Elsevier

Journal of Hepatology

Volume 57, Issue 3, September 2012, Pages 621-627
Journal of Hepatology

Research Article
Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: Possible implications on survival

https://doi.org/10.1016/j.jhep.2012.04.039Get rights and content

Background & Aims

We aimed at determining whether single nucleotide polymorphisms (SNPs) of DNA repair genes influence the development and clinical outcomes of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).

Methods

We evaluated 14 SNPs of eight DNA repair genes in 708 patients with HCC and 388 HBsAg positive controls without HCC. The Kaplan–Meier methods with log-rank test and Cox regression models were used to compare survival of HCC patients according to the genotype.

Results

The SNP of XRCC4 rs1805377 was significantly associated with decreased risk of HCC development (OR, 0.592; p = 0.028) and improved overall survival of patients with HCC (median survival time (MST) of 48, 72, and 89 months for the AA, AG, and GG genotypes, respectively; p = 0.044). In addition, SNP of OGG1 rs1053133 was significantly associated with postoperative recurrence (OR, 0.604; p = 0.049), tumor differentiation (OR, 0.571; p = 0.041), and improved survival of resected HCC (MST of 55 and 108 months for the GG and GC/CC genotypes, p = 0.001). The multivariate analysis showed that OGG1 rs1052133, XRCC1 rs25487, ERCC5 rs2018836, ERCC5 rs3818356, and XRCC4 rs1805377 had a significant effect on survival. Moreover, a strong dose-dependent association was observed between the number of putative high-risk genotypes of OGG1, XRCC1, ERCC5, and XRCC4 with the overall survival. The MST of HCC with ⩽2 putative high-risk genotypes was significantly prolonged compared to those with ⩾3 high-risk genotypes (76 vs. 46 months, respectively, p = 0.002).

Conclusions

Polymorphisms of DNA repair genes play a potential role in the development, progression, and survival of Korean HCC patients with chronic HBV infection.

Introduction

Chronic hepatitis B virus (HBV) infection is one of the established etiologic agents of hepatocelluar carcinoma (HCC) worldwide, which contributes to the development of the majority of HCC cases in Korea [1], [2]. However, only a small proportion of chronic HBV carriers develop HCC in their lifetime, suggesting that other risk factors may contribute to the inter-individual variation in susceptibility to hepatocarcinogenesis [3]. In addition, various genetic factors appear to influence the outcome of HBV infections [4], [5], [6]. Based on the current knowledge of cancer molecular pathogenesis, polymorphic variations such as single nucleotide polymorphism (SNP) within several gene classes are considered to be important for tumor development.

It is suggested that the majority of HCC cases result from DNA damage caused by hepatitis viruses; this is the major underlying factor that predisposes to the development of HCC [7]. Damage resulting from endogenous or exogenous exposure may be repaired by enzymes encoded by one or more DNA repair pathways. In humans, more than 70 genes are involved in the five main DNA repair pathways: base excision repair (BER), nucleotide excision repair (NER), mismatch repair, homologous recombination repair, and non-homologous end joining (NHEJ). Defective DNA repair can lead to the accumulation of mutations and microsatellite instability in the genome, increasing the chance of malignant transformation [8]. Genetic variation may alter the function of DNA repair proteins, influencing the risk of development and clinical outcomes of HCC.

Although many studies have been published on the associations between SNPs of DNA repair genes and the risk of various cancers [9], few studies have reported on the associations between SNPs of DNA repair genes and HCC. In this study, we investigated the association between selective SNPs of DNA repair genes and the risk of HCC development and its clinical outcomes.

Section snippets

Study population

Patients with HCC were recruited consecutively from two hospitals (Asan Medical Center and Ulsan University Hospital) in Korea from 1999 to 2010. A total of 708 Korean patients who were hepatitis B virus surface antigen (HBsAg) carriers with HCC were included. The diagnosis of HCC was made by liver biopsy or the combination of increased alpha-fetoprotein (AFP of ⩾200 ng/ml) and the typical vascular pattern on angiography or dynamic imaging [10]. The control group consisted of 388 inactive HBsAg

Characteristics of the study population

The age and gender distributions of the studied population were similar between HCC cases and controls. The mean age at enrollment was 53.3 for the cases and 52.6 years for the control group. The male/female ratio was also similar between HCC patients and controls (582:126 vs. 322:66, p = 0.803). The patient characteristics and clinicopathologic features of the tumor are summarized in Table 2. Of the 708 patients, 314 had their primary tumor surgically resected; the remaining 394 patients

Discussion

In this study, we evaluated the effect of 14 SNPs of eight DNA repair genes on the development, tumor progression, and overall survival of patients with HBV-associated HCC. To the best of our knowledge, this is the first study to describe the association between SNPs of DNA repair genes and clinical outcomes of HCC. We demonstrated that the XRCC4 rs1805377 variant genotype was significantly associated with the development of HCC. Moreover, the SNP of XRCC4 rs1805377, both alone and in

Financial support

This study was supported by Priority Research Center Program through National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology 2009-0094053.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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      Additionally, haplotype analysis of XRCC5 showed that, AA in block 1 (composed of rs828704 and rs16855458) and CGGTT in block 2 (composed of rs668844, rs207916, rs3770502, rs9288516 and rs1051677) were associated with decreased risk of HCC compared with the most common haplotypes [151]. For XRCC5 rs3835 polymorphism, Jung and colleagues investigated its association with the risk of HCC in Korean population but demonstrated no significant association [40]. Furthermore, no significant relation between XRCC5 rs80309960 polymorphism and risk of HCC induced by AFB1 exposure was found by Long et al. in Chinese population [145].

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