Open access peer-reviewed chapter

X-Ray Repair Cross Complementing 4 (XRCC4) Genetic Single Nucleotide Polymorphisms and the Liver Toxicity of AFB1 in Hepatocellular Carcinoma

Written By

Yan Deng, Xue-Min Wu, Xiao-Ying Huang and Xi-Dai Long

Submitted: April 13th, 2019Reviewed: July 22nd, 2019Published: September 16th, 2019

DOI: 10.5772/intechopen.88752

Chapter metrics overview

608 Chapter Downloads

View Full Metrics

Abstract

Our previous reports have shown that the genetic single-nucleotide polymorphisms (GSNPs) in the DNA repair gene X-ray repair cross complementing 4 (XRCC4) are involved in the carcinogenesis of hepatocellular carcinoma (HCC) induced by aflatoxin B1 (AFB1). However, the effects of GSNPs in the coding regions of XRCC4 on hepatic toxicity of AFB1 have been less investigated. We conducted a hospital-based clinic tissue samples with pathologically diagnosed HCC (n = 380) in a high AFB1 exposure area to explore the possible roles of GSNPs in the coding regions of XRCC4 in AFB1-induced HCC using liver toxicity assays. A total of 143 GSNPs were included in the present study and genotyped using the SNaPshot method, whereas the liver toxicity of AFB1 was evaluated using AFB1-DNA adducts in the tissues with HCC. In the clinicopathological samples with HCC, the average adduct amount is 2.27 ± 1.09 μmol/mol DNA. Among 143 GSNPs of XRCC4, only rs1237462915, rs28383151, rs762419679, rs766287987, and rs3734091 significantly increased the levels of AFB1-DNA adducts. Furthermore, XRCC4 GSNPs (including rs28383151, rs766287987, and rs3734091) also increased cumulative hazard for patients with HCC. These results suggest that the liver toxicity of AFB1 may be modified by XRCC4 GSNPs.

Keywords

  • AFB1
  • liver toxicity
  • XRCC4
  • genetic single-nucleotide polymorphism
  • hepatocellular carcinoma

1. Introduction

Aflatoxin B1 (AFB1) is an important type I chemical toxicant mainly produced by the toxigenic strains of Aspergillus flavus(A. flavus) and Aspergillus parasiticus(A. parasiticus) [1, 2]. This carcinogen is often taken into human body via contaminating human foods such as nuts and cereals and displays its toxic effects, especially hepatic toxicity [1, 2, 3, 4, 5, 6, 7, 8]. AFB1-induced hepatic effects consist of acute toxic damages (such as severe DNA damage, severe liver degeneration and necrosis, and the failure of hepatic function) and chronic cumulative damages (such as a series of cumulative DNA damage, slight hepatocellular degeneration and necrosis, chronic inflammation, liver cirrhosis, and liver cancer) [3, 4, 5]. Increasing evidence has shown that under the same exposure of AFB1, some individuals feature severe hepatic damage; others have no noticeable damage [9, 10, 11, 12, 13, 14]. This suggests that different individuals have different responses to the toxic effects of AFB1 and genetic factors may play a central role in the AFB1-induced hepatic toxicity.

X-ray repair cross complementing 4 (XRCC4), an important DNA repair gene involved in nonhomologous end-joining (NHEJ) repair pathway, plays a scaffold function via stabilizing and localizing DNA repair enzymes LIG IV, Ku70/80 heterodimer, and the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) in the ends of DNA double-stranded breaks (DSBs) during NHEJ [15, 16]. In the past decades, growing reports have exhibited that the abnormal structures and functions of XRCC4 may alter the capacity of DNA repair and ultimately result in human diseases [17, 18, 19, 20, 21, 22]. Several recent studies have also shown that the genetic alterations in the coding regions of XRCC4 can modify hepatocellular carcinoma (HCC) risk and prognosis [23, 24, 25, 26, 27]. However, the effects of this genetic alteration on the hepatic toxicity of AFB1 is unclear. Here, we conducted a clinical sample study exposure to explore whether the genetic single-nucleotide polymorphisms (GSNPs, a type of genetic alterations) in the coding regions of XRCC4 modified the effects of AFB1 on hepatic damage.

Advertisement

2. Materials and methods

2.1 Study population

This was a hospital-based molecular epidemiological study conducted in high AFB1 exposure area, Guangxi Zhuang Region, China. All participants were newly diagnosed HCC cases and recruited from the Affiliated Hospitals of Youjiang Medical University for Nationalities (located at Bose region, a major AFB1 exposure area) between January 2010 and January 2013 inclusively. The inclusive criteria of cases consisted of (a) cases with ultimately histopathologically confirmed HCC; (b) cases without any evidence of hepatitis virus infection; (c) cases with the history of AFB1 exposure which was defined according to positive history of peripheral serum AFB1-albumin adducts [5, 24]; and (d) cases with available tumor tissue samples and clinicopathological data.

According to the criteria, a total of 380 cases with HCC were recruited in this study during the period. With informed consent, the tissue samples with HCC for all patients and clinicopathological data were collected. Additionally, survival follow-up information was also collected through cases themselves or their family contact. In this study, the last follow-up date was set on January 31, 2019. The protocol for clinical samples was approved by Youjiang Medical University for Nationalities Medical Ethics Committee.

2.2 The evaluation of AFB1-related hepatic toxicity

Hepatic toxicity of AFB1 was evaluated using AFB1-DNA adducts in the tissue samples with HCC, and the amounts of AFB1-DNA adducts were tested by the previously described enzyme-linked immunosorbent assay (ELISA).

2.3 GSNP selection

All GSNPs of XRCC4 gene were first screened from the SNPdatabase (http://asia.ensembl.org/Homo_sapiens/Gene/Variation_Gene/Table?db=core;g=ENSG00000152422;r=5:83077498-83353787). According to the data from SNPdatabase, a total of 143 GSNPs can result in missense mutations and the change of amino acids in XRCC4 protein, and thus they were ultimately selected for final analyses.

2.4 Genotypic analyses

Genomic DNA in all tumor tissue samples with HCC was standard phenol-chloroform extraction binding with proteinase K. The GSNPs of XRCC4 were genotyped using SNaPshot method (Applied Biosystems [ABI], Foster City, CA) as previously described [28]. For quality control, all laboratory personnel were blind to the status of every sample with hepatocarcinoma, and controls were also included in each analysis.

2.5 Statistical analysis

The test for genotypic distribution of XRCC4 GSNPs among HCC cases featuring different AFB1-DNA adducts was accomplished using student t-test or one-way analysis of variance (ANOVA) test. Multiple tests were adjusted using a Bonferronicorrection, and the threshold for GSNP screening was defined as α = 3.53 × 10−4. Kaplan-Meier survival model with log-rank test and Cox regression model (the selection of significant varies based on forward-step method with likelihood ratio test) was used to analyze the association between XRCC4 GSNPs and HCC outcomes. Cumulative hazard value for the effects of XRCC4 GSNPs on the hepatic toxicity for AFB1 and corresponding 95% confidence interval (CI) were calculated using hazard ratio (HR) from significant multivariate Cox regression model (including all significant variates). All statistical analyses were performed with SPSS statistical package (Version 18, SPSS Institute, Chicago, IL, USA).

