Xeroderma Pigmentosum Complementation Group D (XPD) Codon 751 and Exonuclease 1 Glu 589 Lysgene Polymorphismsare Associated with Hepatocellular Carcinoma in Egyptian Patients with HCV (Genotype-4)

Research Article

Austin Virol and Retrovirology. 2016; 3(2): 1022.

Xeroderma Pigmentosum Complementation Group D (XPD) Codon 751 and Exonuclease 1 Glu 589 Lysgene Polymorphismsare Associated with Hepatocellular Carcinoma in Egyptian Patients with HCV (Genotype-4)

EL-Abd NE¹, Kamal AM¹, Siam IM² and Shousha HI³*

¹Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Egypt

²Internal Medicine Department, National Research Center, Egypt

³Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Egypt

*Corresponding author: Hend Ibrahim Shousha, Endemic Medicine and Hepatogastroenterology Department - Kasr Al Ainy Hospital, Faculty of Medicine, Cairo University, Egypt

Received: February 27, 2016; Accepted: July 28, 2016; Published: August 03, 2016


Aim: Xeroderma Pigmentosum Complementation Group D (XPD) is a major DNA repair gene in Nucleotide Excision repair system. Exonuclease 1 (Exo 1) is an important modulator in mismatch repair system. Our aim is to investigate the association of XPD/ERCC2 Lys751Gln (A/C) (rs 13181) and Exo- 1 Glu 589 Lys (G/A) (K589E) polymorphisms with Hepatocellular Carcinoma (HCC) in Egyptian patients.

Methods: Fifty HCC patients and 50 healthy controls were included. Genotyping for XPD/ERCC2 Lys751Gln was performed by Real-Time PCR and for Exo- 1 (K589E) Glu/Lys by PCR- RFLP.

Results: Patients with XPD Lys751Gln combined (AC + CC) genotypes had an increased risk of HCC compared to the wild AA genotype (p = 0.027, OR = 2.47). The mutant C allele frequency was higher in HCC than in controls, (p = 0.035). Mean serum albumin level was lower in patients carrying (AC + CC) genotypes than in AA genotype (p = 0.027). Median serum levels of ALT, AFP and creatinine were higher in AA genotype than in combined genotypes (p = 0.011, 0.007, 0.045 respectively). Exo- 1 Glu 589 Lys (AA) mutant genotype was associated with increased risk of HCC (p = 0.031).The frequency of the mutant A allele was higher in HCC compared to controls, (p = 0.044). Serum creatinine in wild type was higher than in other genotypes (p = 0.034).

Conclusion: XPD Lys751Gln and Exo- 1 Glu589 Lys gene polymorphisms are important HCC modulators in Egyptian patients with HCV genotype 4.

Keywords: HCC; XPD Lys751Gln (A/C); Exo- 1 Glu 589 Lys (G/A); RTPCR; RFLP


Globally, Hepatocellular Carcinoma (HCC) is one of the most common malignancies ranking the sixth [1] and it is the fastest growing cause of death in cancer patients in Asia [2]. In Egypt, HCC is the principal cancer among men; with the main risk factors are Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV) [3]. Being a complex process with multiple etiologies, the pathogenesis of HCC is not fully understood and thus requires urgent studies [2]. DNA response to cell damage during the early stages of carcinogenesis has been reported in many types of cancer [4]. Genomic instability preceding HCC has been accused for malignant transformation [5]. The genomic integrity is seriously threatened by DNA break. Inactivation of DNA repair results in uncontrolled cell proliferation and hence increases cancer risk [6]. Xeroderma Pigmentosum group D (XPD) is one of the major players in Nucleotide Excission Repair (NER) pathway [7]. The XPD Lys751Gln (rs13181) polymorphism has been shown to have an effect on DNA repair capacity, possibly by altering the amino acid sequence of the protein [8], leading to reduced repair capacity and increased cancer susceptibility [9].

In HCC, the XPD Lys751Gln was strongly related to HCC risk in Chinese population [10]. Human DNA repair mechanisms are thought to prevent or delay genetic instability, thus acting as a barrier against cancer development [11,12]. The Mismatch Repair (MMR) is one of the major DNA repair pathways in human cells, which maintains the stability of genome, mediates DNA recombination, and modulates cell cycle arrest [13]. The gene Exonuclease 1 (Exo 1) belongs to the MMR system, A guanine (G)/adenine (A) common single nucleotide polymorphism at first position of codon 589 in exon 13 of Exo 1 gene, results in the substitution of glutamic acid (Glu, E) residue (GAG) bylysine (Lys, K) residue (AAG) (Exo 1 K589E) and has been suggested to influence the products of Exo 1 mRNA [14]. Several studies have investigated the relation between Exo- 1 (K589E) polymorphism and risk of cancer such as; lung cancer [15], breast cancer [16], gastric cancer [17] and gliomas [18]. Accordingly, we hypothesized that K589E polymorphism in Exo 1 gene may act as a genetic modifier in the susceptibility to HCC. We aimed to study the relationship of XPD/ERCC2 Lys751Gln (A/C) and Exo- 1 Glu 589 Lys (G/A) genes and HCC.


This is a case control study carried out on 100 subjects divided into two groups:

Group I: included 50 patients with HCC, selected from Endemic medicine and hepatogastroentrology department at Kasr al Ainy Hospital, Cairo University. Patients with liver masses discovered on surveillance by ultrasonography were further investigated by serum Alpha Fetoprotein Level (AFP) and Computed Tomography (CT) scan or Magnetic Resonance (MRI). HCC was diagnosed according to the American Association for the Study of Liver Diseases (AASLD) updated practice guidelines [19].

Group II: Included 50 apparently healthy participants with no evidence of liver disease as a control group.

Before the start of enrolling our participants, we obtained a written informed consent from all of them. Our study protocol and consent were approved by ethics committee of Cairo University Hospital. All procedures performed in our study were in accordance with the ethical standards of the ethics committee of Cairo University Hospital and with the 1964 Helsinki declaration and its later amendments.

HCC patients were subjected to: