Saray Duran-Sanchon1, Lorena Moreno1, Josep M Augé2, Miquel Serra-Burriel3, Míriam Cuatrecasas4, Leticia Moreira1, Agatha Martín1, Anna Serradesanferm5, Àngels Pozo5, Rosa Costa1, Antonio Lacy6, Maria Pellisé1, Juan José Lozano7, Meritxell Gironella1, Antoni Castells8. 1. Gastroenterology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain. 2. Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain. 3. Center for Research in Health and Economics, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain. 4. Pathology Department and Tumour Bank-Biobank, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain. 5. Preventive Medicine and Hospital Epidemiology Department, Hospital Clínic, Barcelona, Catalonia, Spain. 6. Gastrointestinal Surgery Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain. 7. Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain. 8. Gastroenterology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain. Electronic address: castells@clinic.cat.
Abstract
BACKGROUND & AIMS: Screening for colorectal cancer (CRC) is effective in the population at average risk. The most extended strategy in organized programs involves the fecal immunochemical test, which is limited by low sensitivity for the detection of advanced adenomas (AAs). We aimed to identify microRNA (miRNA) signatures in fecal samples that identify patients with AAs or CRC and might be used in noninvasive screening. METHODS: Our study comprised 4 stages. In the discovery phase, we performed genome-wide miRNA expression profiling of 124 fresh, paired colorectal tumor and nontumor samples (30 CRC; 32 AAs) from patients in Spain. In the technical validation stage, miRNAs with altered expression levels in tumor vs nontumor tissues were quantified by reverse-transcription polymerase chain reaction in fecal samples from a subset of patients included in the discovery phase (n = 39) and individuals without colorectal neoplasms (controls, n = 39). In the clinical validation stage, the miRNAs found to be most significantly up-regulated by quantitative reverse transcription polymerase chain reaction analysis were measured in an independent set of fecal samples (n = 767) from patients with positive results from fecal immunochemical tests in a CRC screening program. Finally, we developed a model to identify patients with advanced neoplasms (CRCs or AAs) based on their miRNA profiles, using findings from colonoscopy as the reference standard. RESULTS: Among 200 and 324 miRNAs significantly deregulated in CRC and AA tissues, respectively, 7 and 5 of these miRNAs were also found to be deregulated in feces (technical validation). Of them, MIR421, MIR130b-3p, and MIR27a-3p were confirmed to be upregulated in fecal samples from patients with advanced neoplasms. In our model, the combination of fecal level of MIR421, MIR27a-3p, and hemoglobin identified patients with CRC with an area under the curve (AUC) of 0.93, compared with an AUC of 0.67 for fecal hemoglobin concentration alone. CONCLUSIONS: We found that increased levels of 2 miRNAs and hemoglobin in feces can identify patients with AAs or CRC more accurately than fecal hemoglobin concentration alone. Assays for these miRNAs might be added to fecal tests for the detection of CRC or AAs.
BACKGROUND & AIMS: Screening for colorectal cancer (CRC) is effective in the population at average risk. The most extended strategy in organized programs involves the fecal immunochemical test, which is limited by low sensitivity for the detection of advanced adenomas (AAs). We aimed to identify microRNA (miRNA) signatures in fecal samples that identify patients with AAs or CRC and might be used in noninvasive screening. METHODS: Our study comprised 4 stages. In the discovery phase, we performed genome-wide miRNA expression profiling of 124 fresh, paired colorectal tumor and nontumor samples (30 CRC; 32 AAs) from patients in Spain. In the technical validation stage, miRNAs with altered expression levels in tumor vs nontumor tissues were quantified by reverse-transcription polymerase chain reaction in fecal samples from a subset of patients included in the discovery phase (n = 39) and individuals without colorectal neoplasms (controls, n = 39). In the clinical validation stage, the miRNAs found to be most significantly up-regulated by quantitative reverse transcription polymerase chain reaction analysis were measured in an independent set of fecal samples (n = 767) from patients with positive results from fecal immunochemical tests in a CRC screening program. Finally, we developed a model to identify patients with advanced neoplasms (CRCs or AAs) based on their miRNA profiles, using findings from colonoscopy as the reference standard. RESULTS: Among 200 and 324 miRNAs significantly deregulated in CRC and AA tissues, respectively, 7 and 5 of these miRNAs were also found to be deregulated in feces (technical validation). Of them, MIR421, MIR130b-3p, and MIR27a-3p were confirmed to be upregulated in fecal samples from patients with advanced neoplasms. In our model, the combination of fecal level of MIR421, MIR27a-3p, and hemoglobin identified patients with CRC with an area under the curve (AUC) of 0.93, compared with an AUC of 0.67 for fecal hemoglobin concentration alone. CONCLUSIONS: We found that increased levels of 2 miRNAs and hemoglobin in feces can identify patients with AAs or CRC more accurately than fecal hemoglobin concentration alone. Assays for these miRNAs might be added to fecal tests for the detection of CRC or AAs.