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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 44  |  Issue : 3  |  Page : 175-182

X-ray cross-complement 1 gene polymorphisms (Arg399Gln and Arg194Trp) in patients with acute myeloid leukemia


1 Hematology Unit, Clinical Pathology Department, Faculty of Medicine, Mansoura University (OCMU), Mansoura, Egypt
2 Medical Oncology Department, Oncology Center, Mansoura University (OCMU), Mansoura, Egypt

Date of Submission06-Jun-2019
Date of Acceptance18-Sep-2019
Date of Web Publication05-Dec-2019

Correspondence Address:
Ahmed H El-Sebaie
PhD of Clinical Pathology, Lecturer of Clinical Pathology, Hematology Unit, Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_22_19

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  Abstract 


Background Acute myeloid leukemia (AML) is a clonal disorder characterized by acquisition of somatic mutations in hematopoietic progenitors leading to disruption of differentiation. X-ray cross-complement 1 (XRCC1) gene is a key component of the base excision repair pathway that may be involved in the repair of SS-DNA breaks. Polymorphisms in DNA repair genes may affect the DNA repair capacity and modulate cancer susceptibility by means of gene–environment interactions. This study aimed to evaluate the association between XRCC1 gene polymorphisms and the risk of development of AML and their impact on patients’ outcome.
Materials and methods This study was conducted on 92 adult patients with AML of different FAB subtypes before induction of chemotherapy. They were selected from the Oncology Center Mansoura University, Egypt. Ninety-two healthy individuals served as a control group.
Results The data obtained after the XRCC1 gene polymorphism study revealed that the Trp194Trp genotype and Trp allele showed higher frequency in AML cases compared with the control group. In addition, they were associated with a significant high risk of AML development within healthy participants (P=0.04). No significant differences were found in rs1799782 and rs25487 genotypes and alleles between cases and controls. Also, there was significant difference in overall survival in cases with XRCC1 Trp194Arg genotypes (P=0.048) and cases with Trp194Arg+ Trp194Trp (P=0.023) when compared with those with the Arg194Arg genotype.
Conclusion Individuals with mutant Trp194Trp allele had a higher risk to develop AML and that the Trp194Arg+Trp194Trp genotype could predict poor prognosis in AML patients. This suggests XRCC1 polymorphism to be a novel target for new effective therapies of AML.

Keywords: acute myeloid leukemia, DNA, polymorphisms, X-ray cross-complement 1


How to cite this article:
Mortada MI, El-Sebaie AH, Aladle DA, Elzaafarany ME, Mahmoud LA. X-ray cross-complement 1 gene polymorphisms (Arg399Gln and Arg194Trp) in patients with acute myeloid leukemia. Egypt J Haematol 2019;44:175-82

How to cite this URL:
Mortada MI, El-Sebaie AH, Aladle DA, Elzaafarany ME, Mahmoud LA. X-ray cross-complement 1 gene polymorphisms (Arg399Gln and Arg194Trp) in patients with acute myeloid leukemia. Egypt J Haematol [serial online] 2019 [cited 2020 Apr 4];44:175-82. Available from: http://www.ehj.eg.net/text.asp?2019/44/3/175/272370




  Introduction Top


Acute myeloid leukemia (AML) is a clonal malignant disorder of the hematopoietic tissue, which is characterized by the proliferation of abnormal (leukemic) stem cells mainly in the marrow leading to impaired production of normal blood cells. It accounts for 15–20% of acute leukemia in children and 80% in adults with a slight male predominance [1].

The leukemic stem cell is capable of imperfect differentiation and maturation and the clone may contain cells that have morphologic or immunophenotypic features of erythroblasts, megakaryocytes, monocytes, eosinophils, or rarely basophiles in addition to myeloblasts or promyelocytes [2].

AML can arise in patients with an underlying hematological disorder, genetic disease, or a consequence of therapy (e.g. topoisomerases II, alkylating agents, or radiation). However in majority of cases, it appears as a de-novo malignancy [3].

The pathogenesis of AML involves abnormal proliferation and differentiation of a clonal population of myeloid stem cells. Well-characterized chromosomal translocations are detected such as t(8:21) (CBF-AML) in AML(M2), t(15:17) (PML-RARA) in AML(M3), AML with inv(16) or t(16;16) (CBEB-MYH11), AML with t(9;11) (MLLT3-MLL), AML with t(6;9) (DEK-NUP214), and AML with inv(3) or t(3;3) (RPN1-EVI1). These mutations result in the formation of chimeric proteins which alter the normal maturation process of myeloid precursor cells [4].

In addition to large chromosomal rearrangements, molecular changes have also been concerned with the development of AML. In fact, genetic mutations are identified in more than 97% of cases, often in the absence of large chromosomal abnormalities. So, with initiation of next-generation sequencing technologies, novel therapies have emerged, including multiple molecular target inhibitors and immunotherapies [5].

DNA in most cells is regularly damaged by endogenous and exogenous mutagens. Unrepaired damage can result in apoptosis or may lead to unregulated cell growth and cancer. If DNA damage is recognized, several responses may occur to prevent replication in the presence of genetic errors through arresting the cell cycle and transcription process ended by cell apoptosis [6]. Alternatively, the damage can be repaired at the DNA level enabling the cell to replicate as planned and involving numerous molecules to perform such repair and maintain genomic integrity in the general and specialized functions of cells preventing carcinogenesis [7].

There are at least four pathways of DNA repair acting on specific types of damaged DNA, and each pathway involves numerous molecules. Base excision repair (BER) operates on small lesions such as oxidized or reduced bases, fragmented or nonbulky adducts, or those produced by methylating agents. The single damaged base is removed by base-specific DNA glycosylases, the basic site is then restored by endonuclease action, removal of the sugar residue, DNA synthesis using the other strand as a template, and the occurrence of ligation [8]. The nucleotide excision repair system that is able to recognize, remove, and fix/repair a wide variety of large DNA lesions, bulky DNA adducts, UV light-induced DNA damage, and cross-linked DNA distortions [9].

Repair of double-strand breaks, which is produced by replication errors and by exogenous agents such as ionizing radiation, is more difficult than other types of DNA damage because no undamaged template is available. It occurred by a homologous recombination pathway, where DNA ends are restricted and the newly exposed single-stranded tails of partner molecules are extended by DNA polymerase, then cross-overs yield two intact DNA molecules. This pathway is thought to involve more than 16 molecules including the products of the BRCA1 and BRCA2 and X-ray repair cross-complementing 3 (XRCC3). The nonhomologous end-joining repair pathway involves direct ligation of the two double-strand-break ends and also involves numerous molecule repairs [10].

The human XRCC1 gene encodes a protein that plays an important role in a BER. Moreover, some reports indicate that XRCC1 plays a role in the repair of DNA both single-strand breaks repair and double-strand breaks [11].

XRCC1 gene is located on chromosome (19q13.2) and consists of 17 exons encoding a 633 amino acid protein. XRCC1 has three common single-nucleotide polymorphisms (SNPs), a common genetic variant in XRCC (C>T) in exon 6 results in an Arg to Trp (rs25487) substitution at codon 194 while another polymorphism (G>A) in exon 9 changes amino acid Arg to His (rs25489) in codon 280 and yet another polymorphism (G>A) in exon 10 changes amino acid Arg to Gln in codon 399. These polymorphisms may change the DNA repair activity [12].

Two common polymorphisms in XRCC1, Arg194Trp and Arg399Gln, are reportedly associated with high risk for many cancers. Furthermore, several investigations demonstrated that individuals with XRCC1 399Gln allele have higher levels of DNA adducts and sister chromatid changes than individuals with XRCC1 399Arg allele [13].

Recently, association studies between genetic variants of the XRCC1 gene (Arg194Trp, Arg280His and Arg399Gln) and different hematological malignancies, such as acute AML, have been performed [14].

