title: Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.
abstract: OBJECTIVE
  Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated.
  
  
  METHODS
  Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS,n= 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n= 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n= 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model.
  
  
  RESULTS
  iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively;P< 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P< 0.05) and patients with benign biliary obstruction (P< 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P< 0.05) and at clinical diagnosis (P< 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P< 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P= 0.01).
  
  
  CONCLUSIONS
  Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Jenkinson
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Elliott
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Evans
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Oldfield
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: Rosalind E
authors.initials: RE
authors.lastname: Jenkins
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.
authors.forename: Darragh P
authors.initials: DP
authors.lastname: O'Brien
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Apostolidou
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gentry-Maharaj
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.
authors.forename: Evangelia-O
authors.initials: EO
authors.lastname: Fourkala
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.|Faculty of Medical & Human Sciences, 1.018 Core Technology Facility, University of Manchester, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Cox
authors.affiliation: Department of Pathology, University of Liverpool, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.affiliation: Institute for Liver and Digestive Health, University College London.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Timms
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK.|National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000150:complications / Q000175:diagnosis; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004195:Disease Models, Animal; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000150:complications / Q000175:diagnosis* / Q000401:mortality; D063868:Patient Outcome Assessment; D010976:Platelet Count; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D019700:Thrombospondin 1 / Q000097:blood*; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D019700:Thrombospondin 1