Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus

Alok K. Shah, Gunter F Hartel, Ian Brown, Clay Winterford, Renhua Na, Kim Anh Lê Cao, Bradley A. Spicer, Michelle A. Dunstone, Wayne A. Phillips, Reginald V. Lord, Andrew Barbour, David I. Watson, Virendra Joshi, David C Whiteman, Michelle M Hill

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett’s esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/ lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.

Original languageEnglish
Pages (from-to)2324-2334
Number of pages11
JournalMolecular and Cellular Proteomics
Volume17
Issue number12
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Shah, Alok K. ; Hartel, Gunter F ; Brown, Ian ; Winterford, Clay ; Na, Renhua ; Cao, Kim Anh Lê ; Spicer, Bradley A. ; Dunstone, Michelle A. ; Phillips, Wayne A. ; Lord, Reginald V. ; Barbour, Andrew ; Watson, David I. ; Joshi, Virendra ; Whiteman, David C ; Hill, Michelle M. / Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus. In: Molecular and Cellular Proteomics. 2018 ; Vol. 17, No. 12. pp. 2324-2334.
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title = "Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus",
abstract = "Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett’s esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/ lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.",
author = "Shah, {Alok K.} and Hartel, {Gunter F} and Ian Brown and Clay Winterford and Renhua Na and Cao, {Kim Anh L{\^e}} and Spicer, {Bradley A.} and Dunstone, {Michelle A.} and Phillips, {Wayne A.} and Lord, {Reginald V.} and Andrew Barbour and Watson, {David I.} and Virendra Joshi and Whiteman, {David C} and Hill, {Michelle M}",
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Shah, AK, Hartel, GF, Brown, I, Winterford, C, Na, R, Cao, KAL, Spicer, BA, Dunstone, MA, Phillips, WA, Lord, RV, Barbour, A, Watson, DI, Joshi, V, Whiteman, DC & Hill, MM 2018, 'Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus' Molecular and Cellular Proteomics, vol. 17, no. 12, pp. 2324-2334. https://doi.org/10.1074/mcp.RA118.000734

Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus. / Shah, Alok K.; Hartel, Gunter F; Brown, Ian; Winterford, Clay; Na, Renhua; Cao, Kim Anh Lê; Spicer, Bradley A.; Dunstone, Michelle A.; Phillips, Wayne A.; Lord, Reginald V.; Barbour, Andrew; Watson, David I.; Joshi, Virendra; Whiteman, David C; Hill, Michelle M.

In: Molecular and Cellular Proteomics, Vol. 17, No. 12, 01.12.2018, p. 2324-2334.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus

AU - Shah, Alok K.

AU - Hartel, Gunter F

AU - Brown, Ian

AU - Winterford, Clay

AU - Na, Renhua

AU - Cao, Kim Anh Lê

AU - Spicer, Bradley A.

AU - Dunstone, Michelle A.

AU - Phillips, Wayne A.

AU - Lord, Reginald V.

AU - Barbour, Andrew

AU - Watson, David I.

AU - Joshi, Virendra

AU - Whiteman, David C

AU - Hill, Michelle M

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N2 - Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett’s esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/ lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.

AB - Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett’s esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/ lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.

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