Advertisement

3. Results

3.1 The characteristics of subjects

All subjects suffered from hepatic carcinoma, and Table 1 summarized their characteristics. The mean age of all participants was 50.74 ± 11.55 years, and more than 70% of them are male. For these cancer patients, 70.3% (267/380) and 26.3% (100/380) cases featured TNM II and III stages of tumor, and they also had an average AFB1 exposure value of 2.27 ± 1.09 μmol/mol DNA.

n%
Total380100.0
Age (years)
≤355313.9
36–403810.0
41–455514.5
46–504311.3
51–555614.7
56–604211.1
61–654912.9
≥664411.6
Gender
Male27171.3
Female10928.7
Race
Han22158.2
Zhuang15941.8
TNM stage
I–II133.4
III26770.3
IV10026.3

Table 1.

The characteristics of subjects.

3.2 XRCC4 GSNPs increased AFB1-DNA adducts

A total of 143 GSNPs in the coding regions of XRCC4 gene were selected in our final analyses, and Table 2 showed the genotypic distribution of all GSNPs. To evaluate the effects of these potential GSNPs on AFB1-DNA adducts, the role of each GSNP in the coding regions of XRCC4 gene was tested using Student t-test or ANOVA test with the adjustment of multiple test. Among these GSNPs, only rs1237462915 (cat#SNP016, at codon 38), rs28383151 (cat#SNP026, at codon 56), rs762419679 (cat#SNP069, at codon 127), rs766287987 (cat#SNP112, at codon 203), and rs3734091 (cat#SNP138, at codon 247) significantly affected the levels of AFB1-DNA adducts in the tumor tissues with HCC. The adduct amounts of their wild genotypes (defined as XX genotype) were 2.15 ± 0.97 μmol/mol DNA, 2.07 ± 0.99 μmol/mol DNA, 2.12 ± 0.86 μmol/mol DNA, 2.11 ± 0.89 μmol/mol DNA, and 2.09 ± 0.97 μmol/mol DNA, respectively. For their mutant heterozygotic genotypes (defined as XY genotype), the amounts of AFB-DNA adduct were from 2.64 to 4.33 μmol/mol DNA, whereas the adduct levels were from 3.04 to 5.78 for the mutant homozygotic genotypes (defined as YY genotype) (Table 2).

No.SNP IDChr: bpAlleles (x/y)aGenotypes (xx/xy/yy)bAmino acid positionAmino acid changeNxx/xy/yycAdducts (mean ± SD)Pd
SNP001rs1425751705:83104923G/AGG/GA/AA2E/K323/54/32.28 ± 1.09/2.21 ± 1.08/2.36 ± 1.050.23
SNP002rs14496314255:83104929A/GAA/AG/GG4K/E377/3/02.27 ± 1.09/2.21 ± 0.54/−0.99
SNP003rs11668908645:83104930A/GAA/AG/GG4K/R378/2/02.27 ± 1.09/1.57 ± 0.03/−0.99
SNP004rs14256429305:83104933T/GTT/TG/GG5I/R376/4/02.27 ± 1.09/2.10 ± 0.61/−0.96
SNP005rs12528239085:83104946C/ACC/CA/AA9H/Q376/4/02.27 ± 1.09/2.16 ± 0.56/−0.94
SNP006rs283831385:83104954C/GCC//CG/GG12S/C319/47/142.26 ± 1.09/2.41 ± 1.06/2.00 ± 1.070.23
SNP007rs7740711305:83104966T/CTT/TC/CC16I/T370/10/02.28 ± 1.09/2.05 ± 0.94/−0.99
SNP008rs7616954705:83104971C/TCC/CT/TT18H/Y371/6/32.24 ± 1.03/2.87 ± 2.00/4.42 ± 2.930.04
SNP009rs7557765725:83104983G/AGG/GA/AA22V/I380/0/02.27 ± 1.09/−/−
SNP010rs12711809275:83104986T/ATT/TA/AA23S/T364/13/32.26 ± 1.09/2.52 ± 1.04/2.44 ± 0.770.89
SNP011rs12886817865:83104992G/AGG/GA/AA25E/K354/26/02.28 ± 1.10/2.16 ± 0.96/−0.56
SNP012rs5507733085:83104999C/TCC/CT/TT27T/I367/13/02.26 ± 1.06/2.51 ± 1.80/−0.63
SNP013rs14842505825:83105006A/CAA/AC/CC29E/D376/4/02.27 ± 1.09/2.18 ± 1.42/−0.87
SNP014rs13056794085:83105013T/ATT/TA/AA32F/I350/30/02.27 ± 1.08/2.26 ± 1.14/−0.96
SNP015rs12320774875:83105022A/GAA/AG/GG35T/A380/0/02.27 ± 1.09/−/−
SNP016rs12374629155:83105031G/TGG/GT/TT38D/Y352/19/92.15 ± 0.97/3.62 ± 1.40/4.21 ± 0.932.96 × 10−5
SNP017rs7485407435:83105032A/TAA/AT/TT38D/V380/0/02.27 ± 1.09/−/−
SNP018rs7587790995:83105039T/GTT/TG/GG40H/Q353/25/22.23 ± 1.03/2.78 ± 1.61/2.63 ± 0.010.04
SNP019rs5877793515:83105046T/CTT/TC/CC43W/R380/0/02.27 ± 1.09/−/−
SNP020rs7711118165:83105050C/TCC/CT/TT44T/I362/25/32.26 ± 1.08/2.33 ± 1.23/2.68 ± 0.070.78
SNP021rs14600041205:83105053G/CGG/GC/CC45G/A375/5/02.27 ± 1.09/2.21 ± 0.82/−0.91
SNP022rs12488353275:83111031C/TCC/CT/TT48S/F370/10/02.27 ± 1.09/2.21 ± 1.01/−0.87
SNP023rs13263596945:83111033G/AGG/GA/AA49E/K355/25/02.28 ± 1.11/2.16 ± 0.76/−0.61
SNP024rs8682070055:83111039G/AGG/GA/AA51E/K380/0/02.27 ± 1.09/−/−
SNP025rs9451552695:83111049A/CAA/AC/CC54Q/P364/26/02.29 ± 1.07/2.02 ± 1.04/−0.24
SNP026rs283831515:83111054G/AGG/GA/AA56A/T277/63/402.07 ± 0.99/2.64 ± 1.33/3.04 ± 0.782.83 × 10−55
SNP027rs12451277675:83111063A/GAA/AG/GG59M/V354/25/12.27 ± 1.10/2.18 ± 0.92/2.78*0.67*
SNP028rs7481245095:83111066G/TGG/GT/TT60A/S354/23/32.25 ± 1.11/2.36 ± 0.74/2.78 ± 1.010.66
SNP029rs7605463085:83111070T/CTT/TC/CC61M/T352/28/02.27 ± 1.04/2.25 ± 1.56/−0.91
SNP030rs13695654705:83111071G/CGG/GC/CC61M/I380/0/02.27 ± 1.09/−/−
SNP031rs8675745055:83111072G/AGG/GA/AA62E/K380/0/02.27 ± 1.09/−/−
SNP032rs12855576995:83111073A/GAA/AG/GG62E/G380/0/02.27 ± 1.09/−/−
SNP033rs12482974535:83111085A/GAA/AG/GG66Y/C351/29/02.26 ± 1.07/2.36 ± 1.25/−0.63
SNP034rs7763628145:83111087G/AGG/GA/AA67V/I350/30/02.26 ± 1.11/2.31 ± 0.84/−0.83
SNP035rs14239280755:83111090G/AGG/GA/AA68G/S380/0/02.27 ± 1.09/−/−
SNP036rs14785059615:83111093G/AGG/GA/AA69E/K250/28/22.27 ± 1.07/2.24 ± 1.28/2.69 ± 1.160.86
SNP037rs7590643785:83111097T/CTT/TC/CC70L/P354/26/02.28 ± 1.09/2.15 ± 1.01/−0.58
SNP038rs3713070715:83111100G/CGG/GC/CC71R/T380/0/02.27 ± 1.09/−/−
SNP039rs617629705:83111112T/CTT/TC/CC75L/S356/24/02.29 ± 1.10/1.99 ± 0.89/−0.20
SNP040rs7635014785:83111117G/AGG/GA/AA77G/R361/29/02.27 ± 1.09/−/−
SNP041rs7645724195:83111120G/TGG/GT/TT78A/S349/31/02.26 ± 1.09/2.39 ± 1.09/−0.52
SNP042rs5282594645:83111121C/TCC/CT/TT78A/V376/4/02.26 ± 1.09/2.77 ± 0.44/−0.36
SNP043rs7576449475:83111126C/TCC/CT/TT80P/S369/11/02.26 ± 1.07/2.51 ± 1.51/−0.46
SNP044rs5726133615:83111138T/CTT/TC/CC84Y/H351/27/22.27 ± /2.24 ± 1.02/3.09 ± 0.470.57
SNP045rs13989277375:83111141A/CAA/AC/CC85T/P380/0/02.27 ± 1.09/−/−
SNP046rs7562475525:83111142C/TCC/CT/TT85T/M374/6/02.26 ± 1.08/2.56 ± 1.35/−0.50
SNP047rs1493559965:83111147A/TAA/AT/TT87N/Y371/9/02.27 ± 1.10/2.36 ± 0.70/−0.81
SNP048rs10496316865:83111162T/ATT/TA/AA92S/T364/26/02.27 ± 1.09/−/−
SNP049rs7721904205:83111169A/GAA/AG/GG94Y/C354/26/02.28 ± 1.08/2.08 ± 1.23/−0.36
SNP050rs12390841985:83111171T/GTT/TG/GG95F/V356/24/02.26 ± 1.07/2.36 ± 1.34/−0.68
SNP051rs11847634005:83111174T/ATT/TA/AA96F/I380/0/02.27 ± 1.09/−/−
SNP052rs12363263835:83111177T/CTT/TC/CC97F/L366/14/02.28 ± 1.09/1.92 ± 0.92/−0.24
SNP053rs14728434655:83111180G/AGG/GA/AA98E/K377/3/02.27 ± 1.09/2.58 ± 0.84/−0.63
SNP054rs1446531145:83111195G/AGG/GA/AA103N/D240/127/132.17 ± 1.09/2.48 ± 1.08/2.11 ± 0.840.03
SNP055rs795614515:83195782T/CTT/TC/CC110S/P352/25/32.28 ± 1.11/2.20 ± 0.84/1.82 ± 0.370.74
SNP056rs7571133915:83195787C/GCC//CG/GG111F/L380/0/02.27 ± 1.09/−/−
SNP057rs13787859465:83195794G/CGG/GC/CC114E/Q360/20/02.277 ± 1.10/2.227 ± 0.84/−0.83
SNP058rs12407714895:83195795A/GAA/AG/GG114E/G281/80/192.297 ± 1.09/2.197 ± 1.06/−0.75
SNP059rs7695564945:83195797A/GAA/AG/GG115K/E340/40/02.277 ± 1.09/2.277 ± 1.04/−0.99
SNP060rs10569391255:83195798A/CAA/AC/CC115K/T380/0/02.27 ± 1.09/−/−
SNP061rs13011377295:83195800G/CGG/GC/CC116V/L359/21/02.27 ± 1.09/2.19 ± 0.99/−0.74
SNP062rs5501787385:83195807A/TAA/AT/TT118N/I341/39/02.27 ± 1.10/2.28 ± 1.00/−0.93
SNP063rs3751571055:83195809C/ACC/CA/AA119P/T352/28/02.29 ± 1.102.06 ± 0.83/−0.28
SNP064rs7681757175:83195810C/TCC/CT/TT119P/L380/0/02.27 ± 1.09/−/−
SNP065rs3696415365:83195816A/GAA/AG/GG121E/G380/0/02.27 ± 1.09/−/−
SNP066rs13951940115:83195819T/ATT/TA/AA122V/D289/81/102.24 ± 1.07/2.62 ± 1.22/−0.05
SNP067rs11984919105:83195821A/GAA/AG/GG123I/V348/32/02.27 ± 1.09/2.25 ± 1.13/−0.95
SNP068rs11598523765:83195824A/GAA/AG/GG124R/G369/11/02.26 ± 1.10/2.40 ± 0.88/−0.64
SNP069rs7624196795:83195834T/CTT/TC/CC127I/T359/15/62.12 ± 0.86/4.33 ± 1.99/5.99 ± 1.121.17 × 10−43
SNP070rs14125064845:83195840A/GAA/AG/GG129Y/C349/31/02.27 ± 1.10/2.26 ± 1.32/−0.96
SNP071rs11788706825:83195848G/CGG/GC/CC132D/H365/15/02.27 ± 1.10/2.26 ± 0.78/−0.98
