Tags

Type your tag names separated by a space and hit enter

Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.
Proc Natl Acad Sci U S A. 2019 11 26; 116(48):24285-24295.PN

Abstract

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.

Authors+Show Affiliations

EA7375 (EC2M3 Research Team), Université Paris Est, Créteil 94000, France; iradj.sobhani@aphp.fr philippe.sansonetti@pasteur.fr. Service de Gastroenterologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil 94000, France.EA7375 (EC2M3 Research Team), Université Paris Est, Créteil 94000, France. Unité de Pathogénie Microbienne Moléculaire, INSERM U1202, Institut Pasteur, Paris 75015, France.EA7375 (EC2M3 Research Team), Université Paris Est, Créteil 94000, France.EA7375 (EC2M3 Research Team), Université Paris Est, Créteil 94000, France. Service de Gastroenterologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil 94000, France.Service de Microbiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil 94000, France.Plateforme de Ressources Biologique, Hôpital Henri Mondor, Créteil 94000, France.Service de Chirurgie Digestive, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil 94000, France.Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris-Saclay, Jouy-en-Josas 78352, France.Service de Santé Publique, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil 94000, France.EA7375 (EC2M3 Research Team), Université Paris Est, Créteil 94000, France. Bioinformatics Core Lab, INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil 94000, France.Unité de Pathogénie Microbienne Moléculaire, INSERM U1202, Institut Pasteur, Paris 75015, France.Department of Immunology, Mayo Clinic, Rochester, MN 55905.Unité de Pathogénie Microbienne Moléculaire, INSERM U1202, Institut Pasteur, Paris 75015, France; iradj.sobhani@aphp.fr philippe.sansonetti@pasteur.fr. Chaire de Microbiologie et Maladies Infectieuses, Collège de France, Paris 75005, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31712445

Citation

Sobhani, Iradj, et al. "Colorectal Cancer-associated Microbiota Contributes to Oncogenic Epigenetic Signatures." Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 48, 2019, pp. 24285-24295.
Sobhani I, Bergsten E, Couffin S, et al. Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc Natl Acad Sci U S A. 2019;116(48):24285-24295.
Sobhani, I., Bergsten, E., Couffin, S., Amiot, A., Nebbad, B., Barau, C., de'Angelis, N., Rabot, S., Canoui-Poitrine, F., Mestivier, D., Pédron, T., Khazaie, K., & Sansonetti, P. J. (2019). Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proceedings of the National Academy of Sciences of the United States of America, 116(48), 24285-24295. https://doi.org/10.1073/pnas.1912129116
Sobhani I, et al. Colorectal Cancer-associated Microbiota Contributes to Oncogenic Epigenetic Signatures. Proc Natl Acad Sci U S A. 2019 11 26;116(48):24285-24295. PubMed PMID: 31712445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. AU - Sobhani,Iradj, AU - Bergsten,Emma, AU - Couffin,Séverine, AU - Amiot,Aurélien, AU - Nebbad,Biba, AU - Barau,Caroline, AU - de'Angelis,Nicola, AU - Rabot,Sylvie, AU - Canoui-Poitrine,Florence, AU - Mestivier,Denis, AU - Pédron,Thierry, AU - Khazaie,Khashayarsha, AU - Sansonetti,Philippe J, Y1 - 2019/11/11/ PY - 2019/11/13/pubmed PY - 2020/4/28/medline PY - 2019/11/13/entrez KW - biomarker KW - cancer KW - colon KW - gene methylation KW - microbiota SP - 24285 EP - 24295 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 116 IS - 48 N2 - Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/31712445/Colorectal_cancer_associated_microbiota_contributes_to_oncogenic_epigenetic_signatures_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=31712445 DB - PRIME DP - Unbound Medicine ER -