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

Author(s):Show less -

Thomas, Andrew Maltez ^{[1, 2, 3]} ; Manghi, Paolo ^{[2, 3]} ; Asnicar, Francesco ^[2] ; Pasolli, Edoardo ^[2] ; Armanini, Federica ^[2] ; Zolfo, Moreno ^[2] ; Beghini, Francesco ^[2] ; Manara, Serena ^[2] ; Karcher, Nicolai ^[2] ; Pozzi, Chiara ^[4] ; Gandini, Sara ^[4] ; Serrano, Davide ^[4] ; Tarallo, Sonia ^[5] ; Francavilla, Antonio ^[5] ; Gallo, Gaetano ^{[6, 7]} ; Trompetto, Mario ^[7] ; Ferrero, Giulio ^[8] ; Mizutani, Sayaka ^{[9, 10]} ; Shiroma, Hirotsugu ^[9] ; Shiba, Satoshi ^[11] ; Shibata, Tatsuhiro ^{[11, 12]} ; Yachida, Shinichi ^{[11, 13]} ; Yamada, Takuji ^{[9, 14]} ; Wirbel, Jakob ^[15] ; Schrotz-King, Petra ^{[16, 17]} ; Ulrich, Cornelia M. ^{[18, 19]} ; Brenner, Hermann ^{[20, 16, 17, 21]} ; Arumugam, Manimozhiyan ^{[22, 23]} ; Bork, Peer ^{[24, 15, 25, 26]} ; Zeller, Georg ^[15] ; Cordero, Francesca ^[8] ; Dias-Neto, Emmanuel ^{[27, 3]} ; Setubal, Joao Carlos ^{[1, 28]} ; Tett, Adrian ^[2] ; Pardini, Barbara ^{[29, 5]} ; Rescigno, Maria ^[30] ; Waldron, Levi ^{[31, 32]} ; Naccarati, Alessio ^{[5, 33]} ; Segata, Nicola ^[2]

Affiliation:Show less -

^[1] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil

^[2] Univ Trento, Dept CIBIO, Trento - Italy

^[3] CIPE AC Camargo Canc Ctr, Med Genom Lab, Sao Paulo - Brazil

^[4] European Inst Oncol, Milan - Italy

^[5] Italian Inst Genom Med, Turin - Italy

^[6] Univ Catanzaro, Dept Surg & Med Sci, Catanzaro - Italy

^[7] Clin S Rita, Dept Colorectal Surg, Vercelli - Italy

^[8] Univ Turin, Dept Comp Sci, Turin - Italy

^[9] Tokyo Inst Technol, Sch Life Sci & Technol, Tokyo - Japan

^[10] Japan Soc Promot Sci, Tokyo - Japan

^[11] Natl Canc Ctr, Res Inst, Div Canc Genom, Tokyo - Japan

^[12] Univ Tokyo, Inst Med Sci, Human Genome Ctr, Tokyo - Japan

^[13] Osaka Univ, Dept Canc Genome Informat, Osaka - Japan

^[14] Japan Sci & Technol Agcy, PRESTO, Saitama - Japan

^[15] European Mol Biol Lab, Struct & Computat Biol Unit, Heidelberg - Germany

^[16] German Canc Res Ctr, Heidelberg - Germany

^[17] Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg - Germany

^[18] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT - USA

^[19] Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT - USA

^[20] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg - Germany

^[21] German Canc Res Ctr, German Canc Consortium, Heidelberg - Germany

^[22] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen - Denmark

^[23] Univ Southern Denmark, Fac Hlth Sci, Odense - Denmark

^[24] Max Delbruck Ctr Mol Med, Berlin - Germany

^[25] Mol Med Partnership Unit, Heidelberg - Germany

^[26] Univ Wurzburg, Bioctr, Dept Bioinformat, Wurzburg - Germany

^[27] Univ Sao Paulo, Inst Psychiat, Lab Neurosci, Sao Paulo - Brazil

^[28] Virginia Tech, Biocomplex Inst, Blacksburg, VA - USA

^[29] Univ Turin, Dept Med Sci, Turin - Italy

^[30] Humanitas Res Hosp, Mucosal Immunol & Microbiota Unit, Milan - Italy

^[31] CUNY, Grad Sch Publ Hlth & Hlth Policy, New York, NY 10021 - USA

^[32] CUNY, Inst Implementat Sci Populat Hlth, New York, NY 10021 - USA

^[33] Inst Expt Med, Dept Mol Biol Canc, Prague - Czech Republic

• Document type: Journal article
• Source: Nature Medicine; v. 25, n. 4, p. 667+, APR 2019.
• Web of Science Citations: 24

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 trimethylaminelyase 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. (AU)

• FAPESP's process: 14/26897-0 - Epidemiology and genomics of gastric adenocarcinomas in Brazil
• Grantee: Emmanuel Dias-Neto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/23527-2 - Identification of microbial biomarkers for colorectal cancer using strain-level metagenomic profiling
• Grantee: Andrew Maltez Thomas
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate