Plasma miRNA-based Signatures in CRC Screening Programs.

Zanutto S1,2, Ciniselli CM3, Belfiore A1,4, Lecchi M3, Masci E5, Delconte G5, Primignani M6, Tosetti G6, Dal Fante M7, Fazzini L7, Airoldi A8, Vangeli M8, Turpini F9, Rubis Passoni GG9, Viaggi P10, Arena M10, Motta RIO11, Cantù AM12, Crosta C13, De Roberto G13, Iannuzzi F14, Cassinotti A14, Dall'Olio V15, Tizzoni L15, Sozzi G1, Meroni E5, Bisanti L16, Pierotti MA2,16, Verderio P3, Gariboldi M1,2.

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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, 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 ROC curve (95%CI) of the signatures were respectively 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL. 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. This article is protected by copyright. All rights reserved.