Optimized digital polymerase chain reaction enables detection of telomerase reverse transcriptase C228T mutation for prognostic assessment in hepatocellular carcinoma

doi:10.4251/wjgo.v17.i12.113289

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World Journal of Gastrointestinal Oncology

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1948-5204

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastrointest Oncol. Dec 15, 2025; 17(12): 113289
Published online Dec 15, 2025. doi: 10.4251/wjgo.v17.i12.113289

Optimized digital polymerase chain reaction enables detection of telomerase reverse transcriptase C228T mutation for prognostic assessment in hepatocellular carcinoma

Zulihumaer Aizimuaji, Nan Hu, Hai-Yang Li, Xi-Jun Wang, Sheng Ma, Ya-Ru Wang, Rui-Qi Zheng, Zhuo Li, Huan Zhao, Wei-Qi Rong, Ting Xiao

Zulihumaer Aizimuaji, Hai-Yang Li, Xi-Jun Wang, Sheng Ma, Ya-Ru Wang, Rui-Qi Zheng, Ting Xiao, State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Nan Hu, Wei-Qi Rong, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Zhuo Li, Huan Zhao, Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Co-first authors: Zulihumaer Aizimuaji and Nan Hu.

Co-corresponding authors: Wei-Qi Rong and Ting Xiao.

Author contributions: Rong WQ, Zhao H, and Xiao T conceived and designed the study; Aizimuaji Z, Hu N, and Li HY performed experiments and data analysis; Rong WQ, Aizimuaji Z, Ma S, and Wang XJ collected samples and clinical information; Data interpretation was done by Aizimuaji Z, Li Z, Rong WQ, Wang YR, Ma S, Zheng RQ, and Li HY; Aizimuaji Z and Hu N drafted the manuscript and made equal contributions as co-first authors; Xiao T, Rong WQ, Li Z, and Zhao H revised and supervised the study; Rong WQ and Xiao T made equal contributions as co-corresponding authors. All authors reviewed the final version of the manuscript.

Supported by National Key Research and Development Program of China, No. 2023YFF0613304; and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, No. 2023-I2M-2-004, No. 2024-I2M-C&T-B-069, and No. 2025-I2M-C&T-B-057.

Institutional review board statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 24/427-4707.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Data sharing statement: The data associated with this study are present in the paper or Supplementary material. Data available on request from the corresponding author. The raw data is also available from the corresponding authors upon reasonable request. Enquiries for data, analytic methods and materials can be directed to the corresponding author.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Wei-Qi Rong, MD, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan South Lane, Beijing 100021, China. dr_rongweiqi@163.com

Received: August 21, 2025
Revised: September 30, 2025
Accepted: October 29, 2025
Published online: December 15, 2025
Processing time: 112 Days and 19.1 Hours

Abstract

BACKGROUND

Recurrence remains the leading cause of poor prognosis in hepatocellular carcinoma (HCC), particularly among patients infected with hepatitis B virus (HBV). The telomerase reverse transcriptase (TERT) promoter is the most frequently mutated site in HBV-related HCC; however, its prognostic significance is not fully established.

AIM

To evaluate the prognostic impact of TERT promoter mutations and efficiency of digital polymerase chain reaction (dPCR).

METHODS

A total of 66 HBV-related HCC patients who underwent hepatectomy were enrolled in this study. DNA extracted from fresh tumor tissues was analyzed for TERT promoter mutations using Sanger sequencing and dPCR. The dPCR assay was optimized by adding 7-deaza-dGTP, CviQ1, and ethylenediaminetetraacetic acid to improve detection sensitivity. Concordance between methods was assessed, and nomogram survival prediction models were developed to evaluate prognostic value based on mutation status.

RESULTS

TERT promoter mutations were detected in 26/66 (39.39%) cases by Sanger sequencing and 30/66 (45.45%) by dPCR. The two methods showed high concordance (93.939%, κ = 0.876), with dPCR demonstrating 100% sensitivity and 90% specificity. Patients harboring TERT promoter mutations exhibited reduced overall survival and higher recurrence risk. Nomogram models successfully distinguished mutant from non-mutant cases for both overall survival (C-index: 0.7651) and disease-free survival (C-index: 0.6899).

CONCLUSION

TERT promoter mutation predicts poor prognosis in HBV-related HCC and serves as a biomarker for risk stratification. Optimized dPCR outperforms Sanger sequencing, and nomograms with TERT status guide precision therapy.

Keywords: Hepatocellular carcinoma; Hepatitis B virus; Mutation; Polymerase chain reaction; Hepatectomy; Nomograms; Prognosis

Core Tip: Telomerase reverse transcriptase (TERT) promoter mutation is the most frequent genetic alteration in hepatitis B virus-related hepatocellular carcinoma, yet its prognostic role remains uncertain. In this study, optimized digital polymerase chain reaction outperformed Sanger sequencing in detecting TERT promoter mutations. Patients with TERT mutations had significantly worse survival and higher recurrence risk after hepatectomy. Incorporating TERT mutation status into a nomogram model provides a practical tool for individualized prognosis prediction and may guide precision treatment in hepatitis B virus-related hepatocellular carcinoma.