Abstract
Simple SummaryColon cancer (CC) is one of the most common types of cancer. Circular RNAs (circRNAs) appear to play an important role in tumor progression of CC. They are stably expressed in saliva, blood, and exosomes, potentially rendering them promising biomarkers for the diagnosis, prognosis, and treatment of CC. In this study we describe the identification of an extensive catalog of circRNAs in a large cohort of 181 chemonaive, stage I/II primary colon tumors and related circRNA expression to consensus molecular subtypes (CMS), microsatellite instability (MSI) status and clinical outcome. We observed that a high diversity in circRNAs was associated with favorable disease-free survival, and that several circRNAs were associated with MSI and CMS, demonstrating the potential clinical value of circRNAs in CC.Circular RNAs (circRNAs) appear important in tumor progression of colon cancer (CC). We identified an extensive catalog of circRNAs in 181 chemonaive stage I/II colon tumors, who underwent curative surgery between 2007 and 2014. We identified circRNAs from RNAseq data, investigated common biology related to circRNA expression, and studied the association between circRNAs and relapse status, tumor stage, consensus molecular subtypes (CMS), tumor localization and microsatellite instability (MSI). We identified 2606 unique circRNAs. 277 circRNAs (derived from 260 genes) were repeatedly occurring in at least 20 patients of which 153 showed a poor or even negative (R < 0.3) correlation with the expression level of their linear gene. The circular junctions for circSATB2, circFGD6, circKMT2C and circPLEKHM3 were validated by Sanger sequencing. Multiple correspondence analysis showed that circRNAs were often co-expressed and that high diversity in circRNAs was associated with favorable disease-free survival (DFS), which was confirmed by Cox regression analysis (Hazard Ratio (HR) 0.60, 95% CI 0.38–0.97, p = 0.036). Considering individual circRNAs, absence of circMGA was significantly associated with relapse, whereas circSATB2, circNAB1, and circCEP192 were associated with both MSI and CMS. This study represents a showcase of the potential clinical utility of circRNAs for prognostic stratification in patients with stage I–II colon cancer and demonstrated that high diversity in circRNAs is associated with favorable DFS.
Highlights
In this study we describe the identification of an extensive catalog of circRNAs in a large cohort of 181 chemonaive, stage I/II primary colon tumors and related these to tumor stage, localization, Consensus Molecular subtypes (CMS), microsatellite instability (MSI) status and clinical outcome
Molecules in a sample) we found that a high diversity in circRNAs is associated with a favorable disease-free survival (DFS): Cox regression using circRNA diversity as continuous variable: Hazard Ratio (HR) 0.60, 95% CI 0.38–0.97, p = 0.036
In the studied cohort of chemonaive lymph node negative colon cancer patients, a first highlight was the finding that high diversity of circRNAs present in colon cancer tissue was associated with favorable DFS
Summary
Colon cancer is one of the most common types of cancer with over 1 million new cases worldwide and around 9800 new cases in the Netherlands in 2018 [1]. Recent studies have shown that non-coding microRNAs can function as promising biomarkers for stage II [10,11] and stage I–II colon cancer patients [12]. Increasing evidence shows that circRNAs can function as miRNA sponges, transcription regulators, and interfere with splicing, as well [20] They are conserved, abundant and often exhibit tissue-, developmental-, and stage-specific expression [24,25]. Compared to conventional available cancer biomarkers (e.g., PSA and CEA), circRNAs are expected to have higher sensitivity and specificity in diagnosis and prognosis [28] Taken together, these characteristics indicate that circRNAs could represent new clinical diagnostic and prognostic markers, and possibly provide new leads for the treatment of diseases. In this study we describe the identification of an extensive catalog of circRNAs in a large cohort of 181 chemonaive, stage I/II primary colon tumors and related these to tumor stage, localization, Consensus Molecular subtypes (CMS), microsatellite instability (MSI) status and clinical outcome
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