A reduction of XRCC1 protein levels results in decreased repair capacity and increases the sensitivity to DNA-damaging agents and ionizing radiation. XRCC1 mutant cells are hypersensitive to DNA-damaging agents and display genetic instability after DNA damage. Thus, XRCC1 is required for efficient single-strand breaks repair and genomic stability in human cells [15].

This study aimed to evaluate the association between XRCC1 gene polymorphisms and the risk of development of AML and their impact on patients’ outcome.


  Materials and methods Top


This study was conducted on 92 cases with newly diagnosed AML, 48 (52.2%) men and 44 (47.8%) women with ages that ranged between 20 and 70 years. They were one case of AML(M0), 10 cases of AML(M1), 23 cases of AML(M2), 10 cases of AML(M3), 29 cases of AML(M4), 13 cases of AML (M5), and six cases of AML (M6). Patients were selected from the Oncology Center Mansoura University, Egypt. Ninety-two apparently healthy individuals were considered as a control group. All laboratory procedures were performed in the clinical pathology labs of Oncology Center Mansoura University. The study included adult patients at the time of diagnosis and before induction therapy and excluded patients with therapy-related AML and childhood AML.

Methods

All patients were subjected to through history taking, physical examination for purpura, ecchymosis, lymphadenopathy, and organomegaly.

Routine investigations were performed to patients and controls including routine complete blood count (CBC), liver function tests, renal capacity test, and serum lactate dehydrogenase. Workup for AML diagnosis: microscopic study of peripheral blood films and bone marrow slides and cytochemical staining of bone marrow (BM) slides [e.g. Myeloperoxidase (MPO), periodic acid schif (PAS), a naphthyl acetate estrase (NSE)]. Immunophenotyping was performed using a BD flow-cytometer (Counter Epics XL flowcytometer PN 42372238B counter corporation, Miami, Florida 33196, USA) device to diagnose the cases and to exclude other types of leukemia by using cell surface markers including myeloid and lymphoid lineages.

Specific workup (for patients and controls)

Sampling

Two milliliters of blood was collected in a tube containing an EDTA for genomic DNA extraction and prepared for detection of XRCC1 (Arg399Gln and Arg194Trp) gene polymorphism using the PCR-RFLP test.

DNA extraction

DNA extraction was done using the DNA extraction kit by GeneJET Whole Blood Genomic DNA Purification Mini Kit (#K0781) (Thermo Fisher Scientific Inc., Waltham, MA, USA).

PCR

The test was done in three steps: (a) amplification of extracted genomic DNA. (b) The amplified product is then digested by a suitable restriction enzyme. (c) Detection of the digested products using gel electrophoresis and ultraviolet light transillumination.

The electronic warm cycler might have been programmed to the emulating states to XRCC1 (Arg399Gln and Arg194Trp); those accompanying cycles were utilized: a beginning high-temperature activation step at 95°C for 10 min, denaturation toward 95°C for 1 min, and then last development in 72°C for 10 min.

For XRCC1 genotype (Arg194Trp) the following primers were used:
  1. XRCC1-194 F: 5′-G-C-C-C-C-G-T-C-C-C-A-G-G-T-A-3′.
  2. XCC1-194 R: 5′-A-G-C-C-C-C-A-A-G-A-C-C-C-T-T-T-C-A-C-T-3′.


The 304 bp PCR products were digested at 37°C with 10U MspI resulting in:
  1. 194Arg (wild allele): three bands 20, 117, and 167 bp product.
  2. 194Trp (mutated allele): two bands 137 and 167 bp products.


For the XRCC1 genotype (Arg399Gln) the following primers were used:
  1. XRCC1-399 F: 5′-T-T-G-T-G-C-T-T-T-C-T-C-T-G-T-G-T-C-C-A-3′.
  2. XRCC1-399 R: 5′-T-C-C-T-C-C-A-G-C-C-T-T-T-T-C-T-G-A-T-A-3′.


The 616 bp PCR products were digested at 37°C with 10U MspI resulting in:
  1. 339Arg (wild allele): two bands of 376 and 240 bp.
  2. 339Gln (mutated allele): one band only of 616 bp.