SNP072rs14840477165:83195852C/GCC//CG/GG133T/S374/6/02.26 ± 1.07/2.71 ± 1.90/−0.32
SNP073rs283601355:83195855T/CTT/TC/CC134I/T304/64/122.31 ± 1.13/2.12 ± 0.90/2.12 ± 0.690.39
SNP074rs13358017745:83195856T/GTT/TG/GG134I/M380/0/02.27 ± 1.09/−/−
SNP075rs3727747935:83195857G/CGG/GC/CC135A/P358/22/02.27 ± 1.06/2.25 ± 1.46/−0.92
SNP076rs13848329195:83195863A/GAA/AG/GG137N/D368/12/02.27 ± 1.10/2.00 ± 0.59/−0.38
SNP077rs563345225:83195865T/GTT/TG/GG137N/K366/13/12.26 ± 1.10/2.53 ± 0.80/1.34b0.89
SNP078rs3700371645:83195869G/AGG/GA/AA139A/T292/84/42.28 ± 1.06/2.23 ± 1.18/2.49 ± 0.830.89
SNP079rs3748925155:83195876A/GAA/AG/GG141N/S380/0/02.27 ± 1.09/−/−
SNP080rs283601365:83195878G/CGG/GC/CC142E/Q254/111/152.33 ± 1.10/2.12 ± 1.02/2.35 ± 1.260.21
SNP081rs5531112665:83195883C/ACC/CA/AA143H/Q373/7/02.26 ± 1.09/2.75 ± 1.07/−0.24
SNP082rs10222115085:83195897A/GAA/AG/GG148N/S342/38/02.30 ± 1.11/2.03 ± 0.79/−0.15
SNP083rs7572786305:83195903G/AGG/GA/AA150R/K378/12/02.27 ± 1.09/1.99 ± 1.01/−0.36
SNP084rs13751075695:83195905C/TCC/CT/TT151L/F380/0/02.27 ± 1.09/−/−
SNP085rs12778647225:83195912G/AGG/GA/AA153R/K355/25/02.29 ± 1.01/1.93 ± 0.72/−0.02
SNP086rs7457517155:83195922T/GTT/TG/GG156N/K289/89/22.28 ± 1.04/2.25 ± 1.23/2.12 ± 1.830.97
SNP087rs12018117425:83195924A/CAA/AC/CC157D/A353/26/12.24 ± 1.07/2.67 ± 1.22/2.72e0.13
SNP088rs3694998845:83195930A/GAA/AG/GG159Q/R367/13/02.28 ± 1.09/2.03 ± 1.08/−0.42
SNP089rs3724938825:83195933G/TGG/GT/TT160G/V250/30/02.29 ± 1.10/2.07 ± 0.97/−0.30
SNP090rs11566891635:83203553T/GTT/TG/GG162F/V380/0/02.27 ± 1.09/−/−
SNP091rs13251516925:83203554T/ATT/TA/AA162F/Y345/95/02.26 ± 1.04/2.39 ± 1.46/−0.49
SNP092rs3757315845:83203566T/GTT/TG/GG166V/G355/25/02.25 ± 1.09/2.48 ± 0.97/−0.32
SNP093rs13594882755:83203568A/TAA/AT/TT167S/C380/0/02.27 ± 1.09/−/−
SNP094rs7536053515:83203575A/CAA/AC/CC169K/T385/15/02.26 ± 1.10/2.40 ± 0.89/−0.64
SNP095rs13762954515:83203587A/TAA/AT/TT173E/V340/40/02.28 ± 1.10/2.18 ± 0.98/−0.58
SNP096rs7784220155:83203595C/TCC/CT/TT176L/F380/0/02.27 ± 1.09/−/−
SNP097rs7773007425:83203599A/GAA/AG/GG177Y/C354/26/02.26 ± 1.08/2.39 ± 1.24/−0.57
SNP098rs1401434475:83203604C/TCC/CT/TT179R/W372/8/02.28 ± 1.09/1.69 ± 0.56/−0.13
SNP099rs7715448815:83203605G/AGG/GA/AA179R/Q380/0/02.27 ± 1.09/−/−
SNP100rs7771956305:83203607T/CTT/TC/CC180F/L354/26/02.22 ± 1.04/2.89 ± 1.51/−0.04
SNP101rs13794086355:83203610A/TAA/AT/TT181I/F338/41/12.26 ± 1.07/2.37 ± 1.22/2.98e0.67
SNP102rs11998848175:83203611T/CTT/TC/CC181I/T345/35/−2.27 ± 1.08/2.26 ± 1.20/−0.96
SNP103rs10188794955:83203623A/TAA/AT/TT185N/I366/14/02.27 ± 1.09/2.18 ± 0.94/−0.76
SNP104rs14822882795:83203635C/TCC/CT/TT189T/I380/0/02.27 ± 1.09/−/−
SNP105rs7702179165:83203641T/ATT/TA/AA191I/N341/38/12.28 ± 1.10/2.10 ± 0.90/4.31b0.11
SNP106rs7755872995:83203644G/TGG/GT/TT192R/I351/24/52.28 ± 1.09/2.24 ± 1.16/1.94 ± 0.640.79
SNP107rs7631861485:83203652C/TCC/CT/TT195H/Y328/50/22.28 ± 1.11/2.23 ± 0.97/2.18 ± 0.470.95
SNP108rs11737487375:83203653A/GAA/AG/GG195H/R380/0/02.27 ± 1.09/−/−
SNP109rs7641098445:83203654T/GTT/TG/GG195H/Q380/0/02.27 ± 1.09/−/−
SNP110rs14584863325:83203659A/GAA/AG/GG197K/R380/0/02.27 ± 1.09/−/−
SNP111rs12630790735:83203676C/GCC//CG/GG203Q/E355/25/−2.28 ± 1.09/2.18 ± 1.09/−0.69
SNP112rs7662879875:83203678A/TAA/AT/TT203Q/H357/16/72.11 ± 0.89/4.15 ± 0.77/5.78 ± 1.171.05 × 10−59
SNP113rs7787233975:83203683G/AGG/GA/AA205R/Q365/15/02.29 ± 1.09/1.87 ± 0.97/−0.15
SNP114rs7771996095:83203691G/CGG/GC/CC208D/H292/86/22.22 ± 1.05/2.43 ± 1.18/2.86 ± 1.400.20
SNP115rs12247052615:83203694A/GAA/AG/GG209I/V380/0/02.27 ± 1.09/−/−
SNP116rs2016044245:83203698A/GAA/AG/GG210K/R300/72/82.29 ± 1.11/2.15 ± 0.97/2.77 ± 1.030.26
SNP117rs12761578335:83203701A/GAA/AG/GG211Q/R371/9/02.28 ± 1.08/1.82 ± 1.17/−0.22
SNP118rs12984018735:83203706G/AGG/GA/AA213G/R359/21/02.29 ± 1.10/1.93 ± 0.87/−0.14
SNP119rs7464076585:83204816G/AGG/GA/AA214E/K291/79/102.30 ± 1.10/2.22 ± 1.09/1.72 ± 0720.23
SNP120rs9694675945:83204820C/GCC//CG/GG215T/S380/0/02.27 ± 1.09/−/−
SNP121rs7803306535:83204823C/ACC/CA/AA216A/E307/61/122.24 ± 1.08/2.46 ± 1.19/2.06 ± 0.720.28
SNP122rs13484643425:83204825A/GAA/AG/GG217I/V375/5/02.27 ± 1.09/2.46 ± 0.94/−0.69
SNP123rs7496478605:83204828T/GTT/TG/GG218C/G358/22/02.27 ± 1.08/2.22 ± 1.23/−0.84
SNP124rs9083261265:83204840A/GAA/AG/GG222T/A380/0/02.27 ± 1.09/−/−
SNP125rs13476646695:83204847A/GAA/AG/GG224D/G354/26/02.26 ± 1.09/2.38 ± 1.12/−0.58
SNP126rs8664776945:83204848C/ACC/CA/AA224D/E380/0/02.27 ± 1.09/−/−
SNP127rs7745556755:83204850G/AGG/GA/AA225R/Q348/32/02.28 ± 1.10/2.11 ± 0.97/−0.39
SNP128rs7483075855:83204852G/AGG/GA/AA226D/N285/86/92.29 ± 1.09/2.20 ± 1.09/2.37 ± 1.120.77
SNP129rs3681069555:83204867G/AGG/GA/AA231E/K380/0/02.27 ± 1.09/−/−
SNP130rs1405799165:83204874C/ACC/CA/AA233T/N342/38/02.26 ± 1.07/2.39 ± 1.23/2.27 ± 1.090.46
SNP131rs7628128255:83204882G/AGG/GA/AA236E/K357/21/22.26 ± 1.08/2.43 ± 1.33/2.23 ± 0.260.78
SNP132rs5744367735:83204897A/TAA/AT/TT241T/S376/4/02.27 ± 1.09/1.96 ± 1.19/−0.57
SNP133rs5421872365:83204901A/GAA/AG/GG242D/G380/0/02.27 ± 1.09/−/−
SNP134rs10131372845:83204904T/ATT/TA/AA243L/H374/6/02.26 ± 1.09/3.00 ± 0.56/−0.10
SNP135rs12616414875:83204906T/CTT/TC/CC244S/P380/0/02.27 ± 1.09/−/−
SNP136rs7671760805:83204907C/TCC/CT/TT244S/F376/6/02.27 ± 1.09/1.71 ± 0.34/−0.31
SNP137rs3718249735:83204910G/AGG/GA/AA245G/E380/0/02.27 ± 1.09/−/−
SNP138rs37340915:83204915G/TGG/GT/TT247A/S296/46/382.09 ± 0.97/2.79 ± 1.49/3.08 ± 0.771.20 × 10−70
SNP139rs1411221195:83258556A/GAA/AG/GG258I/V363/17/02.28 ± 1.10/2.04 ± 0.82/−0.37
SNP140rs1388376785:83258665A/CAA/AC/CC294Q/P372/8/02.28 ± 1.09/1.98 ± 0.79/−0.45
SNP141rs617496115:83353207A/CAA/AC/CC324N/H348/30/22.27 ± 1.09/2.21 ± 1.14/2.53 ± 0.160.90
SNP142rs1482734905:83353231G/CGG/GC/CC332D/H356/24/02.29 ± 1.10/2.02 ± 0.86/−0.25
SNP143rs1413049495:83353238T/CTT/TC/CC334I/T344/35/12.26 ± 1.07/2.39 ± 1.26/1.37e0.58

