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Plasma miRNA-based signatures in CRC screening programs
Authors:Susanna Zanutto  Chiara Maura Ciniselli  Antonino Belfiore  Mara Lecchi  Enzo Masci  Gabriele Delconte  Massimo Primignani  Giulia Tosetti  Marco Dal Fante  Linda Fazzini  Aldo Airoldi  Marcello Vangeli  Francesca Turpini  Giovanni Giuseppe Rubis Passoni  Paolo Viaggi  Monica Arena  Roberta Ilaria Olimpia Motta  Anna Maria Cantù  Cristiano Crosta  Giuseppe De Roberto  Francesca Iannuzzi  Andrea Cassinotti  Valentina Dall'Olio  Laura Tizzoni  Gabriella Sozzi  Emanuele Meroni  Luigi Bisanti  Marco Alessandro Pierotti  Paolo Verderio  Manuela Gariboldi
Affiliation:1. Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;2. Bioinformatics and Biostatistics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;3. Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;4. CRC “A. M. e A. Migliavacca” Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy;5. Gastroenterology and Endoscopy Unit, Humanitas San Pio X, Milan, Italy;6. Hepatology and Gastroenterology Unit, Niguarda Ca' Granda Hospital, Milan, Italy;7. Digestive Endoscopy Unit, Department of Gastro Hepatology, ASST Santi Paolo e Carlo, San Carlo Borromeo Hospital, Milan, Italy;8. Digestive Endoscopy Unit, ASST Santi Paolo e Carlo, San Paolo Hospital, Milan, Italy;9. Gastroenterology and Digestive Endoscopy Service - Casa di Cura Igea, Milan, Italy;10. Laboratory Medicine Service - Casa di Cura Igea, Milan, Italy;11. Division of Endoscopy, European Institute of Oncology IRCCS, Milan, Italy;12. Gastrointestinal Unit - ASST Fatebenefratelli Sacco, Milan, Italy;13. Cogentech srl Società Benefit, Milan, Italy;14. Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;15. Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;16. Molecular Genetics of Cancer Unit, Fondazione Istituto FIRC Oncologia Molecolare (IFOM), Milan, Italy

Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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.
Keywords:colorectal cancer  miRNA  early diagnosis  screening program
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