Dataset Information

Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.

ABSTRACT:

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.

SUBMITTER: Jenkinson C

PROVIDER: S-EPMC4820087 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Publications

Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.

Jenkinson Claire C Elliott Victoria L VL Evans Anthony A Oldfield Lucy L Jenkins Rosalind E RE O'Brien Darragh P DP Apostolidou Sophia S Gentry-Maharaj Aleksandra A Fourkala Evangelia-O EO Jacobs Ian J IJ Menon Usha U Cox Trevor T Campbell Fiona F Pereira Stephen P SP Tuveson David A DA Park B Kevin BK Greenhalf William W Sutton Robert R Timms John F JF Neoptolemos John P JP Costello Eithne E

Clinical cancer research : an official journal of the American Association for Cancer Research 20151116 7

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 healt ...[more]

PMID: 26573598

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Project description:Purpose: Using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial samples, we identified cell-free DNA (cfDNA) biomarker candidate genes bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that detect occult colorectal cancer (CRC) up to 36 mo prior to clinical diagnosis. Methods: PLCO study subjects were matched by age, race, and sex as cases (n = 201, diagnosed with CRC within 36 mo of blood collection) and controls (n = 402, no cancer diagnosis on follow-up, average 16.3 years after entering the study). Archived plasma samples (300 µL per study subject) were obtained from the National Cancer Institute (NCI), and we employed the sensitive 5hmC-Seal chemical labeling approach on 3 - 8 ng of extracted cfDNA. Following next-generation sequencing (NGS) and genome-wide mapping of 5hmC, we then conducted association studies and machine-learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio. Results: Robust genome-wide 5hmC profiles were successfully obtained from these decades-old samples. Association analyses using the Cox proportional hazards models suggested several epigenetic pathways relevant to CRC development distinguishing cases from controls. A weighted Cox model, comprised of 32-associated gene bodies, showed predictive detection value for CRC as early as 24-36 mo prior to overt tumor diagnosis. Furthermore, a trend for increased predictive power was observed for blood samples collected closer to CRC diagnosis. Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and self-reported race/ethnicity, and significantly outperformed risk factors such as age and obesity assessed as BMI (body mass index). Conclusion: An assay and machine learning modeling of 5hmC epigenetic signals on cfDNA revealed candidate biomarkers and a scoring algorithm with the potential to predict CRC occurrence despite the absence of clinical symptoms or the availability of effective predictors. Developing a minimally-invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient outcomes. Future investigations to expand this strategy to prospectively collected samples are warranted.

Dataset Information

Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.

Purpose

Experimental design

Results

Conclusions

Publications

Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.

Similar Datasets

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