Abstract
The functions and biomarker potential of circular RNAs (circRNAs) in various cancer types are a rising field of study, as emerging evidence relates circRNAs to tumorigenesis. Here, we profiled the expression of circRNAs in 457 tumors from patients with non-muscle-invasive bladder cancer (NMIBC). We show that a set of highly expressed circRNAs have conserved core splice sites, are associated with Alu repeats, and enriched with Synonymous Constraint Elements as well as microRNA target sites. We identified 113 abundant circRNAs that are differentially expressed between high and low-risk tumor subtypes. Analysis of progression-free survival revealed 13 circRNAs, among them circHIPK3 and circCDYL, where expression correlated with progression independently of the linear transcript and the host gene. In summary, our results demonstrate that abundant circRNAs possess multiple biological features, distinguishing them from low-expressed circRNAs and non-circularized exons, and suggest that circRNAs might serve as a new class of prognostic biomarkers in NMIBC.
Highlights
Circular RNA derived from precursor mRNA is a large class of non-coding RNA that was first identified in the early 1990s.1 Since thousands of circRNAs in mammalian cells have been reported, some of which are highly abundant and conserved among species.[2,3,4] They are characterized by a covalently closed circular structure, formed in a process where a downstream donor splice site “backsplices” to an upstream acceptor splice site.[5]
Some wellstudied circRNAs are able to sponge microRNAs as shown for ciRS-7, circ-SRY, and circHIPK3.2,7,8 Other circRNAs can interact with RNA-binding proteins, such as circMbl that affects splicing by binding Mbl protein[9] and circFoxo[3] that blocks cell cycle progression by forming a ternary complex with p21 and CDK2.10 Recently, studies have suggested that some circRNAs are translated into proteins, e.g., circZNF609 and circMbl3.11,12 Other examples have been reviewed recently.[13,14]
Since patients diagnosed with nonmuscle-invasive bladder cancer (NMIBC) are routinely monitored due to the risk of tumor recurrence and progression, Bladder cancer (BC) is one of the most expensive cancer types to treat measured on a per-patient cost from diagnosis to death.[23]
Summary
Circular RNA (circRNA) derived from precursor mRNA is a large class of non-coding RNA that was first identified in the early 1990s.1 Since thousands of circRNAs in mammalian cells have been reported, some of which are highly abundant and conserved among species.[2,3,4] They are characterized by a covalently closed circular structure, formed in a process where a downstream donor splice site “backsplices” to an upstream acceptor splice site.[5]. Patients with muscle-invasive BC (MIBC) have a survival rate of ~50%,21 which further drops to ~5% in the presence of distant metastasis.[22] Since patients diagnosed with NMIBC are routinely monitored due to the risk of tumor recurrence and progression, BC is one of the most expensive cancer types to treat measured on a per-patient cost from diagnosis to death.[23] Identification of biomarkers that can predict the outcome of patients diagnosed with NMIBC, e.g., disease recurrence, progression, and death, would be cost effective and beneficial to clinicians in order to improve prognosis and treatment response of patients Due to their structural stability, specificity, and accessibility, circRNAs may represent an attractive new class of biomarkers. Clinical annotation backsplicespanning read pre-mRNA linear spliced read annotated circRNAs
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