title: Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma.
abstract: Currently, the majority of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) present with locally invasive and/or metastatic disease, resulting in five-year survival of less than 5%. The development of an early diagnostic test is, therefore, expected to significantly impact the patient's prognosis. In this study, we successfully evaluated the feasibility of identifying diagnostic cell free microRNAs (miRNAs) for early stage PDAC, through the analysis of urine samples. Using Affymetrix microarrays, we established a global miRNA profile of 13 PDAC, six chronic pancreatitis (CP), and seven healthy (H) urine specimens. Selected differentially expressed miRNAs were subsequently investigated using an independent technique (RT-PCR) on 101 urine samples including 46 PDAC, 29 CP and 26 H. Receiver operating characteristic (ROC) and logistic regression analyses were applied to determine the discriminatory potential of the candidate miRNA biomarkers. Three miRNAs (miR-143, miR-223, and miR-30e) were significantly over-expressed in patients with Stage I cancer when compared with age-matched healthy individuals (P=0.022, 0.035 and 0.04, respectively); miR-143, miR-223 and miR-204 were also shown to be expressed at higher levels in Stage I compared to Stages II-IV PDAC (P=0.025, 0.013 and 0.008, respectively). Furthermore, miR-223 and miR-204 were able to distinguish patients with early stage cancer from patients with CP (P=0.037 and 0.036). Among the three biomarkers, miR-143 was best able to differentiate Stage I (n=6) from healthy (n=26) with area under the curve (AUC) of 0.862 (95% CI 0.695-1.000), with sensitivity (SN) of 83.3% (95% CI 50.0-100.0), and specificity (SP) of 88.5% (95% CI 73.1-100.0). The combination of miR-143 with miR-30e was significantly better at discriminating between these two groups, achieving an AUC of 0.923 (95% CI 0.793-1.000), with SN of 83.3% (95% CI 50.0-100.0) and SP of 96.2% (95% CI 88.5-100.0). In this feasibility study, we demonstrate for the first time the utility of miRNA biomarkers for non-invasive, early detection of PDAC in urine specimens.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Silvana
authors.initials: S
authors.lastname: Debernardi
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London London, UK.
authors.forename: Nathalie J
authors.initials: NJ
authors.lastname: Massat
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Radon
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Ajanthah
authors.initials: A
authors.lastname: Sangaralingam
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Banissi
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Ennis
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dowe
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Institute for Liver and Digestive Health, University College London London, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of LondonLondon, UK; Barts and The London HPB Centre, Barts Health NHS Trust, Royal London HospitalLondon, UK.
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.affiliation: Barts and The London HPB Centre, Barts Health NHS Trust, Royal London Hospital London, UK.
authors.forename: Giles
authors.initials: G
authors.lastname: Bond-Smith
authors.affiliation: Barts and The London HPB Centre, Barts Health NHS Trust, Royal London Hospital London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Hutchins
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London London, UK.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Crnogorac-Jurcevic
keywords: Pancreatic ductal adenocarcinoma; diagnostic biomarkers; miR-143; miR-204; miR-223; miR-30e; urine