Decreased serum thrombospondin-1 levels in pancreatic cancer patients up to 24 months prior to clinical diagnosis: association with diabetes mellitus

Jenkinson, C., Elliott, V., Evans, A., Oldfield, L., Jenkins, R. E., O'Brien, D. P., Apostolidou, S., Gentry-Maharaj, A., Fourkala, E. O., Jacobs, I., Menon, U., Cox, T. F., Campbell, F., Pereira, S. P., Tuveson, D. A., Park, P. K., Greenhalf, W., Sutton, R. Professor, Timms, J. F., Neoptolemos, J., Costello, E. (April 2016) Decreased serum thrombospondin-1 levels in pancreatic cancer patients up to 24 months prior to clinical diagnosis: association with diabetes mellitus. Clin Cancer Res, 22 (7). pp. 1734-43. ISSN 1078-0432 (Electronic)1078-0432 (Linking)

DOI: 10.1158/1078-0432.ccr-15-0879


PURPOSE: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with pre-clinical disease and at diagnosis were investigated. EXPERIMENTAL DESIGN: 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). iTRAQ enabled comparisons of pooled serum from a test set (n=150). Validation was undertaken using 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 & 0.77 respectively; P<0.01). TSP-1 was also decreased in PDAC patients compared to healthy controls (P<0.05) and patients with benign biliary obstruction (P<0.01). Low levels of TSP-1 correlated with poorer survival, pre-clinically (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 observed in PDAC patients with diabetes compared to individuals with type 2 DM (P=0.01). CONCLUSIONS: Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behaviour should be considered in future studies.

Item Type: Paper
Subjects: diseases & disorders > nutritional and metabolic diseases > diabetes
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Matt Covey
Date: 1 April 2016
Date Deposited: 19 Nov 2015 20:45
Last Modified: 22 Oct 2020 21:12
PMCID: PMC4820087
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