HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma

Na Sun; Ceng Zhang; Yi Te Lee; Benjamin V. Tran; Jing Wang; Hyoyong Kim; Junseok Lee; Ryan Y. Zhang; Jasmine J. Wang; Junhui Hu; Zhicheng Zhang; Manaf S. Alsudaney; Kuan Chu Hou; Hubert Tang; Tiffany X. Zhang; Icy Y. Liang; Ziang Zhou; Mengxiang Chen; Angela Hsiao Jiun Yeh; Wenyuan Li; Xianghong Jasmine Zhou; Helena R. Chang; Steven Huy B. Han; Saeed Sadeghi; Richard S. Finn; Sammy Saab; Ronald W. Busuttil; Mazen Noureddin; Walid S. Ayoub; Alexander Kuo; Vinay Sundaram; Buraq Al-Ghaieb; Juvelyn Palomique; Kambiz Kosari; Irene K. Kim; Tsuyoshi Todo; Nicholas N. Nissen; Maria Lauda Tomasi; Sungyong You; Edwin M. Posadas; James X. Wu; Madhuri Wadehra; Myung Shin Sim; Yunfeng Li; Hanlin L. Wang; Samuel W. French; Shelly C. Lu; Lily Wu; Renjun Pei; Li Liang; Ju Dong Yang; Vatche G. Agopian; Hsian Rong Tseng; Yazhen Zhu

doi:10.1002/hep.32692

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma

Na Sun, Ceng Zhang, Yi Te Lee, Benjamin V. Tran, Jing Wang, Hyoyong Kim, Junseok Lee, Ryan Y. Zhang, Jasmine J. Wang, Junhui Hu, Zhicheng Zhang, Manaf S. Alsudaney, Kuan Chu Hou, Hubert Tang, Tiffany X. Zhang, Icy Y. Liang, Ziang Zhou, Mengxiang Chen, Angela Hsiao Jiun Yeh, Wenyuan LiXianghong Jasmine Zhou, Helena R. Chang, Steven Huy B. Han, Saeed Sadeghi, Richard S. Finn, Sammy Saab, Ronald W. Busuttil, Mazen Noureddin, Walid S. Ayoub, Alexander Kuo, Vinay Sundaram, Buraq Al-Ghaieb, Juvelyn Palomique, Kambiz Kosari, Irene K. Kim, Tsuyoshi Todo, Nicholas N. Nissen, Maria Lauda Tomasi, Sungyong You, Edwin M. Posadas, James X. Wu, Madhuri Wadehra, Myung Shin Sim, Yunfeng Li, Hanlin L. Wang, Samuel W. French, Shelly C. Lu, Lily Wu, Renjun Pei, Li Liang, Ju Dong Yang, Vatche G. Agopian, Hsian Rong Tseng, Yazhen Zhu

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

Background and Aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. Approach and Results: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations (E pCAM+ CD63+, C D147+ CD63+, and G PC3+ CD63+ HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort (n = 106) and an independent validation cohort (n = 72). Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). Conclusion: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

Original language	English (US)
Pages (from-to)	774-788
Number of pages	15
Journal	Hepatology
Volume	77
Issue number	3
DOIs	https://doi.org/10.1002/hep.32692
State	Published - Mar 2023

Keywords

Humans
Carcinoma, Hepatocellular/diagnosis
Liver Neoplasms/diagnosis
Biomarkers, Tumor/analysis
Extracellular Vesicles/chemistry
Membrane Proteins
Electrocardiography
Glypicans

ASJC Scopus subject areas

Hepatology

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10.1002/hep.32692

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Sun, N., Zhang, C., Lee, Y. T., Tran, B. V., Wang, J., Kim, H., Lee, J., Zhang, R. Y., Wang, J. J., Hu, J., Zhang, Z., Alsudaney, M. S., Hou, K. C., Tang, H., Zhang, T. X., Liang, I. Y., Zhou, Z., Chen, M., Yeh, A. H. J., ... Zhu, Y. (2023). HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma. Hepatology, 77(3), 774-788. https://doi.org/10.1002/hep.32692

Sun, N, Zhang, C, Lee, YT, Tran, BV, Wang, J, Kim, H, Lee, J, Zhang, RY, Wang, JJ, Hu, J, Zhang, Z, Alsudaney, MS, Hou, KC, Tang, H, Zhang, TX, Liang, IY, Zhou, Z, Chen, M, Yeh, AHJ, Li, W, Zhou, XJ, Chang, HR, Han, SHB, Sadeghi, S, Finn, RS, Saab, S, Busuttil, RW , Noureddin, M, Ayoub, WS, Kuo, A, Sundaram, V, Al-Ghaieb, B, Palomique, J, Kosari, K, Kim, IK, Todo, T, Nissen, NN, Tomasi, ML, You, S, Posadas, EM, Wu, JX, Wadehra, M, Sim, MS, Li, Y, Wang, HL, French, SW, Lu, SC, Wu, L, Pei, R, Liang, L, Yang, JD, Agopian, VG, Tseng, HR & Zhu, Y 2023, 'HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma', Hepatology, vol. 77, no. 3, pp. 774-788. https://doi.org/10.1002/hep.32692

