Pilot Study of Blood Biomarker Candidates for Detection of Pancreatic Cancer

Chen, Ru; Crispin, David A.; Pan, Sheng; Hawley, Sarah T.; McIntosh, Martin W.; May, Damon; Anton‐Culver, Hoda; Ziogas, Argyrios; Bronner, Mary P.; Brentnall, Teresa A.

doi:10.1097/mpa.0b013e3181dac920

Cited by 25 publications

(20 citation statements)

References 23 publications

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“…While the performance of the CA19-9 ELISA in this study (AUC 0.57) was not as robust as some reports in the literature, TIMP1 and ICAM biomarkers still performed better than the recently reported CA19-9 AUC of 0.716 66 . Lastly, these data show the importance of testing pancreatic cancer biomarkers on chronic pancreatitis controls as we reported previously 14;67 : many biomarker candidates lost some accuracy when distinguishing chronic pancreatitis and pancreatic cancer – a phenomenon that is frequently seen in pancreatic cancer biomarker candidates.…”

Section: Resultssupporting

confidence: 71%

Protein Alterations Associated with Pancreatic Cancer and Chronic Pancreatitis Found in Human Plasma using Global Quantitative Proteomics Profiling

et al. 2011

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Pancreatic cancer is a lethal disease that is difficult to diagnose at early stages when curable treatments are effective. Biomarkers that can improve current pancreatic cancer detection would have great value in improving patient management and survival rate. A large scale quantitative proteomics study was performed to search for the plasma protein alterations associated with pancreatic cancer. The enormous complexity of the plasma proteome and the vast dynamic range of protein concentration therein present major challenges for quantitative global profiling of plasma. To address these challenges, multi-dimensional fractionation at both protein and peptide levels was applied to enhance the depth of proteomics analysis. Employing stringent criteria, more than thirteen hundred proteins total were identified in plasma across 8-orders of magnitude in protein concentration. Differential proteins associated with pancreatic cancer were identified, and their relationship with the proteome of pancreatic tissue and pancreatic juice from our previous studies was discussed. A subgroup of differentially expressed proteins was selected for biomarker testing using an independent cohort of plasma and serum samples from well-diagnosed patients with pancreatic cancer, chronic pancreatitis and non-pancreatic disease controls. Using ELISA methodology, the performance of each of these protein candidates was benchmarked against CA19-9, the current gold standard for a pancreatic cancer blood test. A composite marker of TIMP1 and ICAM1 demonstrate significantly better performance than CA19-9 in distinguishing pancreatic cancer from the non-pancreatic disease controls and chronic pancreatitis controls. In addition, protein AZGP1 was identified as a biomarker candidate for chronic pancreatitis. The discovery and technical challenges associated with plasma-based quantitative proteomics are discussed and may benefit the development of plasma proteomics technology in general. The protein candidates identified in this study provide a biomarker candidate pool for future investigations.

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Section: Resultssupporting

confidence: 71%

Protein Alterations Associated with Pancreatic Cancer and Chronic Pancreatitis Found in Human Plasma using Global Quantitative Proteomics Profiling

et al. 2011

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“…We tested combinations of 2, 3, or 4 biomarker candidates using “and” and “or” rules 27;37 . At 95% specificity, the combination of gelsolin and lumican using an “and” rule achieved 80% sensitivity, an improvement of 5% over the top performing single marker candidate, gelsolin (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Multiplex Targeted Proteomic Assay for Biomarker Detection in Plasma: A Pancreatic Cancer Biomarker Case Study

Pan¹,

Chen²,

Brand

et al. 2012

J. Proteome Res.

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Biomarkers are most frequently proteins that are measured in the blood. Their development largely relies on antibody creation to test the protein candidate performance in blood samples of diseased versus non-diseased patients. The creation of such antibody assays has been a bottleneck in biomarker progress due to the cost, extensive time and effort required to complete the task. Targeted proteomics is an emerging technology that is playing an increasingly important role to facilitate disease biomarker development. In this study, we applied a SRM-based targeted proteomics platform to directly detect candidate biomarker proteins in plasma to evaluate their clinical utility for pancreatic cancer detection. The characterization of these protein candidates used a clinically well-characterized cohort that included plasma samples from patients with pancreatic cancer, chronic pancreatitis and healthy age-matched controls. Three of the five candidate proteins, including gelsolin, lumican and tissue inhibitor of metalloproteinase 1, demonstrated an AUC value greater than 0.75 in distinguishing pancreatic cancer from the controls. In addition, we provide an analysis of the reproducibility, accuracy, and robustness of the SRM-based proteomics platform. This information addresses important technical issues that could aid in the adoption of the targeted proteomics platform for practical clinical utility.

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“…Future studies of methylation marker panels for pancreatic cancer detection will also need to include diseased controls, such as patients with chronic pancreatitis, early in the development process. 40 …”

Section: Discussionmentioning

confidence: 99%

Stool DNA testing for the detection of pancreatic cancer

Kisiel

Yab

Taylor

et al. 2011

Cancer

107

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BACKGROUND Pancreatic cancer (PanC) presents at late stage with high mortality. Effective early detection methods are needed. Aberrantly methylated genes are unexplored as markers for noninvasive detection by stool testing. We aimed to select discriminant methylated genes and to assess accuracy of these and mutant KRAS in stool to detect PanC. METHODS Nine target genes were assayed by real-time methylation-specific PCR (MSP) in bisulfite-treated DNA from microdissected frozen specimens of 24 PanC cases and 30 normal colon controls. Archived stools from 58 PanC cases and 65 controls matched on sex, age, and smoking were analyzed. Target genes from fecal supernatants were enriched by hybrid capture, bisulfite-treated, and assayed by MSP. KRAS mutations were assayed using the QuARTS technique. RESULTS Areas under the receiver operating characteristics curves (AUCs) for tissue BMP3, NDRG4, EYA4, UCHL1, MDFI, Vimentin, CNTNAP2, SFRP2 and TFPI2 were 0.90, 0.79, 0.78, 0.78, 0.77, 0.77, 0.69, 0.67, and 0.66, respectively. The top 4 markers and mutant KRAS were evaluated in stool. BMP3 was the most discriminant methylation marker in stool. At 90% specificity: methylated BMP3 alone detected 51% of PanCs, mutant KRAS detected 50%, and combination detected 67%. AUCs for methylated BMP3, mutant KRAS, and combination in stool were 0.73, 0.75, and 0.85, respectively. CONCLUSIONS This study demonstrates that stool assay of a methylated gene marker can detect PanC. Among candidate methylated markers discriminant in tissue, BMP3 alone performed well in stool. Combining methylated BMP3 and mutant KRAS increased stool detection over either marker alone.

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Pilot Study of Blood Biomarker Candidates for Detection of Pancreatic Cancer

Cited by 25 publications

References 23 publications

Protein Alterations Associated with Pancreatic Cancer and Chronic Pancreatitis Found in Human Plasma using Global Quantitative Proteomics Profiling

Protein Alterations Associated with Pancreatic Cancer and Chronic Pancreatitis Found in Human Plasma using Global Quantitative Proteomics Profiling

Multiplex Targeted Proteomic Assay for Biomarker Detection in Plasma: A Pancreatic Cancer Biomarker Case Study

Stool DNA testing for the detection of pancreatic cancer

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