Associations between the gut microbiome and colorectal cancer (CRC) have been uncovered, but larger and more diverse studies are needed to assess their potential clinical use. We expanded upon 12 metagenomic datasets of patients with CRC (n = 930), adenomas (n = 210) and healthy control individuals (n = 976; total n = 2,116) with 6 new cohorts (n = 1,625) providing granular information on cancer stage and the anatomic location of tumors. We improved CRC prediction accuracy based solely on gut metagenomics (average area under the curve = 0.85) and highlighted the contribution of 19 newly profiled species and distinct Fusobacterium nucleatum clades. Specific gut species distinguish left-sided versus right-sided CRC (area under the curve = 0.66) with an enrichment of oral-typical microbes. We identified strain-specific CRC signatures with the commensal Ruminococcus bicirculans and Faecalibacterium prausnitzii showing subclades associated with late-stage CRC. Our analysis confirms that the microbiome can be a clinical target for CRC screening and characterizes it as a biomarker for CRC progression.

• MeSH
• adenom mikrobiologie   patologie   genetika   MeSH
• Faecalibacterium prausnitzii genetika   MeSH
• feces * mikrobiologie   MeSH
• Fusobacterium nucleatum genetika   MeSH
• kohortové studie MeSH
• kolorektální nádory * mikrobiologie   patologie   genetika   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metagenom * genetika   MeSH
• metagenomika metody   MeSH
• nádorové biomarkery * genetika   MeSH
• Ruminococcus genetika   MeSH
• senioři MeSH
• střevní mikroflóra * genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové biomarkery * MeSH

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis. METHODS: In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples. RESULTS: Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR. CONCLUSIONS: These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.

• Klíčová slova
• Adenoma, Circular RNAs, Colorectal cancer, Precancerous lesions, RNA-binding proteins, RNA-sequencing,
• Publikační typ
• časopisecké články MeSH