@article{b7c82f3432384194b2c195cf05b35364,

title = "HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma",

abstract = "Background and Aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. Approach and Results: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations (E pCAM+ CD63+, C D147+ CD63+, and G PC3+ CD63+ HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort (n = 106) and an independent validation cohort (n = 72). Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). Conclusion: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.",

keywords = "Humans, Carcinoma, Hepatocellular/diagnosis, Liver Neoplasms/diagnosis, Biomarkers, Tumor/analysis, Extracellular Vesicles/chemistry, Membrane Proteins, Electrocardiography, Glypicans",

author = "Na Sun and Ceng Zhang and Lee, {Yi Te} and Tran, {Benjamin V.} and Jing Wang and Hyoyong Kim and Junseok Lee and Zhang, {Ryan Y.} and Wang, {Jasmine J.} and Junhui Hu and Zhicheng Zhang and Alsudaney, {Manaf S.} and Hou, {Kuan Chu} and Hubert Tang and Zhang, {Tiffany X.} and Liang, {Icy Y.} and Ziang Zhou and Mengxiang Chen and Yeh, {Angela Hsiao Jiun} and Wenyuan Li and Zhou, {Xianghong Jasmine} and Chang, {Helena R.} and Han, {Steven Huy B.} and Saeed Sadeghi and Finn, {Richard S.} and Sammy Saab and Busuttil, {Ronald W.} and Mazen Noureddin and Ayoub, {Walid S.} and Alexander Kuo and Vinay Sundaram and Buraq Al-Ghaieb and Juvelyn Palomique and Kambiz Kosari and Kim, {Irene K.} and Tsuyoshi Todo and Nissen, {Nicholas N.} and Tomasi, {Maria Lauda} and Sungyong You and Posadas, {Edwin M.} and Wu, {James X.} and Madhuri Wadehra and Sim, {Myung Shin} and Yunfeng Li and Wang, {Hanlin L.} and French, {Samuel W.} and Lu, {Shelly C.} and Lily Wu and Renjun Pei and Li Liang and Yang, {Ju Dong} and Agopian, {Vatche G.} and Tseng, {Hsian Rong} and Yazhen Zhu",

note = "Publisher Copyright: {\textcopyright} 2023 American Association for the Study of Liver Diseases.",

year = "2023",

month = mar,

doi = "10.1002/hep.32692",

language = "English (US)",

volume = "77",

pages = "774--788",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

number = "3",

}

TY - JOUR

T1 - HCC EV ECG score

T2 - An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma

AU - Sun, Na

AU - Zhang, Ceng

AU - Lee, Yi Te

AU - Tran, Benjamin V.

AU - Wang, Jing

AU - Kim, Hyoyong

AU - Lee, Junseok

AU - Zhang, Ryan Y.

AU - Wang, Jasmine J.

AU - Hu, Junhui

AU - Zhang, Zhicheng

AU - Alsudaney, Manaf S.

AU - Hou, Kuan Chu

AU - Tang, Hubert

AU - Zhang, Tiffany X.

AU - Liang, Icy Y.

AU - Zhou, Ziang

AU - Chen, Mengxiang

AU - Yeh, Angela Hsiao Jiun

AU - Li, Wenyuan

AU - Zhou, Xianghong Jasmine

AU - Chang, Helena R.

AU - Han, Steven Huy B.

AU - Sadeghi, Saeed

AU - Finn, Richard S.

AU - Saab, Sammy

AU - Busuttil, Ronald W.

AU - Noureddin, Mazen

AU - Ayoub, Walid S.

AU - Kuo, Alexander

AU - Sundaram, Vinay

AU - Al-Ghaieb, Buraq

AU - Palomique, Juvelyn

AU - Kosari, Kambiz

AU - Kim, Irene K.

AU - Todo, Tsuyoshi

AU - Nissen, Nicholas N.

AU - Tomasi, Maria Lauda

AU - You, Sungyong

AU - Posadas, Edwin M.

AU - Wu, James X.

AU - Wadehra, Madhuri

AU - Sim, Myung Shin

AU - Li, Yunfeng

AU - Wang, Hanlin L.

AU - French, Samuel W.

AU - Lu, Shelly C.

AU - Wu, Lily

AU - Pei, Renjun

AU - Liang, Li

AU - Yang, Ju Dong

AU - Agopian, Vatche G.

AU - Tseng, Hsian Rong

AU - Zhu, Yazhen

PY - 2023/3

Y1 - 2023/3

N2 - Background and Aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. Approach and Results: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations (E pCAM+ CD63+, C D147+ CD63+, and G PC3+ CD63+ HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort (n = 106) and an independent validation cohort (n = 72). Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). Conclusion: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

AB - Background and Aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. Approach and Results: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations (E pCAM+ CD63+, C D147+ CD63+, and G PC3+ CD63+ HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort (n = 106) and an independent validation cohort (n = 72). Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). Conclusion: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

KW - Humans

KW - Carcinoma, Hepatocellular/diagnosis

KW - Liver Neoplasms/diagnosis

KW - Biomarkers, Tumor/analysis

KW - Extracellular Vesicles/chemistry

KW - Membrane Proteins

KW - Electrocardiography

KW - Glypicans

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UR - http://www.scopus.com/inward/citedby.url?scp=85137367051&partnerID=8YFLogxK

U2 - 10.1002/hep.32692

DO - 10.1002/hep.32692

M3 - Article

C2 - 35908246

AN - SCOPUS:85137367051

SN - 0270-9139

VL - 77

SP - 774

EP - 788

JO - Hepatology

JF - Hepatology

IS - 3

ER -

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma

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