Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 48; pp. 24285 - 24295
• Main Authors: Sobhani, Iradj, Bergsten, Emma, Couffin, Séverine, Amiot, Aurélien, Nebbad, Biba, Barau, Caroline, de’Angelis, Nicola, Rabot, Sylvie, Canoui-Poitrine, Florence, Mestivier, Denis, Pédron, Thierry, Khazaie, Khashayarsha, Sansonetti, Philippe J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.11.2019
• Subjects: Animals; Biological Sciences; Biomarkers; Blood; Blood levels; Cancer; Cohort Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - microbiology; Deoxyribonucleic acid; DNA; DNA Methylation; DNA sequencing; Dysbacteriosis; Dysbiosis - genetics; Dysbiosis - microbiology; Dysbiosis - pathology; Environmental stress; Epigenesis, Genetic; Epigenetics; Fecal Microbiota Transplantation; Feces; Feces - microbiology; Female; Frizzled-related protein 1; Gastrointestinal Microbiome - genetics; Gene Expression Regulation; Genes; Germ-Free Life; Germfree; Humans; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Life Sciences; Male; Methylation; Mice, Inbred C3H; Microbiota; Mucosa; Multivariate analysis; Neuropeptide Y; Promoter Regions, Genetic; Promoters; Risk analysis; Risk factors; RNA, Ribosomal, 16S; microbiota; colon; cancer; biomarker; gene methylation
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1912129116

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.