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Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers.

ABSTRACT: Colorectal cancer (CRC) is the most frequently occurring malignancy in the world. However, the mortality from CRC can be reduced through early diagnostics, selection of the most effective treatment, observation of the therapy success, and the earliest possible diagnosis of recurrences. A comprehensive analysis of genetic and epigenetic factors contributing to the CRC development is needed to refine diagnostic, therapeutic, and preventive strategies and to ensure appropriate decision making in managing specific CRC cases. The liquid biopsy approach utilizing circulating markers has demonstrated its good performance as a tool to detect the changes in the molecular pathways associated with various cancers. In this review, we attempted to brief the main tendencies in the development of circulating DNA and RNA-based markers in CRC such as cancer-associated DNA mutations, DNA methylation changes, and non-coding RNA expression shifts. Attention is devoted to the existing circulating nucleic acid-based CRC markers, the possibility of their application in clinical practice today, and their future improvement. Approaches to the discovery and verification of new markers are described, and the existing problems and potential solutions for them are highlighted.

SUBMITTER: Ponomaryova AA

PROVIDER: S-EPMC10419249 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers.

Ponomaryova Anastasia A AA Rykova Elena Yu EY Solovyova Anastasia I AI Tarasova Anna S AS Kostromitsky Dmitry N DN Dobrodeev Alexey Yu AY Afanasiev Sergey A SA Cherdyntseva Nadezhda V NV

International journal of molecular sciences 20230803 15

Colorectal cancer (CRC) is the most frequently occurring malignancy in the world. However, the mortality from CRC can be reduced through early diagnostics, selection of the most effective treatment, observation of the therapy success, and the earliest possible diagnosis of recurrences. A comprehensive analysis of genetic and epigenetic factors contributing to the CRC development is needed to refine diagnostic, therapeutic, and preventive strategies and to ensure appropriate decision making in ma ...[more]

PMID: 37569782

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Project description:AimThe study was designed to assess the possibility of using circulating miRNAs (serum miRNAs) as diagnostic biomarkers in colorectal cancer (CRC) and to identify their possibility as candidates for targeted therapy.MethodsThe study involved two sample sets: 1- a training set which included 90 patients with colorectal related disease (30 with CRC, 18 with inflammatory bowel disease (IBD), 18 with colonic polyps (CP) and 24 with different colonic symptoms but without any colonoscopic abnormality who were enrolled as control group) and 2- a validation set which included 100 CRC patients. Serum miRNAs were extracted from all subjects to assess the expression profiles for the following miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-146a, miR-223, miR-24, miR-454, miR-183, miR-135a, miR- 135b and miR- 92a) using the custom miScript miRNA PCR-based sybergreen array. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of the studied miRNAs for colorectal cancer diagnosis.ResultsData analysis of miRNA from the training set showed that; compared to control group, only miR-19b was significantly up-regulated in patients with IBD group (fold change = 5.24, p = 0.016), whereas in patients with colonic polyps, miR-18a was significantly up-regulated (fold change = 3.49, p-value = 0.018). On the other hand, miR-17, miR-19a, miR-20a and miR-223 were significantly up-regulated (fold change = 2.35, 3.07, 2.38 and 10.35; respectively and p-value = 0.02, 0.015, 0.017 and 0.016; respectively in CRC patients. However, the validation set showed that only miR-223 was significantly up-regulated in CRC patients (fold change = 4.06, p-value = 0.04).ConclusionAberrant miRNA expressions are highly involved in the cascade of colorectal carcinogenesis. We have found that (miR-17, miR-19a, miR-20a and miR-223) could be used as diagnostic biomarkers for CRC. On the other hand, miR-19b and miR-18a could be used as diagnostic biomarkers for CP and IBD respectively.

Project description:BackgroundIt remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC).Patients and methodsWe carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]).ResultsIn multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04).ConclusionsOur results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

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Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers.

Publications

Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers.

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