Global protease activity profiling provides differential diagnosis of pancreatic cysts

Sam L. Ivry, Jeremy M. Sharib, Dana A. Dominguez, Nilotpal Roy, Stacy E. Hatcher, Michele Yip-Schneider, C. Schmidt, Randall E. Brand, Walter G. Park, Matthias Hebrok, Grace E. Kim, Anthony J. O'Donoghue, Kimberly S. Kirkwood, Charles S. Craik

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Purpose: Pancreatic cysts are estimated to be present in 2%–3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 mL of cyst fluid. Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

Original languageEnglish (US)
Pages (from-to)4865-4874
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

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gastricsin
Pancreatic Cyst
Cathepsin E
Differential Diagnosis
Peptide Hydrolases
Cyst Fluid
Cysts
Carcinoembryonic Antigen
Aspartic Acid Proteases
Sensitivity and Specificity
Fluorescent Dyes
Proteolysis
Neoplasms
Research Design
Biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ivry, S. L., Sharib, J. M., Dominguez, D. A., Roy, N., Hatcher, S. E., Yip-Schneider, M., ... Craik, C. S. (2017). Global protease activity profiling provides differential diagnosis of pancreatic cysts. Clinical Cancer Research, 23(16), 4865-4874. https://doi.org/10.1158/1078-0432.CCR-16-2987

Global protease activity profiling provides differential diagnosis of pancreatic cysts. / Ivry, Sam L.; Sharib, Jeremy M.; Dominguez, Dana A.; Roy, Nilotpal; Hatcher, Stacy E.; Yip-Schneider, Michele; Schmidt, C.; Brand, Randall E.; Park, Walter G.; Hebrok, Matthias; Kim, Grace E.; O'Donoghue, Anthony J.; Kirkwood, Kimberly S.; Craik, Charles S.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4865-4874.

Research output: Contribution to journalArticle

Ivry, SL, Sharib, JM, Dominguez, DA, Roy, N, Hatcher, SE, Yip-Schneider, M, Schmidt, C, Brand, RE, Park, WG, Hebrok, M, Kim, GE, O'Donoghue, AJ, Kirkwood, KS & Craik, CS 2017, 'Global protease activity profiling provides differential diagnosis of pancreatic cysts', Clinical Cancer Research, vol. 23, no. 16, pp. 4865-4874. https://doi.org/10.1158/1078-0432.CCR-16-2987
Ivry, Sam L. ; Sharib, Jeremy M. ; Dominguez, Dana A. ; Roy, Nilotpal ; Hatcher, Stacy E. ; Yip-Schneider, Michele ; Schmidt, C. ; Brand, Randall E. ; Park, Walter G. ; Hebrok, Matthias ; Kim, Grace E. ; O'Donoghue, Anthony J. ; Kirkwood, Kimberly S. ; Craik, Charles S. / Global protease activity profiling provides differential diagnosis of pancreatic cysts. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4865-4874.
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AU - Ivry, Sam L.

AU - Sharib, Jeremy M.

AU - Dominguez, Dana A.

AU - Roy, Nilotpal

AU - Hatcher, Stacy E.

AU - Yip-Schneider, Michele

AU - Schmidt, C.

AU - Brand, Randall E.

AU - Park, Walter G.

AU - Hebrok, Matthias

AU - Kim, Grace E.

AU - O'Donoghue, Anthony J.

AU - Kirkwood, Kimberly S.

AU - Craik, Charles S.

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N2 - Purpose: Pancreatic cysts are estimated to be present in 2%–3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 mL of cyst fluid. Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

AB - Purpose: Pancreatic cysts are estimated to be present in 2%–3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 mL of cyst fluid. Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

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