Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population

Jimmy Bok Yan So; Ritika Kapoor; Feng Zhu; Calvin Koh; Lihan Zhou; Ruiyang Zou; Yew Chung Tang; Patrick C.K. Goo; Sun Young Rha; Hyun Cheol Chung; Joanne Yoong; Celestial T. Yap; Jaideepraj Rao; Chung King Chia; Stephen Tsao; Asim Shabbir; Jonathan Lee; Kong Peng Lam; Mikael Hartman; Wei Peng Yong; Heng Phon Too; Khay Guan Yeoh

doi:10.1136/gutjnl-2020-322065

Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population

Jimmy Bok Yan So, Ritika Kapoor, Feng Zhu, Calvin Koh, Lihan Zhou, Ruiyang Zou, Yew Chung Tang, Patrick C.K. Goo, Sun Young Rha, Hyun Cheol Chung, Joanne Yoong, Celestial T. Yap, Jaideepraj Rao, Chung King Chia, Stephen Tsao, Asim Shabbir, Jonathan Lee, Kong Peng Lam, Mikael Hartman, Wei Peng YongHeng Phon Too, Khay Guan Yeoh

Department of Internal Medicine

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

49 Citations (Scopus)

Abstract

Objective An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. Design We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. Results We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). Conclusion We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer.

Original language	English
Article number	33028667
Pages (from-to)	829-837
Number of pages	9
Journal	Gut
Volume	70
Issue number	5
DOIs	https://doi.org/10.1136/gutjnl-2020-322065
Publication status	Published - 2021 May 1

Bibliographical note

Funding Information:
Funding The Singapore Gastric Cancer Consortium (SGCC) is a national translational research group comprising clinicians and scientists working in gastric cancer research from academic medical centres, universities, hospitals and research institutes across Singapore. It receives funding from the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme and Open Fund-Large Collaborative Grant (OF-LCG), administered by the Singapore Ministry of Health’s National Medical Research Council. This study was supported by the Bedside & Bench grant (NMRC/BnB/0014b/2014) and the Translational and Clinical Research grant administered by Singapore Ministry of Health’s National Medical Research Council (NMRC/TCR/009-NUHS/2013, NMRC/ TCR/001-NUS/2007) and RIE2020 Centre Grant (CG) Programme (NMRC/CG/ M005/2017_NCIS), as well as the COT and GAP grants administered by Singapore A*STAR Exploit Technology.

Funding Information:
Competing interests KGY, JBYS, WPY, HPT, LZ, RZ and FZ were coinventors in the patent application ’Serum MicroRNA Biomarker for the Diagnosis of Gastric Cancer’. HPT, LZ and RZ are founders and shareholders of MiRXES. LZ, RZ and YCT are employees of MiRXES. HCC received grants from Lilly, GSK, MSD. Merck-Serono, BMS-Ono, Taiho outside the submitted work. The rest of authors declare no competing interests.

Funding Information:
The Singapore Gastric Cancer Consortium (SGCC) is a national translational research group comprising clinicians and scientists working in gastric cancer research from academic medical centres, universities, hospitals and research institutes across Singapore. It receives funding from the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme and Open Fund-Large Collaborative Grant (OF-LCG), administered by the Singapore Ministry of Health's National Medical Research Council. This study was supported by the Bedside & Bench grant (NMRC/BnB/0014b/2014) and the Translational and Clinical Research grant administered by Singapore Ministry of Health's National Medical Research Council (NMRC/TCR/009-NUHS/ 2013, NMRC/ TCR/001-NUS/ 2007) and RIE2020 Centre Grant (CG) Programme (NMRC/CG/ M005/2017-NCIS), as well as the COT and GAP grants administered by Singapore A?STAR Exploit Technology.

Publisher Copyright:
© 2021 Author(s).

All Science Journal Classification (ASJC) codes

Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2020-322065

Cite this

So, J. B. Y., Kapoor, R., Zhu, F., Koh, C., Zhou, L., Zou, R., Tang, Y. C., Goo, P. C. K., Rha, S. Y., Chung, H. C., Yoong, J., Yap, C. T., Rao, J., Chia, C. K., Tsao, S., Shabbir, A., Lee, J., Lam, K. P., Hartman, M., ... Yeoh, K. G. (2021). Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population. Gut, 70(5), 829-837. [33028667]. https://doi.org/10.1136/gutjnl-2020-322065

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abstract = "Objective An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. Design We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. Results We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). Conclusion We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer.",

author = "So, {Jimmy Bok Yan} and Ritika Kapoor and Feng Zhu and Calvin Koh and Lihan Zhou and Ruiyang Zou and Tang, {Yew Chung} and Goo, {Patrick C.K.} and Rha, {Sun Young} and Chung, {Hyun Cheol} and Joanne Yoong and Yap, {Celestial T.} and Jaideepraj Rao and Chia, {Chung King} and Stephen Tsao and Asim Shabbir and Jonathan Lee and Lam, {Kong Peng} and Mikael Hartman and Yong, {Wei Peng} and Too, {Heng Phon} and Yeoh, {Khay Guan}",