Table 2.

The association between SNPs in the coding region of XRCC4 and AFB1-DNA adducts in tissues with hepatocellular carcinoma.

x/y represents wild-type allele/ variant type allele.


xx/xy/yy represents wild-type homozygote/heterozygote/variant-type homozygote.


Nxx/xy/yy represents the number of subjects with xx genotype, the number of subjects with xy genotype, and the number of subjects with yy genotype.


P values are calculated using t-test or one-way analysis of variance.


SD is not determined.* SD for genotype yy is not determined and P-value is used for genotypes xx and xy.


Additionally, mutant genotypes of several other GSNPs, including rs761695470 (SNP008, at codon 18), rs758779099 (SNP018, at codon 40), rs144653114 (SNP054, at codon 103), rs1277864722 (SNP085, at codon 153), and rs777195630 (SNP100, at codon 180), also increased the amounts of AFB1-DNA adducts; however, they had no statistical significance according to screening threshold value.

3.3 XRCC4 GSNPs modified the AFB1-related HCC prognosis

Because the poor prognosis of patients with HCC has been associated with the toxicity of AFB1, we followed up the survival information of all patients and explored whether positive GSNPs of XRCC4 modified HCC outcomes, including overall survival (OS) and disease recurrence-free survival (RFS) (Figures 1 and 2). Results from Kaplan-Meier survival model (based on the cumulative risk models) and Cox regression model analyses showed that compared with their wild genotypes (XX genotypes), the mutant genotypes (including XY and YY genotypes) of rs28383151, rs766287987, and rs3734091 polymorphisms increased cumulative hazard for OS [HR = 1.31 (1.04–1.67), 1.72 (1.09–2.71), and 1.42 (1.10–1.82), respectively] (Figure 1). For RFS, the corresponding hazard values were 3.31 (2.33–4.69) for rs28383151, 1.85 (1.03–3.67) for rs766287987, and 4.45 (3.13–6.34) for rs3734091, respectively (Figure 2).

Figure 1.

XRCC4 GSNPs significantly correlating with the overall survival (OS) of hepatocellular carcinoma (HCC). Cumulative hazard function was plotted by Kaplan-Meier methodology, andPvalue was calculated with two-sided log-rank tests. The relative hazard ratio (HR) values for genotypes were calculated using multivariable Cox regression models (with all significant variables) based on forward-step method with likelihood ratio test.

Figure 2.

XRCC4 GSNPs significantly correlating with the disease recurrence-free survival (RFS) of hepatocellular carcinoma (HCC). Cumulative hazard function was plotted by Kaplan-Meier methodology, andPvalue was calculated with two-sided log-rank tests. The relative hazard ratio (HR) values for genotypes were calculated using multivariable Cox regression models (with all significant variables) based on forward-step method with likelihood ratio test.

Advertisement

4. Discussion

In this study, we investigated the association between the GSNPs in the coding regions of XRCC4 gene and the toxic effects of AFB1 on the liver. We found that five XRCC4 GSNPs, including rs1237462915 (at codon 38), rs28383151 (at codon 56), rs762419679 (at codon 127), rs766287987 (at codon 203), and rs3734091 (at codon 247), significantly increased the amount of AFB1-DNA adducts in tissues with HCC (2.07–2.15 μmol/mol DNA for XY genotypes and 2.64–4.33 μmol/mol DNA for YY genotypes, respectively) and progressed the cumulative hazard of AFB1 hepatic toxicity.

AFB1 acts as a type of human chemical toxicant, and the toxic effects of this toxicant are characterized by organophilism (mainly causing hepatic damage), genic toxicity (mainly inducing DNA damages such as hotspot mutation at codon 249 of TP53 gene, AFB1-DNA adduct formation, and so on), and carcinogenicity (mainly resulting in HCC) [6, 7, 8]. Among the hepatic toxicity of AFB1, the formation of AFB1-DNA adducts in hepatic cells is a key step during the metabolism of this toxicant [9, 10, 11, 12, 13, 14]. Evidence from molecular epidemiological studies and clinical studies has proved that the levels of AFB1-DNA adducts in the hepatic tissues are positively associated with the levels and time of AFB1 exposure [3, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. This is indicative of AFB1-DNA adduct acting as the biomarker for AFB1’s toxic capacity in the liver. In this study, AFB1-DNA adduct in the tumor tissues with HCC was used to evaluate hepatic toxicity related to AFB1, mainly because normal liver tissue samples cannot be obtained. Our results exhibited HCC tumor samples from high AFB1 exposure areas have an average adduct amount of 2.27 ± 1.09 μmol/mol DNA. Supporting our findings, several studies from high AFB1 exposure areas Nanning and Tiandong, China, have also shown the similar level of DNA adducts [4, 5, 26, 27, 37, 39, 45]. Taken together, the amount of AFB1-DNA adducts should be able to reflect the hepatic toxic potential of AFB1.

