of Healthy Sciences, University of Southern Denmark, Odense, Denmark.
22
Molecular Medicine Partnership Unit, Heidelberg, Germany.
23
Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
24
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
25
Laboratory of Neurosciences, Institute of Psychiatry, University of São Paulo, São Paulo, Brazil.
26
Biocomplexity Institute of Virginia Tech, Blacksburg, VA, USA.
27
Department of Medical Sciences, University of Turin, Turin, Italy.
28
Mucosal Immunology and Microbiota Unit, Humanitas Research Hospital, Milan, Italy.
29
Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA.
30
Institute for Implementation Science in Population Health, City University of New York, New York, NY, USA.
31
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Prague, Czech Republic.
32
Department CIBIO, University of Trento, Trento, Italy. nicola.segata@unitn.it.

Abstract

Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.

PMID:
30936548
DOI:
10.1038/s41591-019-0405-7

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