note = "Funding Information: Funding The Singapore Gastric Cancer Consortium (SGCC) is a national translational research group comprising clinicians and scientists working in gastric cancer research from academic medical centres, universities, hospitals and research institutes across Singapore. It receives funding from the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme and Open Fund-Large Collaborative Grant (OF-LCG), administered by the Singapore Ministry of Health{\textquoteright}s National Medical Research Council. This study was supported by the Bedside & Bench grant (NMRC/BnB/0014b/2014) and the Translational and Clinical Research grant administered by Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC/TCR/009-NUHS/2013, NMRC/ TCR/001-NUS/2007) and RIE2020 Centre Grant (CG) Programme (NMRC/CG/ M005/2017_NCIS), as well as the COT and GAP grants administered by Singapore A*STAR Exploit Technology. Funding Information: Competing interests KGY, JBYS, WPY, HPT, LZ, RZ and FZ were coinventors in the patent application {\textquoteright}Serum MicroRNA Biomarker for the Diagnosis of Gastric Cancer{\textquoteright}. HPT, LZ and RZ are founders and shareholders of MiRXES. LZ, RZ and YCT are employees of MiRXES. HCC received grants from Lilly, GSK, MSD. Merck-Serono, BMS-Ono, Taiho outside the submitted work. The rest of authors declare no competing interests. Funding Information: The Singapore Gastric Cancer Consortium (SGCC) is a national translational research group comprising clinicians and scientists working in gastric cancer research from academic medical centres, universities, hospitals and research institutes across Singapore. It receives funding from the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme and Open Fund-Large Collaborative Grant (OF-LCG), administered by the Singapore Ministry of Health's National Medical Research Council. This study was supported by the Bedside & Bench grant (NMRC/BnB/0014b/2014) and the Translational and Clinical Research grant administered by Singapore Ministry of Health's National Medical Research Council (NMRC/TCR/009-NUHS/ 2013, NMRC/ TCR/001-NUS/ 2007) and RIE2020 Centre Grant (CG) Programme (NMRC/CG/ M005/2017-NCIS), as well as the COT and GAP grants administered by Singapore A?STAR Exploit Technology. Publisher Copyright: {\textcopyright} 2021 Author(s).",

year = "2021",

month = may,

day = "1",

doi = "10.1136/gutjnl-2020-322065",

language = "English",

volume = "70",

pages = "829--837",

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So, JBY, Kapoor, R, Zhu, F, Koh, C, Zhou, L, Zou, R, Tang, YC, Goo, PCK, Rha, SY , Chung, HC, Yoong, J, Yap, CT, Rao, J, Chia, CK, Tsao, S, Shabbir, A, Lee, J, Lam, KP, Hartman, M, Yong, WP, Too, HP & Yeoh, KG 2021, 'Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population', Gut, vol. 70, no. 5, 33028667, pp. 829-837. https://doi.org/10.1136/gutjnl-2020-322065

TY - JOUR

T1 - Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population

AU - So, Jimmy Bok Yan

AU - Kapoor, Ritika

AU - Zhu, Feng

AU - Koh, Calvin

AU - Zhou, Lihan

AU - Zou, Ruiyang

AU - Tang, Yew Chung

AU - Goo, Patrick C.K.

AU - Rha, Sun Young

AU - Chung, Hyun Cheol

AU - Yoong, Joanne

AU - Yap, Celestial T.

AU - Rao, Jaideepraj

AU - Chia, Chung King

AU - Tsao, Stephen

AU - Shabbir, Asim

AU - Lee, Jonathan

AU - Lam, Kong Peng

AU - Hartman, Mikael

AU - Yong, Wei Peng

AU - Too, Heng Phon

AU - Yeoh, Khay Guan

N1 - Funding Information: Funding The Singapore Gastric Cancer Consortium (SGCC) is a national translational research group comprising clinicians and scientists working in gastric cancer research from academic medical centres, universities, hospitals and research institutes across Singapore. It receives funding from the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme and Open Fund-Large Collaborative Grant (OF-LCG), administered by the Singapore Ministry of Health’s National Medical Research Council. This study was supported by the Bedside & Bench grant (NMRC/BnB/0014b/2014) and the Translational and Clinical Research grant administered by Singapore Ministry of Health’s National Medical Research Council (NMRC/TCR/009-NUHS/2013, NMRC/ TCR/001-NUS/2007) and RIE2020 Centre Grant (CG) Programme (NMRC/CG/ M005/2017_NCIS), as well as the COT and GAP grants administered by Singapore A*STAR Exploit Technology. Funding Information: Competing interests KGY, JBYS, WPY, HPT, LZ, RZ and FZ were coinventors in the patent application ’Serum MicroRNA Biomarker for the Diagnosis of Gastric Cancer’. HPT, LZ and RZ are founders and shareholders of MiRXES. LZ, RZ and YCT are employees of MiRXES. HCC received grants from Lilly, GSK, MSD. Merck-Serono, BMS-Ono, Taiho outside the submitted work. The rest of authors declare no competing interests. Funding Information: The Singapore Gastric Cancer Consortium (SGCC) is a national translational research group comprising clinicians and scientists working in gastric cancer research from academic medical centres, universities, hospitals and research institutes across Singapore. It receives funding from the National Research Foundation Singapore under its Translational and Clinical Research (TCR) Flagship Programme and Open Fund-Large Collaborative Grant (OF-LCG), administered by the Singapore Ministry of Health's National Medical Research Council. This study was supported by the Bedside & Bench grant (NMRC/BnB/0014b/2014) and the Translational and Clinical Research grant administered by Singapore Ministry of Health's National Medical Research Council (NMRC/TCR/009-NUHS/ 2013, NMRC/ TCR/001-NUS/ 2007) and RIE2020 Centre Grant (CG) Programme (NMRC/CG/ M005/2017-NCIS), as well as the COT and GAP grants administered by Singapore A?STAR Exploit Technology. Publisher Copyright: © 2021 Author(s).

PY - 2021/5/1

Y1 - 2021/5/1

N2 - Objective An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. Design We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. Results We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). Conclusion We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer.

AB - Objective An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. Design We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. Results We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). Conclusion We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer.

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U2 - 10.1136/gutjnl-2020-322065

DO - 10.1136/gutjnl-2020-322065

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VL - 70

SP - 829

EP - 837

JO - Gut

JF - Gut

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M1 - 33028667

ER -

Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population

Abstract

Bibliographical note

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UN SDGs

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