XRCC4, a key gene in the V(D)J recombination repair pathway, is located at 5q14.2 and consists of 13 exons (PubMed). Normally, XRCC4 is mainly expressed in genital meatus, alimentary tract, and lymphoid tissue; however, its expression will noticeably increase in other tissues such as the skin and liver under the condition of in vitro and in vivo injuries. This gene’s encoding protein plays a vital role in both NHEJ and the completion of V(D)J recombination via acting as a scaffold protein for DNA ligase IV and DNA-PK in the repair of DNA DSBs [15, 19]. Mutations in XRCC4, including GSNPs and other non-GSNPs variants, can cause endocrine dysfunction, microcephaly, short stature, and diseases [16, 21]. With the development of human Geno projects, more than 1000 GSNPs are identified. Among these GSNPs, we focused on genetic alterations in the coding regions of XRCC4, mainly because they will result in missense mutations and ultimately cause the structure damage and function deficiency of XRCC4 protein. Molecular epidemiological studies have displayed that the GSNPs in the XRCC4 genes can increase DNA repair capacity and increase the risk of some tumors such as lung cancer, colon cancer, HCC, and so on [21, 46, 47, 48, 49, 50, 51]. Evidence from in vitro and in vivo studies has also proved that XRCC4 GSNPs increase the amount of DNA damage and induce more gene mutations [23, 24, 26, 27]. In our study, we tested the genotypic distributions of all known GSNPs in the coding region of XRCC4 in liver tumor tissues. Five positive GSNPs were identified, and they result in the change of amino acid D to Y at codon 38 for rs1237462915, A to T at codon 56 for rs28383151, I to T at codon 127 for rs762419679, Q to H at codon 203 for rs766287987, and A to S at codon 247 for rs3734091, respectively. Although evidence that several other GSNPs, including rs761695470, rs758779099, rs144653114, rs1277864722, and rs777195630, increased the amounts of AFB1-DNA adducts was not statistically significant according to our defined threshold value, their effects should not be neglected because small-size samples may underestimate values.

Because the toxic effects of AFB1 also modify the prognosis of patients with HCC [26, 27, 33, 52, 53], we accomplished patients’ survival analyses on the basis of the cumulative risk models and found only rs28383151, rs766287987, and rs3734091 polymorphisms shortened HCC cases’ OS and RFS. Supporting our findings, several previous reports have proved that XRCC4 GSNPs can alter the levels of XRCC4 mRNA and protein expression and dysregulation of XRCC4 expression increasing the amount of AFB1-DNA adducts and mutative risk of TP53 gene [23, 24, 26, 27].

To conclude, this study is the first report investigating the modified function of XRCC4 GSNPs on AFB1’s hepatic toxicity. Our findings suggest that the GSNPs in the coding regions of XRCC4 gene, like rs1237462915, rs28383151, rs762419679, rs766287987, and rs3734091, may alter the DNA repair capacity of DNA damage induced by AFB1. If these individuals with mutant genotypes of these GSNPs decrease their exposure to AFB1, they will be free from toxic effects of AFB1 on hepatic damage. Several limitations should be focused for our study. First, relatively small-size samples may underestimate the effects of XRCC4 GSNPs on AFB1 hepatic toxicity. Second, the hospital-based design may result in selective bias. Third, we only accomplished the cumulative risk analyses but not the cumulative survival analyses. Finally, we did not finish functional and mechanical analyses. Thus, XRCC4 GSNPs may be valuable biomarkers for predicting the toxic effects of AFB1 on the liver once the present findings were proved by larger samples and toxic function analyses.

Advertisement

Acknowledgments

We thank Dr. Qiu-Xiang Liang, Dr. Yun Yi, Dr. Yun Xia, Dr. Yong-Zhi Huang, and Dr. Yuan-Feng Zhou for sample collection and management and Dr. Hua Huang for molecular biochemical technique. We also thank all members of the Department of Medical Test and Infective Control, Affiliated Hospital of Youjiang Medical University for Nationalities for their help.

Advertisement

Conflicts of interest and source of funding

The authors declare no competing financial interests. This study was supported in part by the National Natural Science Foundation of China (Nos. 81860489, 81760502, 81572353, and 81660495), the Natural Science Foundation of Guangxi (Nos. 2018GXNSFAA281043, 2017GXNSFAA198002, and 2017GXNSFGA198002), Research Program of Guangxi “Zhouyue Scholar” (No. 2017-38), Research Program of Guangxi Specially Invited Expert (No. 2017-6th), “12th Five-Year” Planning Program of Guangxi Education Science (No. 2015C397), Innovative Program of Guangxi Graduate Education (No. JGY2015139), Research Program of Guangxi Clinic Research Center of Hepatobiliary Diseases (No. AD17129025), and Open Research Program from Molecular Immunity Study Room Involving in Acute and Severe Diseases in Guangxi Colleges and Universities (Nos. kfkt20160062 and kfkt20160063).

Advertisement

Abbreviations

AFB1aflatoxin B1
CIconfidence interval
GSNPsthe genetic single-nucleotide polymorphisms
HCChepatocellular carcinoma
HRhazard ratio
OSoverall survival
RFSdisease recurrence-free survival
XRCC4X-ray repair cross complementing 4

