A Large-Scale Multicenter Study Validates Aldo-Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

Xu Ye, Cunyan Li, Xuyu Zu, Minglin Lin, Qiang Liu, Jianghua Liu, Guoguo Xu, Zhiyong Chen, Yongliang Xu, Long Liu, Diteng Luo, Zhe Cao, Guiyuan Shi, Zirui Feng, Hongyu Deng, Qianjin Liao, Chuan Cai, Duan-Fang Liao, Jing Wang, Junfei Jin, Deliang Cao, Xu Ye, Cunyan Li, Xuyu Zu, Minglin Lin, Qiang Liu, Jianghua Liu, Guoguo Xu, Zhiyong Chen, Yongliang Xu, Long Liu, Diteng Luo, Zhe Cao, Guiyuan Shi, Zirui Feng, Hongyu Deng, Qianjin Liao, Chuan Cai, Duan-Fang Liao, Jing Wang, Junfei Jin, Deliang Cao

Abstract

Aldo-keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time-resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha-fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early-stage HCC and AFP-negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early-stage HCC, with better diagnostic performance than AFP.

© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

Figures

Figure 1
Figure 1
Study flow. A total of 135 participants, including 69 HCC and 66 healthy controls, were enrolled as an exploratory discovery cohort for evaluation of potential of serum AKR1B10 as a diagnostic marker of HCC. A training cohort was then designed to test the diagnostic value of AKR1B10 for discrimination of HCC from healthy controls and other liver diseases, followed by a validation cohort to verify the findings in the training cohort. An independent cohort of 68 surgical patients were recruited and followed up for serum AKR1B10 changes after operation. *Participants from the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University at Changsha, China. †Participants from the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University at Changsha, China; Hunan Provincial People's Hospital at Changsha, China; and the First Affiliated Hospital of University of South China at Hengyang, China.
Figure 2
Figure 2
Exploratory data from discovery cohort: AKR1B10 as a potential serum marker for detection of HCC, alone or in combination with AFP. (A) Serum AKR1B10 levels in HCC and HC. (B) Serum AFP levels in HCC and HC. (C) ROC curve analyses for diagnostic potential of AKR1B10, AFP, and combination of AKR1B10 and AFP. Abbreviation: CI, confidence interval.
Figure 3
Figure 3
Serum AKR1B10 and AFP levels in training and validation cohorts. (A) Training cohort: AKR1B10 (left); AFP (right). (B) Validation cohort: AKR1B10 (left); AFP (right).
Figure 4
Figure 4
Serum AKR1B10 for detection of HCC. (A) Training cohort: ROC curves for HCC versus all controls (left); ROC curves for HCC versus high‐risk controls (CHB + LC) (middle); positive rates for AKR1B10, AFP, or both in HCC and for AKR1B10 by AFP status (right). (B) Validation cohort: ROC curves for HCC versus all controls (left); ROC curves for HCC versus high‐risk controls (CHB + LC) (middle); positive rates for AKR1B10, AFP, or both in HCC and for AKR1B10 by AFP status (right).
Figure 5
Figure 5
Serum AKR1B10 in detection of early‐stage HCC. (A) Training cohort: ROC curves for early‐stage HCC versus all controls (left); ROC curves for early‐stage HCC versus high‐risk controls (CHB + LC) (middle); positive rates for AKR1B10, AFP, or both in HCC and for AKR1B10 by AFP status (right). (B) Validation cohort: ROC curves for early‐stage HCC versus all controls (left); ROC curves for early‐stage HCC versus high‐risk controls (CHB + LC) (middle); positive rates for AKR1B10, AFP, or both in HCC and for AKR1B10 by AFP status (right).
Figure 6
Figure 6
Changes of serum AKR1B10 concentrations by surgical resection of HCC mass. (A) Tendency chart of AKR1B10 concentrations in serum of patients with HCC before surgical resection and at 1 day and 3 days after operation. (B) One‐way repeated measures analysis of variance to evaluate AKR1B10 concentrations in serum collected before and after surgical resection of HCC. AKR1B10 levels decreased significantly after operation (P < 0.0001).

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