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Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization

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Abstract

Purpose

Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) copy number (mtDNAcn) and relative telomere length (RTL) may be implicated in the tumorigenesis of several malignancies. Alterations of both RTL and mtDNAcn are generally accepted as independent biomarkers for predicting risk and prognosis in various cancers. The aim of this study was to evaluate the prognostic value of combining leukocyte RTL with mtDNAcn (RTL–mtDNAcn) in hepatocellular carcinoma (HCC).

Methods

RTL and mtDNAcn in peripheral blood leukocytes (PBLs) were measured using a real-time PCR-based method in a total of 250 HCC patients treated with transcatheter arterial chemoembolization (TACE). We evaluated the associations between RTL and/or mtDNAcn and HCC overall survival using Kaplan–Meier curve analysis and Cox proportional hazards regression model.

Results

We found that patients with longer leukocyte RTL or lower mtDNAcn had shorter overall survival time. The univariate analysis (HR 1.63, 95 % CI 1.23–2.17, P = 7.7 × 10−4) and multivariate analysis (HR 1.78, 95 % CI 1.31–2.42, P = 2.4 × 10−4) indicated that longer leukocyte RTL was significantly associated with poorer OS in HCC patients. Kaplan–Meier curve analysis showed that patients with longer RTL had shorter overall survival time than those with shorter RTL (log-rank P = 0.001). Patients with lower mtDNA copy number was significantly associated with poorer OS by Cox proportional hazards model using both univariate (HR 1.60, 95 % CI 1.21–2.13, P = 0.001) and multivariate analyses (HR 1.77, 95 % CI 1.30–2.41, P = 2.8 × 10−4). Kaplan–Meier curve analysis showed that patients with lower mtDNA content had significantly shorter overall survival time than those with higher mtDNA content (log-rank P = 0.001). Furthermore, combination of leukocyte RTL and mtDNAcn significantly improved the efficacy of predicting HCC prognosis. Patients with longer RTL and lower mtDNAcn exhibited a significantly poorer overall survival in both the univariate analysis (HR 2.21, 95 % CI 1.52–3.22, P = 3.5 × 10−5) and multivariate analysis (HR 2.60, 95 % CI 1.73–3.90, P = 4.3 × 10−6). The effect on patient prognosis was more evident in patients with longer RTL and lower mtDNAcn than in those with shorter RTL and lower mtDNA (HR 2.11, 95 % CI 1.34–3.32, P = 0.001) or in those with longer RTL and higher mtDNA (HR 2.10, 95 % CI 1.34–3.27, P = 0.001).

Conclusions

Our data suggest that combination of leukocyte RTL-mtDNAcn may be a potential efficient prognostic marker for HCC patients receiving the TACE treatment.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grants 81320108021) and the National Basic Research Program of China (Grant 2015CB553703).

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    Authors and Affiliations

    1. Institute of Pharmacy, Pharmaceutical College of Henan University, Kaifeng, 475004, Henan, China

      Dengke Bao, Jing Zhao, Qi Yang & Shaogui Wan

    2. Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shanxi, China

      Yanna Ba & Zhenbiao Wu

    3. Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710032, Shanxi, China

      Feng Zhou

    4. State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, Shanxi, China

      Xu Guo & Jinliang Xing

    5. Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, Shanxi, China

      Hongxin Zhang

    6. Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China

      Naijian Ge

    7. Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA

      Hushan Yang

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    1. Dengke Bao
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    Correspondence to Shaogui Wan or Jinliang Xing.

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    Dengke Bao and Yanna Ba have contributed equally to this work.

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    Supplementary Figure 1

    Correlation between leukocyte mtDNA copy number and RTL (A), age, and relative telomere length (B) or mtDNA copy number (C). Values of mtDNA copy number were analyzed after log transformation. P values were calculated by Pearson’s correlation (TIFF 3023 kb)

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    Bao, D., Ba, Y., Zhou, F. et al. Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization. Cancer Chemother Pharmacol 78, 791–799 (2016). https://doi.org/10.1007/s00280-016-3128-1

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