Associations between sequence variations in the mitochondrial DNA D-loop region and outcome of hepatocellular carcinoma.

Shilai Li,Tao Peng,Quanlin Qin,Kaiyin Xiao,Zhixiong Su,Liming Shang,Peiqi Wan,Banghao Xu,Xinping Ye,Lequn Li,Ming Su,Ning Peng

doi:10.3892/ol.2016.4466

Abstract

The association between mitochondrial DNA (mtDNA) polymorphisms or mutations and the prognoses of cancer have been investigated previously, but the results have been ambiguous. In the present study, the associations between sequence variations in the mtDNA D-loop region and the outcomes of patients with hepatocellular carcinoma (HCC) were analysed. A total of 140 patients with HCC (123 males and 17 females), who were hospitalised to undergo radical resection, were studied. Polymerase chain reaction and direct sequencing were performed to detect the sequence variations in the mtDNA D-loop region. Multivariate and univariate analyses were conducted to determine important factors in the prognosis of HCC. A total of 150 point sequence variations were observed in the 140 cases (13 point mutations, 8 insertions, 20 deletions and 116 polymorphisms). The variation rate was 13.4% (150/1, 122). mtDNA nucleotide 150 (C/T) was an independent factor in the logistic regression for early/late recurrence of HCC. Patients with 150T appeared to have later recurrences. In a Cox proportional hazards regression model, hepatitis B virus DNA, Child-Pugh class, differentiation degree, tumour-node-metastasis (TNM) stage, nucleotide 16263 (T/C) and nucleotide 315 (N/insertion C) were independent factors for tumour-free survival time. Patients with the 16263T allele had a greater tumour-free survival time than patients with the 16263C allele. Similarly, patients with 315 insertion C had a superior tumour-free survival time when compared with patients with 315 N (normal). In the Cox proportional hazards regression model, recurrence type (early/late), Child-Pugh class, TNM stage and adjuvant treatment after tumour recurrence (none or one/more than one treatment) were independent factors for overall survival. None of the mtDNA variations served as independent factors. Patients with late recurrence, Child-Pugh class A, and low TNM stages and/or those who received more than one adjuvant treatment following tumour recurrence had favourable outcomes. mtDNA D-loop polymorphisms were associated with early recurrence and tumour-free survival time, but not with overall survival. mtDNA D-loop mutations in HCC were infrequent and lacked prognostic utility. The detection of mtDNA D-loop polymorphisms may assist in identifying risk factors for HCC prognosis, particularly for the short-term outcome, thereby aiding the construction of an appropriate therapeutic strategy.

Highlights

Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer worldwide, and is associated with chronic liver diseases, including hepatitis B and/or hepatitis C viral infection [1,2]
Mitochondrial DNA contains a non‐coding region that accommodates a unique displacement loop (D‐loop), which controls the transcription and replication of mitochondrial DNA (mtDNA). mtDNA is considered to be more vulnerable to oxidative damage and to have a higher mutation rate compared with nuclear DNA due to the lack of a repair system and protective histones within the mitochondria [5,6]
Damage to and somatic mutations of mtDNA may lead to impairment of the oxidative phosphorylation (OXPHOS) system and increased reactive oxygen species (ROS) production, which subsequently enhances the rate of LI et al: MITOCHONDRIAL DNA D-LOOP REGION VARIATIONS AND OUTCOMES OF HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer worldwide, and is associated with chronic liver diseases, including hepatitis B and/or hepatitis C viral infection [1,2]. Chronic viral inflammation and reactive oxygen species (ROS), which are increased by chronic inflammation, are considered as the most important factors in HCC carcinogenesis [4]. Mitochondrial DNA (mtDNA) contains a non‐coding region that accommodates a unique displacement loop (D‐loop), which controls the transcription and replication of mtDNA. MtDNA is considered to be more vulnerable to oxidative damage and to have a higher mutation rate compared with nuclear DNA due to the lack of a repair system and protective histones within the mitochondria [5,6]. Damage to and somatic mutations of mtDNA may lead to impairment of the OXPHOS system and increased ROS production, which subsequently enhances the rate of LI et al: MITOCHONDRIAL DNA D-LOOP REGION VARIATIONS AND OUTCOMES OF HCC

Methods

Results

Conclusion