title: Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma.
abstract: OBJECTIVE
  Noninvasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early-stage PDAC from healthy individuals.
  
  
  METHODS
  Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples.
  
  
  RESULTS
  LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (CI), 0.84-0.94] in the training (70% of the data) and 0.92 (95% CI, 0.86-0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I-II (n = 71) with healthy urine specimens, the panel achieved AUCs of 0.90 (95% CI, 0.84-0.96) and 0.93 (95% CI, 0.84-1.00) in the training and validation datasets, respectively. In PDAC stage I-II and healthy samples with matching plasma CA19.9, the panel achieved a higher AUC of 0.97 (95% CI, 0.94-0.99) than CA19.9 (AUC = 0.88; 95% CI, 0.81-0.95, P = 0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95% CI, 0.94-0.99) to 0.99 (95% CI, 0.97-1.00, P = 0.04), but did not improve the comparison of stage I-IIA PDAC (n = 17) with healthy urine.
  
  
  CONCLUSIONS
  We have established a novel, three-protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Radon
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Nathalie J
authors.initials: NJ
authors.lastname: Massat
authors.affiliation: MS Bioworks, LLC, Ann Arbor, Michigan.
authors.forename: Richard
authors.initials: R
authors.lastname: Jones
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Wasfi
authors.initials: W
authors.lastname: Alrawashdeh
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Laurent
authors.initials: L
authors.lastname: Dumartin
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Darren
authors.initials: D
authors.lastname: Ennis
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Duffy
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.affiliation: Institute for Liver and Digestive Health, University College London, London, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.affiliation: Hospital General Universitari Vall Hebron, Barcelona, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Guarner posthumous
authors.affiliation: Hospital del Mar - Parc de Salut Mar, Barcelona, Spain.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Murta-Nascimento
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.affiliation: The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Neoptolemos
authors.affiliation: The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Nick R
authors.initials: NR
authors.lastname: Lemoine
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. t.c.jurcevic@qmul.ac.uk.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Crnogorac-Jurcevic
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000652:urine*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000652:urine; D014408:Biomarkers, Tumor / Q000652:urine*; D055088:Early Detection of Cancer; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051847:Lithostathine / Q000652:urine*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000652:urine*; D020543:Proteome / Q000235:genetics; D053719:Tandem Mass Spectrometry; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000652:urine*; D033921:Vesicular Transport Proteins / Q000652:urine*
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D014408:Biomarkers, Tumor; C119248:LYVE1 protein, human; D051847:Lithostathine; D020543:Proteome; C497617:REG1A protein, human; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; C578959:carbohydrate antigen 199, human