Plasma miRNA‐based signatures in CRC screening programs

Abstract

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT‐positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real‐time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low‐grade adenoma [LgA], high‐grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two‐miRNA‐based signature for CL and six‐miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607–0.682), 0.670 (0.626–0.714) and 0.682 (0.580–0.785) for LgA, HgA and CL, respectively. A miRNA‐based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.

A Five-microRNA Signature as Prognostic Biomarker in Colorectal Cancer by Bioinformatics Analysis

“…However, overwhelming studies manifested that multiple miRNA signature have bigger advantages than single miRNA on the hand of statistically robust analysis. Thence before our study, there have been a lot of prognostic markers based on multiple miRNA signature in tumors (24–26), especially colorectal cancer (9, 10, 27). There are many differences between our research and previous studies yet, such as research methods, sample size, and most importantly, we use miRNA matures and sample groupings to validate the model.…”

Analysis of A 6-Mirna Signature in Serum from Colorectal Cancer Screening Participants as Non-Invasive Biomarkers for Advanced Adenoma and Colorectal Cancer Detection

“…Moreover, it is noteworthy that in this study all the serum samples were obtained from CRC screening participants and, therefore, the CRC cohort has a greater presence of early stages, mainly stage I. It is important to highlight a recent study also carried out in FIT-positive screening participants discovering and validating three miRNA signatures in plasma from patients with CRC, high-grade adenomas and low-grade adenomas, respectively [31]. Although differences may exist between serum and plasma miRNA profiles, as well as using different centrifugation speeds, it is important to mention that those signatures and ours share one miRNA (i.e., miR-335-5p).…”

Circulating let-7e-5p, miR-106a-5p, miR-28-3p, and miR-542-5p as a Promising microRNA Signature for the Detection of Colorectal Cancer

“…The authors categorized miRNA signatures as specific for low-grade adenoma, high-grade adenoma, or cancerous lesions. Interestingly, they found increased expression of some miRNAs in high-grade adenomas but reduced expression of the same in low-grade adenomas and cancerous lesions [24]. Such an approach diverges from ours, since we propose identifying miRNAs that are progressively expressed along with the carcinogenic process.…”

“…Considering that changes in miRNAs expression are expected during tumor development [35], a tumor signature essentially must be validated as a whole and bear the diagnostic power of their units combined. In line with that, Zanutto and colleagues proposed a plasma miRNA-based test associated with the fecal immunochemical test to identify patients that could benefit from subsequent colonoscopy [24]. The authors categorized miRNA signatures as specific for low-grade adenoma, high-grade adenoma, or cancerous lesions.…”

“…Although many studies propose detecting miRNA signatures for early CRC diagnosis [18][19][20][21][22][23][24], several limitations are observed, such as reduced coverage for miRNA screening [19,22], variable signatures for different disease stages [24], absence of noncancer groups [20], or lack of data validation. Additionally, some of these studies analyzed only one miRNA as a biomarker [25], miRNA allied with inflammatory mediators [23], or miRNA expression without testing the signature's power [18,21,[26][27][28].…”