The statistical analysis of data was done using the statistical package for the social sciences (SPSS) program (SPSS Inc., Chicago, Illinois, USA) version 20. Qualitative data were presented as frequency and percentage. χ2 and Fisher’s exact tests were used to compare groups. Quantitative data were presented as mean, SD, or median and range. Comparisons between two groups were done using t-test or Mann–Whitney (for nonparametric data), while comparison between more than two groups were done using analysis of variance or Kruskal–Wallis tests (for nonparametric data). The odds ratio and 95% confidence interval obtained from the logistic regression were used. Kaplan–Meier test was used for survival analysis and the statistical significance of differences among curves was determined by log-rank test. Cox regression analysis was used for the prediction of overall survival (OS). P value is significant if less than 0.05 at a confidence interval of 95%.


  Results Top


Regarding 92 adult patients with AML of different FAB types in comparison to 92 apparently healthy individuals subjected as controls we obtained the following data.

As regards hematological data at diagnosis of different studied groups, there were significant decrease in hemoglobin concentration and platelets count in the AML group compared with the control group (P<0.001 for each). A significant increase in TLC was reported in the AML group compared with the control group (P<0.001; [Table 1]).
Table 1 Comparison of age, sex, and hematological data between groups

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Clinical characteristics are shown in [Figure 1], where bleeding tendency was the most common presentation (76.1%), followed by fever/infection (67.4%), hepatosplenomegaly (53.3%), and lymphadenopathy (45.7%).
Figure 1 Clinical characteristics of acute myeloid leukemia patients.

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As regards XRCC1 gene polymorphism, rs1799782 Trp149Trp genotype, Trp allele showed significantly higher proportions in AML cases when compared with control groups, with significantly higher risk to develop AML within healthy control participants in crude and adjusted. The rs1799782 Trp149Arg genotype and the dominant model were not significantly associated with the risk to develop AML. The rs25487 genotypes and alleles’ frequencies did not differ significantly between AML cases and healthy control group as shown in [Table 2].
Table 2 Comparison of rs1799782 and rs25487 genotypes and alleles between cases and control groups

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Furthermore, there were significant differences in OS in the cases with XRCC1 Trp194Arg genotypes (P1=0.048) and the cases with Trp194Arg+ Trp194Trp (P2=0.023) when compared with those with the Arg194Arg genotype as shown in [Table 3] and [Figure 2] and [Figure 3].
Table 3 Comparison of overall survival between rs1799782 genotypes

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Figure 2 Overall survival (OS) according to the rs1799782 genotypes in the studied acute myeloid leukemia cases.

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Figure 3 Overall survival (OS) according to the rs1799782 genotypes in the studied acute myeloid leukemia cases (Trp194Arg+ Trp194Trp vs. Arg194Arg).

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Cox regression analysis was conducted for the prediction of OS, using age, sex, marrow blasts, and lactate dehydrogenase (LDH), rs1799782 and rs25487 genotypes as covariates. Trp194Arg+ Trp194Trp was the only poor prognostic factor for OS in all studied AML cases (P=0.03) as shown in [Table 4].
Table 4 Cox regression analysis for the prediction of overall survival in studied acute myeloid leukemia cases

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  Discussion Top


AML is a heterogeneous group of diseases in which the hematopoietic stem cells and progenitors (blasts) go through uncontrolled proliferation with a decreased ability to differentiate into mature cells. Unsatisfactory outcomes persist for the majority of patients with AML. So, new molecular targets for therapy and biological markers of leukemia pathogenesis and prognosis are needed [16].

DNA repair pathways play a vital role in maintaining genetic integrity, and it is becoming clear that the defects in repair pathways are connected to many different types of diseases and hematological cancers including leukemia [14].

XRCC1 gene is one of the most important DNA repair genes, and plays a key role in the process of BER. XRCC1 SNP Arg399Gln at codon 399 and Arg194Trp at codon 194 has been extensively examined and is associated with diminished capacity to remove DNA adducts, causing DNA damage due to oxidation. Therefore, the Arg399Gln SNP may contribute to leukemia [17].

In this study, determination of polymorphisms that occur in the XRCC1 (Arg399Gln and Arg194Trp) gene was done by the PCR-RFLP method. For Arg194Trp resulting in band in 20, 117, and 167 bp it is considered as the wild type, while if bands appear at 137 and 167 bp is considered as the mutant type and if resulting in 20, 117, 137 and 167 bp it is considered as the heterozygous type. For Arg399Gln resulting in bands in 376 and 240 bp it is considered as the wild type and if the band appears in 616 bp it is considered as the mutant type and if resulting in 376, 240, and 616 bp it is considered as the heterozygous type.

As regards XRCC1 Arg399Gln genotypes, the Arg399Arg genotype was detected in 60.9% of AML cases, while 27.2% belong to Arg399Gln genotype but 12% only was found to be with the Gln399Gln genotype. In the control group, the Arg399Arg genotype was detected in 59.8%, while 30.4% had Arg399Gln genotype and 9.8% had Gln399Gln genotype. There was no remarkable difference between patients and healthy people as regards XRCC1 (Arg399Gln genotypes); this suggests no relation between polymorphism incidence of these genotypes and occurrence of AML. The results of this study agree with other studies that found no correlation between the occurrence of polymorphism in the XRCC1 (Arg399Gln) gene and pathogenesis of leukemia [18]. On the other hand, Huang et al. [14] and Sorour et al. [19] found a remarkable relation between (Arg399Gln genotype) polymorphisms and occurrence of leukemia.

It has been hypothesized that when hematopoietic progenitor cells in bone marrow are damaged by treatment, the cells carrying XRCC1 399Gln variant with decreased DNA repair ability are going through apoptosis, while cells with wild variants are able to repair their damage, so the presence of XRCC1-399 Gln allele is considered as a protective effect [20].

As regards XRCC1 Arg194Trp genotypes, we found that 72.8% of AML cases showed Arg194Arg genotype while 13% of cases were Trp194Arg genotype and 14.1% with Trp194Trp genotype. Among the healthy group, 76.1% had Arg194Arg genotype while 19.6% showed Trp194Arg genotype and 4.3% had Trp194Trp genotype. This means that Trp194Trp genotype could be associated with elevated risk of AML development within healthy people. These results did not agree with other studies [9].

El-Din et al. [21] found a significant association with increased incidence of AML development in patients with XRCC1-399(Arg/Gln) allele and XRCC1-194(Arg/Trp) allele (P=0.025 and 0.002, respectively). In this study, a significant increased incidence was found in AML patients with XRCC1-194(Trp/Trp) allele (P=0.04).

Banescu et al. [9] studied the relation between polymorphisms which occur in XRCC1 Arg194Trp and Arg 399 Gln in AML patients and suggested that XRCC1 Arg194Trp and Arg399Gln polymorphism are involved in genetic predisposition to AML and noted that they could be carried out as prognostic markers in AML as they are remarkably correlated with shorter OS. In this study, there were significant differences in OS times between XRCC1 (Arg194Trp genotypes) (P=0.048). Trp194Arg+Trp194Trp showed significantly shorter OS when compared with Arg194Arg genotype (P=0.023).Cox regression analysis was applied to predict the survival using age, sex, bone marrow blasts, LDH level, XRCC1 Arg194Trp, and Arg399Gln allele genotypes as covariates. The study showed that Trp194Arg+ Trp194Trp were the only poor prognostic factor for OS in all studied AML cases. This is in agreement with Banescu et al. [9], who found that the survival of AML patients was short if Trp194Arg and Trp194Trp and XRCC1 Arg399Gln and Gln399Gln allele genotypes were present.


  Conclusion Top


From this study, we could conclude that mutant Trp194Trp allele had a higher risk to develop AML and that Trp194Arg+Trp194Trp predict poor prognosis in AML patients which could represent a novel target for the effective treatment of AML. Finally, it is recommended that the DNA repair gene (XRCC1 Arg399Gln genotypes and XRCC1 Arg194Trp genotypes) could be incorporated into the initial routine diagnostic workup of AML patients as it is easily determined by PCR-RFLP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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