References

  1. 1.Rushing BR, Selim MI. Adduction to arginine detoxifies aflatoxin B1 by eliminating genotoxicity and altering in vitro toxicokinetic profiles. Oncotarget. 2018;9:4559-4570. DOI: 10.18632/oncotarget.23382
  2. 2.Liu W, Wang L, Zheng C, Liu L, Wang J, Li D, et al. Microcystin-LR increases genotoxicity induced by aflatoxin B1 through oxidative stress and DNA base excision repair genes in human hepatic cell lines. Environmental Pollution. 2018;233:455-463. DOI: 10.1016/j.envpol.2017.10.067
  3. 3.Wang XZ, Huang XY, Yao JG, Wang C, Xia Q, Long XD. Genetic polymorphisms in ataxin-3 and liver cirrhosis risk related to aflatoxin B1. Oncotarget. 2018;9:27321-27332. DOI: 10.18632/oncotarget.24535
  4. 4.Long XD, Deng Y, Huang XY, Yao JG, Su QY, Wu XM, et al. Molecular mechanisms of hepatocellular carcinoma related to aflatoxins: An update. In: Rodrigo L, editor. Liver Research and Clinical Management. 1st ed. Vol. 1. Rijeka: IntechOpen; 2018. pp. 113-136. DOI: 10.5772/intechopen.72883
  5. 5.Wu XM, Xi ZF, Lu J, Wang XZ, Zhang TQ, Huang XY, et al. Genetic single nucleotide polymorphisms (GSNPs) in the DNA repair genes and hepatocellular carcinoma related to aflatoxin B1 among Guangxiese population. In: Parine NR, editor. Genetic Polymorphisms. Vol. 1. Rijeka: IntechOpen; 2017. pp. 97-119. DOI: 10.5772/intechopen.69530
  6. 6.Ellis WO, Smith JP, Simpson BK, Oldham JH. Aflatoxins in food: Occurrence, biosynthesis, effects on organisms, detection, and methods of control. Critical Reviews in Food Science and Nutrition. 1991;30:403-439. DOI: 10.1080/10408399109527551
  7. 7.Park DL, Rua SM Jr. Biological evaluation of aflatoxins and metabolites in animal tissues. Drug Metabolism Reviews. 1990;22:871-890. DOI: 10.3109/03602539008991476
  8. 8.Schoental R. Aflatoxins. Annual Review of Pharmacology. 1967;7:343-356. DOI: 10.1146/annurev.pa.07.040167.002015
  9. 9.Zuberi Z, Eeza MNH, Matysik J, Berry JP, Alia A. NMR-based metabolic profiles of intact Zebrafish embryos exposed to aflatoxin B1 recapitulates hepatotoxicity and supports possible neurotoxicity. Toxins (Basel). 2019;11:258. DOI: 10.3390/toxins11050258
  10. 10.Zhou J, Tang L, Wang JS. Assessment of the adverse impacts of aflatoxin B1 on gut-microbiota dependent metabolism in F344 rats. Chemosphere. 2019;217:618-628. DOI: 10.1016/j.chemosphere.2018.11.044
  11. 11.Singh C, Prakash C, Mishra P, Tiwari KN, Mishra SK, More RS, et al. Hepatoprotective efficacy ofPremna integrifoliaL. leaves against aflatoxin B1-induced toxicity in mice. Toxicon. 2019;166:88-100. DOI: 10.1016/j.toxicon.2019.05.014
  12. 12.Rotimi OA, Rotimi SO, Goodrich JM, Adelani IB, Agbonihale E, Talabi G. Time-course effects of acute aflatoxin B1 exposure on hepatic mitochondrial lipids and oxidative stress in rats. Frontiers in Pharmacology. 2019;10:467. DOI: 10.3389/fphar.2019.00467
  13. 13.Huang B, Mu P, Chen X, Tang S, Ye W, Zhu W, et al. Aflatoxin B1 induces S phase arrest by upregulating the expression of p21 via MYC, PLK1 and PLD1. Biochemical Pharmacology. 2019;166:108-119. DOI: 10.1016/j.bcp.2019.05.008
  14. 14.Ferreira RG, Cardoso MV, de Souza Furtado KM, Espindola KMM, Amorim RP, Monteiro MC. Epigenetic alterations caused by aflatoxin b1: A public health risk in the induction of hepatocellular carcinoma. Translational Research. 2019;204:51-71. DOI: 10.1016/j.trsl.2018.09.001
  15. 15.Wu CN, Liang SY, Tsai CW, Bau DT. The role of XRCC4 in carcinogenesis and anticancer drug discovery. Recent Patents on Anti-Cancer Drug Discovery. 2008;3:209-219. DOI: 10.2174/157489208786242304
  16. 16.Pastwa E, Blasiak J. Non-homologous DNA end joining. Acta Biochimica Polonica. 2003;50:891-908. DOI: 035004891
  17. 17.Wen Y, Dai G, Wang L, Fu K, Zuo S. Silencing of XRCC4 increases radiosensitivity of triple-negative breast cancer cells. Bioscience Reports. 2019;39:BSR20180893. DOI: 10.1042/BSR20180893
  18. 18.Nishikubo K, Izumi Y, Matsumoto Y, Fujii K, Matsuo K, Yokoya A. Structural analysis of DNA repair protein Xrcc4 applying circular dichroism in an aqueous solution. Radiation Protection Dosimetry. 2019;183:36-39. DOI: 10.1093/rpd/ncy275
  19. 19.Liu F, Fan Z, Song N, Han M, Yan M, Guo LH, et al. XRCC4, which is inhibited by PFDA, regulates DNA damage repair and cell chemosensitivity. Journal of Cellular Biochemistry. 2019;120:12665-12676. DOI: 10.1002/jcb.28534
  20. 20.Kitagawa M, Someya M, Hasegawa T, Mikami T, Asaishi K, Hasegawa T, et al. Influence of XRCC4 expression by breast cancer cells on ipsilateral recurrence after breast-conserving therapy. Strahlentherapie und Onkologie. 2019;195:648-658. DOI: 10.1007/s00066-019-01468-z
  21. 21.Garcia JA, Kalacas NA, Sy Ortin T, Ramos MC, Albano PM. XRCC4 c.1394G>T single nucleotide polymorphisms and breast cancer risk among Filipinos. Asian Pacific Journal of Cancer Prevention. 2019;20:1097-1101. DOI: 10.31557/APJCP.2019.20.4.1097
  22. 22.Enguita-Marruedo A, Martin-Ruiz M, Garcia E, Gil-Fernandez A, Parra MT, Viera A, et al. Transition from a meiotic to a somatic-like DNA damage response during the pachytene stage in mouse meiosis. PLoS Genetics. 2019;15:e1007439. DOI: 10.1371/journal.pgen.1007439
  23. 23.Lu J, Wang XZ, Zhang TQ, Huang XY, Yao JG, Wang C, et al. Prognostic significance of XRCC4 expression in hepatocellular carcinoma. Oncotarget. 2017;8:87955-87970. DOI: 10.18632/oncotarget.21360
  24. 24.Yao JG, Huang XY, Long XD. Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma. International Journal of Clinical and Experimental Pathology. 2014;7:6231-6244. DOI: 10.2016/1936-2625.25337275
  25. 25.Lin ZH, Chen JC, Wang YS, Huang TJ, Wang J, Long XD. DNA repair gene XRCC4 codon 247 polymorphism modified diffusely infiltrating astrocytoma risk and prognosis. International Journal of Molecular Sciences. 2014;15:250-260. DOI: 10.3390/ijms15010250
  26. 26.Long XD, Zhao D, Wang C, Huang XY, Yao JG, Ma Y, et al. Genetic polymorphisms in DNA repair genes XRCC4 and XRCC5 and aflatoxin B1-related hepatocellular carcinoma. Epidemiology. 2013;24:671-681. DOI: 10.1097/EDE.0b013e31829d2744
  27. 27.Long XD, Yao JG, Zeng Z, Ma Y, Huang XY, Wei ZH, et al. Polymorphisms in the coding region of X-ray repair complementing group 4 and aflatoxin B1-related hepatocellular carcinoma. Hepatology. 2013;58:171-181. DOI: 10.1002/hep.26311
