TY  - JOUR
ID  - discovery1478233
N2  - PURPOSE: 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. 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). 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.
SN  - 1078-0432
UR  - http://dx.doi.org/10.1158/1078-0432.CCR-15-0879
JF  - Clinical Cancer Research
A1  - Jenkinson, C
A1  - Elliott, VL
A1  - Evans, A
A1  - Oldfield, L
A1  - Jenkins, RE
A1  - O'Brien, DP
A1  - Apostolidou, S
A1  - Gentry-Maharaj, A
A1  - Fourkala, EO
A1  - Jacobs, IJ
A1  - Menon, U
A1  - Cox, T
A1  - Campbell, F
A1  - Pereira, SP
A1  - Tuveson, DA
A1  - Park, BK
A1  - Greenhalf, W
A1  - Sutton, R
A1  - Timms, JF
A1  - Neoptolemos, JP
A1  - Costello, E
TI  - Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus
EP  - 1743
VL  - 22
AV  - public
SP  - 1734
Y1  - 2016/04//
N1  - Copyright © 2015 American Association for Cancer Research. The final, published version of the article is available on the AACR journal website at http://dx.doi.org/10.1158/1078-0432.CCR-15-0879
IS  - 7
ER  -