Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 14, 2019; 25(14): 1715-1728
Published online Apr 14, 2019. doi: 10.3748/wjg.v25.i14.1715
Seven-senescence-associated gene signature predicts overall survival for Asian patients with hepatocellular carcinoma
Xiao-Hong Xiang, Li Yang, Xing Zhang, Xiao-Hua Ma, Run-Chen Miao, Jing-Xian Gu, Yu-Nong Fu, Qing Yao, Jing-Yao Zhang, Chang Liu, Ting Lin, Kai Qu
Xiao-Hong Xiang, Xing Zhang, Xiao-Hua Ma, Run-Chen Miao, Jing-Xian Gu, Yu-Nong Fu, Qing Yao, Jing-Yao Zhang, Chang Liu, Ting Lin, Kai Qu, Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Li Yang, Department of Clinical Laboratory, Liaocheng People’s Hospital, Taishan Medical College, Liaocheng 252000, Shandong Province, China
Author contributions: Qu K, Lin T, Liu C, and Xiang XH designed the research; Yang L, Zhang X, Ma XH, Miao RC, and Gu JX collected and analyzed the data; Qu K, Xiang XH, Fu YN, and Yao Q prepared the figures; Zhang JY, Lin T, Qu K, and Liu C drafted and revised the manuscript.
Supported by the National Natural Science Foundation of China, No. 81773128 and No. 81871998; the Natural Science Basic Research Plan in Shaanxi Province of China, No. 2018JM7013 and No. 2017JM8039; the Research Fund for Young Star of Science and Technology in Shaanxi Province, No. 2018KJXX-022; and China Postdoctoral Science Foundation, No. 2018M641000.
Institutional review board statement: The study was reviewed and approved by the First Affiliated Hospital of Xi’an Jiaotong University Institutional Review Board.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Kai Qu, MD, PhD, Professor, Research Assistant Professor, Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an 710061, Shaanxi Province, China. qukai@xjtu.edu.cn
Telephone: +86-29-85323900 Fax: +86-29-85324695
Received: January 6, 2019
Peer-review started: January 7, 2019
First decision: February 13, 2019
Revised: March 6, 2019
Accepted: March 15, 2019
Article in press: March 16, 2019
Published online: April 14, 2019
Abstract
BACKGROUND

Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma (HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.

AIM

To develop a signature of senescence-associated genes (SAGs) that predicts patients’ overall survival (OS) to improve prognosis prediction of HCC.

METHODS

SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort (GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO (GSE14520) and the Cancer Genome Atlas datasets, respectively. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein (AFP).

RESULTS

A total of 42 SAGs were screened and seven of them, including KIF18B, CEP55, CIT, MCM7, CDC45, EZH2, and MCM5, were used to construct a prognostic formula. All seven genes were significantly downregulated in senescent cells and upregulated in HCC tissues. Survival analysis indicated that our seven-SAG signature was strongly associated with OS, especially in Asian populations, both in discovery and validation cohorts. Moreover, time-dependent ROC curve analysis suggested the seven-gene signature had a better predictive accuracy than serum AFP in predicting HCC patients’ 1-, 3-, and 5-year OS.

CONCLUSION

We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.

Keywords: Senescence-associated genes, Hepatocellular carcinoma, Overall survival, Risk model, Asian patients

Core tip: In the present study, we identified a total of 42 senescence-associated genes (SAGs) and found seven of them were significantly downregulated in senescent cells and upregulated in HCC tissues. By using the least absolute shrinkage and selection operator, we constructed a seven-SAG signature that could predict the overall survival (OS) of hepatocellular carcinoma. This seven-SAG signature was further validated and developed in another independent dataset from The Cancer Genome Atlas project. Moreover, our risk score system showed better utility in predicting the OS than classic serum biomarker α-fetoprotein.