  28. 28.Huang XY, Yao JG, Huang BC, Ma Y, Xia Q, Long XD. Polymorphisms of a disintegrin and metalloproteinase with thrombospondin motifs 5 and aflatoxin B1-related hepatocellular carcinoma. Cancer Epidemiology, Biomarkers & Prevention. 2016;25:334-343. DOI: 10.1158/1055-9965.EPI-15-0774
  29. 29.Wu XM, Xi ZF, Liao P, Huang HD, Huang XY, Wang C, et al. Diagnostic and prognostic potential of serum microRNA-4651 for patients with hepatocellular carcinoma related to aflatoxin B1. Oncotarget. 2017;8:81235-81249. DOI: 10.18632/oncotarget.16027
  30. 30.Long XD, Huang XY, Yao JG, Liao P, Tang YJ, Ma Y, et al. Polymorphisms in the precursor microRNAs and aflatoxin B1-related hepatocellular carcinoma. Molecular Carcinogenesis. 2016;55:1060-1072. DOI: 10.1002/mc.22350
  31. 31.Long XD, Huang HD, Huang XY, Yao JG, Xia Q. XPC codon 939 polymorphism is associated with susceptibility to DNA damage induced by aflatoxin B1 exposure. International Journal of Clinical and Experimental Medicine. 2015;8:1197-1204. DOI: PMC4358568
  32. 32.Long XD, Huang HD, Xia Q. The polymorphism of XRCC3 codon 241 and the hotspot mutation in the TP53 gene in hepatocellular carcinoma induced by aflatoxin B1. Journal of Tumor. 2014;2:272-277. DOI: 10.6051/j.issn.1819-6187.2014.02.57
  33. 33.Liu YX, Long XD, Xi ZF, Ma Y, Huang XY, Yao JG, et al. MicroRNA-24 modulates aflatoxin B1-related hepatocellular carcinoma prognosis and tumorigenesis. BioMed Research International. 2014;2014:482926. DOI: 10.1155/2014/482926
  34. 34.Long XD, Yao JG, Huang YZ, Huang XY, Ban FZ, Yao LM, et al. DNA repair gene XRCC7 polymorphisms (rs#7003908 and rs#10109984) and hepatocellular carcinoma related to AFB1 exposure among Guangxi population, China. Hepatology Research. 2011;41:1085-1093. DOI: 10.1111/j.1872-034X.2011.00866.x
  35. 35.Long XD, Ma Y, Zhou YF, Ma AM, Fu GH. Polymorphism in xeroderma pigmentosum complementation group C codon 939 and aflatoxin B1-related hepatocellular carcinoma in the Guangxi population. Hepatology. 2010;52:1301-1309. DOI: 10.1002/hep.23807
  36. 36.Long XD, Ma Y, Zhou YF, Yao JG, Ban FZ, Huang YZ, et al. XPD codon 312 and 751 polymorphisms, and AFB1 exposure, and hepatocellular carcinoma risk. BMC Cancer. 2009;9:400. DOI: 10.1186/1471-2407-9-400
  37. 37.Long XD, Ma Y, Deng ZL. GSTM1 and XRCC3 polymorphisms: Effects on levels of aflatoxin B1-DNA adducts. Chinese Journal of Cancer Research. 2009;21:177-184. DOI: DOI. DOI: 10.1007/s11670-009-0177-6
  38. 38.Long XD, Ma Y, Qu de Y, Liu YG, Huang ZQ, Huang YZ, et al. The polymorphism of XRCC3 codon 241 and AFB1-related hepatocellular carcinoma in Guangxi population, China. Annals of Epidemiology. 2008;18:572-578. DOI: 10.1016/j.annepidem.2008.03.003
  39. 39.Long XD, Ma Y, Huang HD, Yao JG, Qu de Y, Lu YL. Polymorphism of XRCC1 and the frequency of mutation in codon 249 of the p53 gene in hepatocellular carcinoma among Guangxi population, China. Molecular Carcinogenesis. 2008;47:295-300. DOI: 10.1002/mc.20384
  40. 40.Long XD, Ma Y, Deng ZL, Huang YZ, Wei NB. Association of the Thr241Met polymorphism of DNA repair gene XRCC3 with genetic susceptibility to AFB1-related hepatocellular carcinoma in Guangxi population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008;25:268-271. DOI: 940625058
  41. 41.Long XD, Ma Y, Wei YP, Deng ZL. The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatology Research. 2006;36:48-55. DOI: 10.1016/j.hepres.2006.06.004
  42. 42.Long XD, Ma Y, Wei YP, Deng ZL. X-ray repair cross-complementing group 1 (XRCC1) Arg 399 Gln polymorphism and aflatoxin B1 (AFB1)-related hepatocellular carcinoma (HCC) in Guangxi population. Chinese Journal of Cancer Research. 2005;17:17-21. DOI: 10.1007/s11670-005-0004-7
  43. 43.Long XD, Ma Y, Wei YP, Deng ZL. A study about the association of detoxication gene GSTM1 polymorphism and the susceptibility to aflatoxin B1-related hepatocellular carcinoma. Zhonghua Gan Zang Bing Za Zhi. 2005;13:668-670. DOI: PMID16174455
  44. 44.Long XD, Ma Y, Wei YP, Deng ZL. Study on the detoxication gene gstM1-gstT1-null and susceptibility to aflatoxin B1 related hepatocellular carcinoma in Guangxi. Zhonghua Liu Xing Bing Xue Za Zhi. 2005;26:777-781. DOI: PMID16536303
  45. 45.Xia Q, Huang XY, Xue F, Zhang JJ, Zhai B, Kong DC, et al. Genetic polymorphisms of DNA repair genes and DNA repair capacity related to aflatoxin b1 (AFB1)-induced DNA damages. In: Chen C, editor. New Research Directions in DNA Repair. 1st ed. Rijeka: IntechOpen; 2013. pp. 377-412. DOI: 10.5772/53967
  46. 46.Jin D, Zhang M, Hua H. Impact of polymorphisms in DNA repair genes XPD, hOGG1 and XRCC4 on colorectal cancer risk in a Chinese Han population. Bioscience Reports. 2019;39:BSR20181074. DOI: 10.1042/BSR20181074
  47. 47.Makkoch J, Praianantathavorn K, Sopipong W, Chuaypen N, Tangkijvanich P, Payungporn S. Genetic variations in XRCC4 (rs1805377) and ATF6 (rs2070150) are not associated with hepatocellular carcinoma in Thai patients with hepatitis B virus infection. Asian Pacific Journal of Cancer Prevention. 2016;17:591-595. DOI: 10.7314/APJCP.2016.17.2.591
  48. 48.Shao N, Li J, Xu B, Wang Y, Lu X, Feng N. Role of the functional variant (-652T>G) in the XRCC4 promoter in prostate cancer. Molecular Biology Reports. 2014;41:7463-7470. DOI: 10.1007/s11033-014-3636-1
  49. 49.Jung SW, Park NH, Shin JW, Park BR, Kim CJ, Lee JE, et al. Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: Possible implications on survival. Journal of Hepatology. 2012;57:621-627. DOI: 10.1016/j.jhep.2012.04.039
  50. 50.Yu H, Zhao H, Wang LE, Han Y, Chen WV, Amos CI, et al. An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs. DNA Repair (Amst). 2011;10:398-407. DOI: 10.1016/j.dnarep.2011.01.005
  51. 51.Long XD, Ma Y, Huang YZ, Yi Y, Liang QX, Ma AM, et al. Genetic polymorphisms in DNA repair genes XPC, XPD, and XRCC4, and susceptibility toHelicobacter pyloriinfection-related gastric antrum adenocarcinoma in Guangxi population, China. Molecular Carcinogenesis. 2010;49:611-618. DOI: 10.1002/mc.20630
  52. 52.Engin AB, Engin A. DNA damage checkpoint response to aflatoxin B1. Environmental Toxicology and Pharmacology. 2019;65:90-96. DOI: 10.1016/j.etap.2018.12.006
  53. 53.Kensler TW, Roebuck BD, Wogan GN, Groopman JD. Aflatoxin: A 50-year odyssey of mechanistic and translational toxicology. Toxicological Sciences. 2011;120(Suppl 1):S28-S48. DOI: 10.1093/toxsci/kfq283

Written By

Yan Deng, Xue-Min Wu, Xiao-Ying Huang and Xi-Dai Long

Submitted: April 13th, 2019Reviewed: July 22nd, 2019Published: September 16th, 2019