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.

• Publikační typ
• časopisecké články MeSH

Long-term dysbiosis of the gut microbiome has a significant impact on colorectal cancer (CRC) progression and explains part of the observed heterogeneity of the disease. Even though the shifts in gut microbiome in the normal-adenoma-carcinoma sequence were described, the landscape of the microbiome within CRC and its associations with clinical variables remain under-explored. We performed 16S rRNA gene sequencing of paired tumour tissue, adjacent visually normal mucosa and stool swabs of 178 patients with stage 0-IV CRC to describe the tumour microbiome and its association with clinical variables. We identified new genera associated either with CRC tumour mucosa or CRC in general. The tumour mucosa was dominated by genera belonging to oral pathogens. Based on the tumour microbiome, we stratified CRC patients into three subtypes, significantly associated with prognostic factors such as tumour grade, sidedness and TNM staging, BRAF mutation and MSI status. We found that the CRC microbiome is strongly correlated with the grade, location and stage, but these associations are dependent on the microbial environment. Our study opens new research avenues in the microbiome CRC biomarker detection of disease progression while identifying its limitations, suggesting the need for combining several sampling sites (e.g., stool and tumour swabs).

• Publikační typ
• časopisecké články MeSH

Odpověď na imunoterapii může být ve srovnání s chemoterapií opožděná a může se dostavit i po přechodném zvětšení nádoru nebo po objevení se nových nádorových lézí. Podle standardních evaluačních kritérií (WHO nebo RECIST) by taková odpověď byla hodnocena jako progrese onemocnění. Výsledky klinických studií s některými inhibitory tyrozinkináz, s použitím protinádorových vakcín a zejména s použitím protilátek proti antigenu CTLA-4 ukázaly objektivní odpověď nebo stabilizaci choroby u nemocných, přestože došlo k přechodnému zvětšení nádoru nebo se objevily nové léze. Proto byla navržena nová pravidla pro hodnocení účinku imunoterapie (irRC – immune-related response criteria).

Clinical response to immunotherapy may extend beyond those to cytotoxic agents and can manifest even after initial increaskse in tumor burden or the appearance of new lesions. Using the standard (WHO or RECIST) evaluation criteria, such response would be classified as progressive disease. Results of clinical trials with some tyrosine kinase inhibitors, anticancer vaccines and particularly with anti-CTLA-4 antibodies have shown an objective response or stable disease in patients in spite of temporary increase in tumor burden or the appearance of new lesions. That is why new guidelines for the evaluation of immune therapy activity have been proposed (based on the irRC - immune-related response criteria).

• Klíčová slova
• solidní nádory, sipuleucel-T, tremelimumab,
• MeSH
• chemorezistence imunologie   účinky léků   MeSH
• imunoterapie klasifikace   metody   MeSH
• indukce remise metody   MeSH
• ipilimumab MeSH
• lidé MeSH
• monoklonální protilátky imunologie   klasifikace   terapeutické užití   MeSH
• nádory farmakoterapie   MeSH
• progrese nemoci MeSH
• protinádorové vakcíny klasifikace   terapeutické užití   MeSH
• tyrosinkinasy antagonisté a inhibitory   imunologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH