Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer

doi:10.4236/jct.2013.410181

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Journal of Cancer Therapy, 2013, 4, 1499-1505

Published Online December 2013 (http://www.scirp.org/journal/jct)

http://dx.doi.org/10.4236/jct.2013.410181

Open Access JCT

1499

Detection of Polymorphisms of DNA Repair Genes

(XRCC1 and XPC) in Prostate Cancer*

Amani Fouad Sorour1, Iman Mamdouh Talaat2#, Tamer Mohammed Abou Youssif3,

Mohamed Adel Atta3

1Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 2Department of Pathology, Fac-

ulty of Medicine, Alexandria University, Alexandria, Egypt; 3Department of Genitourinary, Faculty of Medicine, Alexandria Univer-

sity, Alexandria, Egypt.

Email: #[email protected]

Received November 23rd, 2013; revised December 13th, 2013; accepted December 20th, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Prostate cancer is a common disease with a multifactorial and complex etiology. It is the most common male malig-

nancy and the second leading cause of death in many countries. The widespread use of PSA testing has increased the

detection of this cancer at earlier stages, although this diagnostic method has proved to be insufficient to identify the

disease. DNA in most cells is regularly damaged by endogenous and exogenous mutagens. At least four main partially

overlapping damage repair pathways operate in mammals. Common polymorphisms in DNA repair genes may alter

protein function and an individual’s capacity to repair damaged DNA; deficits in repair capacity may lead to genetic

instability and carcinogenesis. In the present study, we investigated the genotypic distribution of XRCC1 and XPC

polymorphisms and its association with prostate cancer risk, pathological staging and Gleason’s scoring. The present

study was conducted in the departments of Clinical Pathology, Pathology, and Urology Faculty of Medicine, Alexandria

University-Egypt. A total number of 50 patients with pathologically confirmed prostate cancer and 50 age-matched

control subjects were enrolled in this study. The diagnosis was made on the basis of histopathological findings, follow-

ing radical prostatectomy or transurethral resection of the prostate (TURP). Genomic DNA was extracted from periph-

eral blood using QIAamp blood DNA isolation kits. PCR followed by enzymatic digestion of the PCR products for

(XRCC1, XPC) was used for the genotyping of these polymorphisms. Statistical analyses were performed using SPSS

statistics version 20. The genotype frequencies of the studied polymorphisms in all the samples (n = 100), PC patients

(n = 50) and healthy controls (n = 50) were consistent with the Hardy-Weinberg equilibrium distribution (p-value >

0.05). There was no statistical difference in the genotypes of the XRCC1 Arg399Gln and XPC Lys939Gln between

cases and controls. The “Gln” allele frequency of XPC Lys939Gln as well as the “Gln” allele frequency of XRCC1

Arg399Gln tended to be lower in controls than in PC patients. Yet, these decreases were not statistically significant. We

also examined the combined effect of XPC and XRCC1 and we found a decreased PC risk when XPC 939 Lys/Lys +

Lys/Gln and XRCC1 399 Arg/Arg + Arg/Gln are combined (OR = 0.370, 95% CI = 0.142 - 0.962).

Keywords: Prostate Cancer; Polymorphisms; PCR; XRCC1; XPC

1. Introduction

Prostate cancer is a common disease with a multifactorial

and complex etiology. It is the most common male ma-

lignancy and the second leading cause of death in many

countries [1]. Several risk factors such as ethnicity, fam-

ily history, and age have been shown to be associated

with the increased prostate cancer risk [2].

The widespread use of PSA testing has increased the

detection of this cancer at earlier stages, although this

diagnostic method has proved to be insufficient to iden-

tify the disease [3].

Pathological staging and Gleason scores for grading

are the most important prognostic factors but they have

*Conflict of interest: The authors report no conflict of interest.

#Corresponding author.

Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer

1500

been shown to imperfectly discriminate patients at risk

for progression [3]. Therefore, research has been directed

toward identifying molecular markers that can predict

prostate cancer predisposition and progression.

DNA in most cells is regularly damaged by endoge-

nous and exogenous mutagens. Unrepaired damage can

lead to effects, triggering cell-cycle arrest or cell death,

or long term effects in the form of irreversible mutations

contributing to oncogenesis [4].

At least four main partially overlapping damage repair

pathways operate in mammals, namely, nucleotide-exci-

sion repair (NER), base-excision repair (BER), homolo-

gous recombination and end joining [4].

Common polymorphisms in DNA repair genes may

alter protein function and an individual’s capacity to re-

pair damaged DNA; deficits in repair capacity may lead

to genetic instability and carcinogenesis [5]. There is

emerging evidence that polymorphic genes may modu-

late effects of endogenous androgens or environmental

toxicans on prostate cancer risk [6].

The xeroderma pigmentosum complementation group

C (XPC) protein plays a key role in NER pathway. The

functional DNA-binding domains of XPC interact with

HR23B to form a complex that recognizes and binds to

the sites of DNA damage. Deficiency in XPC has been

involved in tumorigenesis [7].

The X-ray cross complementing group 1 (XRCC1) is

one of the enzymes participating in the BER pathway and

acts as a scaffolding intermediate by interacting with

ligase III, DNA polymerase-B and poly (ADP-ribose)

polymerase [8].

In the present study, we investigated the genotypic dis-

tribution of XRCC1 and XPC polymorphisms and its

association with prostate cancer risk, pathological staging

and Gleason’s scoring.

2. Subjects and Methods

The present study was conducted in the departments of

Clinical Pathology, Pathology, and Urology Faculty of

Medicine, Alexandria University-Egypt. A total number

of 50 patients with pathologically confirmed prostate

cancer and 50 age-matched control subjects were en-

rolled in this study. The diagnosis was made on the basis

of histopathological findings, following radical prostatec-

tomy or transurethral resection of the prostate (TURP).

The cases were classified according to the WHO criteria,

and staged according to the tumor-node-metastasis

(TNM) classification and the Gleason grading system.

The range of age of the included patients and controls

was 40 - 80 years. Controls were apparently healthy sub-

jects on medical examination. Informed consent was ob-

tained from all subjects included in this study according

to the Ethical Committee for Human Research in Alex-

andria Main University Hospital. Samples (peripheral

blood and prostatic tissue biopsy) were collected from

Urology Department; Faculty of Medicine, Alexandria

University over 1 year between 2010 and 2011.

PCR-RFLP genotyping

Genomic DNA was extracted from peripheral blood

using QIAamp blood DNA isolation kits (Qiagen, Craw-

ley, United Kingdom) according to the manufacturer’s

protocol.

2.1. Polymerase Chain Reaction

(PCR)-Restriction Fragment Length

Polymorphism (RFLP) Analysis

PCR followed by enzymatic digestion of the PCR prod-

ucts for (XRCC1, XPC) was used for the genotyping of

these polymorphisms. Amplification reactions were per-

formed in a total volume 50 l containing 50 - 100 ng

DNA and 20 pmol each primer. 2X PCR master mix

(Fermentas Life Science) was used. It is composed of:

dNTPs (dATP, dCTP, dGTP, and dTTP) 0.4mM of each,

MgCl2 (4 mM) and 0.05 units/ml of Taq polymerase in

reaction buffer. Samples were amplified by DNA thermal

cycler (Techne Cambridge LTD) for XRCC1 Arg399Gln,

and XPC Lys939Gln. The PCR program had an initial

denaturation step of 7 min at 94˚C followed by 35 cycles

of 30 s at 94˚C, 45 s of annealing at 57˚C - 62˚C based

on the primers and 45 s at 72˚C.

2.2. XRCC1 Arg399Gln Polymorphism

The XRCC1 Arg399Gln polymorphism was amplified in

a 616-bp fragment by using the following primers:

xrcc1-399F (5’-TTGTGCTTTCTCTGTGTCCA-3’)

and xrcc1-399R (5’-TCCTCCAGCCTTTACTGATA-3’).

The PCR product was digested with Fast Digest MspI

(Fermentas, life scince). The recognition site for the

MspI restriction endonuclease is present only in the Arg

(WT) allele; hence, digestion of the Arg allele results in

products of 376 bp and 240 bp, whereas the Gln allele

remains undigested.

2.3. XPC Lys939Gln Polymorphism

The XPC Lys939Gln polymorphism was amplified in a

281-bpfragment by using the following primers:

xpc-939F (5’-ACCAGCTCTCAAGCAGAAGC-3’)

and xpc-939R (5’-CTGCCTCAGTTTGCCTTCTC-3’).

The PCR product was digested with Fast Digest PvuII

(Fermentas, life scince). The wild (WT/AA) allele re-

mains undigested, hence Lys digestion (AA) gives 280

bp and variant digestion (Gln/CC) gives 150 and 131 bp

fragments .

Fast Digest enzymes (Fermentas, Life science) are ad-

vanced line of restriction enzymes for rapid DNA diges-

tion in 5 - 15 minutes supplied with 10× Fast Digest

buffer 1 µl of Fast Digest enzyme is formulated to digest

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Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer 1501

up to 0.2 µg of PCR product in 5 minutes.

Each restriction digestion reaction (30 µl) involved the

following components at room temperature in the fol-

lowing order: 17 µl water nuclease free, 2 µl 10× Fast

Digest buffer, 10 µl PCR product and1 µl Fast Digest

enzyme. Then the components were mixed up gently and

spun down and then incubated at 37˚C for 5 - 10 min.

The digested products were resolved on 3% agarosre

gel, stained with ethidium bromide and analyzed under

UV light.

2.4. Statistical Methodology

Statistical analyses were performed suing SPSS® Statis-

tics version 20 (IBM Corp., New York, USA). Associa-

tion between categorical variables was tested using Chi-

square test (Χ2). When more than 20% of the cells have

expected count less than 5, correction for chi-square was

conducted using Firsher’s Exact test(FEP). Odds ratio

(OR) and the corresponding 95% confidence interval (CI)

were computed to quantify the risk associated with gene

polymorphism. Significance test results are quoted as

two-tailed probabilities and judged at the 5% level.

3. Results

1. Clinico-pathological criteria of the patients:

The present study included 50 patients diagnosed with

prostatic cancer and 50 age-matched controls.

Table 1 shows that the mean age of the patients was

65.4 ± 8.7. The average Gleason sum was 6.8 ± 1.6, their

serum PSA was greatly variable ranging from 4 to 297

ng/ml with a median value of 48. Most of the 50 PC pa-

tients were of grade T2 & T3 (n = 40, 80%), had no

nodal metastasis (N0) (32, 64%). Nearly half of them

were classified as stage II (52%).

2. Hardy-Weinberg equilibrium:

The genotype frequencies of the studied polymor-

phisms in all the samples (n = 100); PC patients (n = 50)

and healthy controls (n = 50) were consistent with the

Hardy-Weinberg equilibrium distribution (p-value >

0.05).

3. XRCC1 Arg399Gln and XPC Lys939Gln polymor-

phisms:

Table 2 shows the genotype distribution of the XRCC1

Arg399Gln and XPC Lys939Gln polymorphisms be-

tween the PC cases and controls. There was no statistical

difference in the genotypes of the XRCC1 Arg399Gln

and XPC Lys939Gln between cases and controls.

The frequencies of the variant alleles between cases

and controls were as follows: XPC Lys939Gln (0.43,

0.37) and XRCC1 Arg399Gln (0.29, 0.23) (Table 3)

(Figures 1 and 2).

The “Gln” allele frequency of XPC Lys939Gln as well

as the “Gln” allele frequency of XRCC1 Arg399Gln

Table 1. Characteristics of PC patients.

Cases (N = 50) n (%)

Age

M ± SD 65.4 ± 8.7

(Min.-Max) (52 - 82)

PSA (ng/ml)

Mdn 48

(Min.-Max) (4 - 297)

Gleason sum

M ± SD 6.8 ± 1.6

(Min.-Max) (4 - 10)

T1 6 12.0

T2 20 40.0

T3 20 40.0

T4 4 8.0

N0 32 64.0

N1 13 26.0

Nx 5 10.0

M0 19 38.0

M1 4 8.0

Mx 27 54.0

Stage

II 26 52.0

III 13 26.0

IV 11 22.0

tended to be lower in controls than in PC patients. Yet,

these decreases were not statistically significant.

We also examined the combined effect of XPC and

XRCC1 and we found a decreased PC risk when XPC

939 Lys/Lys + Lys/Gln and XRCC1 399 Arg/Arg +

Arg/Gln are combined (OR= 0.370, 95% CI=0.142-0.962)

(Table 4).

4. Relation of the XPC polymorphism with clinical pa-

rameters in PC patients:

Table 5 shows the relation of XPC polymorphisms

with clinic-pathological parameters including age of on-

set, Gleason score, and the stage of the tumor in PC pa-

tients.

The frequency of Gln/Gln genotype of the XPC tended

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Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer

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Table 2. Distribution of two DNA repair gene polymorphisms in PC patients and controls.

Test of association

Genotype Case (n = 50) n (%)Control (n = 50) n (%)OR (95%)

Χ2 (p-value)

Gln/Gln 8 (16.0) 3 (6.0)

Arg/Arg + Arg /Gln 42 (84.0) 47(94.0)

0.335

(0.083 - 1.346)

2.554

(0.110)

Arg/Arg 29 (58.0) 30(60.0)

XRCC1

Gln/Gln + Arg /Gln 21 (42.0) 20(40.0)

1.086

(0.489 - 2.411)

0.041

(0.839)

Gln/Gln 9 (18.0) 5 (10.0)

Lys/Lys + Lys/Gln 41 (82.0) 45(90.0)

0.506

(0.157 - 1.635)

1.329

(0.249)

Lys/Lys 16 (32.0) 18(36.0)

XPC

Gln/Gln + Lys/Gln 34 (68.0) 32(64.0)

1.195

(0.522 - 2.737)

0.178

(0.673)

Table 3. Comparison of the allele frequency of XPC Lys939Gln and XRCC1 Arg399Gln between PC patients and healthy

controls.

Test of association

Genotype Case (Alleles no. = 100) n (%) Control (Alleles no. = 100) n (%)OR (95%)

Χ2 (p-value)

Arg 71 (71) 77 (77)

XRCC1

Gln 29 (29) 23 (23)

1.367

(0.725 - 2.581)0.936 (0.333)

Lys 57 (57) 63 (63)

XPC

Gln 43 (43) 37 (37)

1.284

(0.729 - 2.265)0.750 (0.386)

Table 4. Comparison of the combined effect of XPC and XRCC between PC patients and healthy control.

Genotype Test of association

XPC XRCC1

Case (n = 50) n (%)Control (n = 50) n (%)OR (95%)

Χ2 (p-value)

Lys/Lys + Lys/Gln Arg/Arg + Arg/Gln 33 (66.0) 42 (84.0) 0.370 (0.142 - 0.962) 4.320 (0.038)

Lys/Lys + Lys/Gln Gln/Gln 8 (16.0) 3 (6.0) 2.984 (0.743 - 11.988) 2.554 (0.110)

Gln/Gln Arg/Arg + Arg/Gln 5 (10.0) 9 (18.0) 0.506 (0.157 - 1.635) 1.329 (0.249)

Gln/Gln Gln/Gln 0 0.0 0 0.0 -- --

Table 5. Association of the XPC Lys939Gln polymorphism with clinical parameters in prostate cancer patients.

Genotype Lys/Lys + Lys/Gln (n = 41) Lys/Lys (n = 9) OR (95%) Test of association

<70 22 (54) 6 (67)

Age

≥70 19 (46) 3 (33)

0.579

(0.127 - 2.636) FEP = 0.713

<50 21 (51) 7 (78)

PSA

(ng/ml) ≥50 20 (49) 2 (22)

0.300

(0.056 - 1.620) FEP = 0.266

<7 19 (46) 5 (56)

Gleason

≥7 22 (54) 4 (44)

0.691

(0.162 - 2.948) FEP = 0.721

II 22 (54) 4 (44)

Stage

III/IV 19 (46) 5 (56)

1.447

(0.339 - 6.177) FEP = 0.721

Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer 1503

Figure 1. Agarose gel electrophoresis of the digested prod-

uct of PvuII restriction endonuclease of XPC in 7 cases and

controls. Lane MMshows a 50 bp molecular weight marker.

Lanes 1, 3, 4 and 6 (131 bp, 150 bp) variant CC genotype.

Lane 2 shows (281 bp, 150 bp and 130 bp)heterozygous

mutated AC genotype, lanes 5 and 7 show (281 bp) wild

type AA genotype.

Figure 2. Agarose gel electrophoresis of the digested prod-

uct of MspI restriction endonuclease of the XRCC1 in 4

subjects. Lane MM shows a 50 bpmolecular weight marker,

Lanes 1 and 3 show wild type GG (269 bp, 133 bp), lane 2

shows heterozygous GA (402 bp, 269 bp and 133 bp), lane 4

shows variant AA (402 bp).

to be lower in older age (≥70) group than in younger age

group (<70) (OR = 0.579, 95%CI = 0.127 - 2.636) as

well as in patients with higher PSA (≥50) than in patients

with lower PSA (<50) (OR = 0.300, 95%CI = 0.056 -

1.620). Yet, these associations were not statistically sig-

nificant.

5. Relation of the XRCC1 polymorphism with clinical

parameters in PC patients:

The associations between XRCC1 polymorphisms

with clinico-pathological parameters were shown in Ta -

ble 6. None of these associations were statistically sig-

nificant. However, the frequency of Gln/Glnwas consid-

erably higher in patients with high Gleason sum (≥7)

than in patients with low Gleason sum (<7).

4. Discussion

Prostate Cancer is the most frequently diagnosed malig-

nancy and a common leading cause of cancer death

among males worldwide [1,9].

Human DNA repair mechanisms protect the genome

from DNA damage caused by endogenous and environ-

mental agents. Genetic polymorphisms of DNA repair

genes have been reported to lead to amino acid substitu-

tion in various cancers [4].

The XPC gene, located on chromosome 3p25, contains

16 exons and 15 introns and encodes a 940 amino acid

protein [10]. Several polymorphic variants in the XPC

gene have been identified and XPC Lys939Gln is one of

the three most common SNPs.

It is located in the coding sequence of the XPC gene.

The nucleotide change from A to C leads to an amino

acid change from lysine to glutamine in the coding se-

quence of the XPC gene and has been reported to lead to

reduced repair capacity. This genetic variation has also

been reported to result in reduced specificity of this gene

in recognition and repair of the DNA damage as well as

in protein expression, thus allowing more somatic DNA

mutations or alterations to occur [11,12].

XPC polymorphism was reported to be associated with

the risk of many cancers, such as head and neck [13],

lung [14], breast [15] and bladder [16].

XRCC1 is located on chromosome 19q13.2. The pro-

tein encoded by this gene is involved in the efficient re-

pair of DNA single-strand breaks formed by exposure to

ionizing radiation and alkylating agents. This protein

interacts with DNA ligase III, polymerase beta and poly

(ADP-ribose) polymerase to participate in the base exci-

sion repair pathway [17].

To our knowledge this is the first study to evaluate the

risk of the XPC Lys939Gln and XRCC Arg399Gln poly-

morphisms with prostate cancer in a sample of Egyptian

population.

Our results showed that no statistical difference in the

enotype of XPC Lys939Gln between cases and controls. g

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Table 6. Association of the XRCC1 Arg399Gln polymorphism with clinical parameters in prostate cancer patients.

Genotype Arg/Arg + Arg/Gln (n = 42) Gln/Gln (n = 8) OR (95%) Test of association

<70 24 (57) 4 (50)

Age

≥70 18 (43) 4 (50)

1.333

(0.293 - 6.064) FEP = 0.718

<50 24 (57) 4 (50)

PSA (ng/ml)

≥50 18 (43) 4 (50)

1.333

(0.293 - 6.064) FEP = 0.718

<7 23 (55) 1 (12)

Gleason

≥7 19 (45) 7 (88)

8.474

(0.956 - 75.082) FEP = 0.050

II 22 (52) 4 (50)

Stage

III/IV 20 (48) 4 (50)

1.100

(0.242 - 4.991) FEP = 1.000

This is in contrast to the report that demonstrated that

prostate cancer patients with at least one variant allele at

XPC Lys939Gln had a slightly reduced risk of prostate

cancer and a slightly reduced risk when both variants

were present.

In the present study, we did not find a significant asso-

ciation between the genotype of the XRCC1 Arg399Gln

and prostatic cancer cases or controls. Our findings are in

agreement with the previously reported non-significant

lower risk associated with this genotype in three different

studies in the U.S. population [18-20]. However, two

other studies found higher prostatic cancer risk for the

carriers of this allele [21,22].

A case-control study in China of 5 DNA repair mark-

ers found a positive association between PC risk and the

XRCC1 399Gln/Gln genotype [18]. A significantly in-

creased risk of PC was observed in white men with the

XRCC1 399Gln allele (OR 1.6; 95% CI 1.1 - 2.4). This

study has found that white men with the following com-

bined genotypes XRCC1 (399Arg/Gln_Gln/Gln)/APE1

(51Gln/Gln) (OR: 4.0; 95% CI: 1.3 - 12.5) and XRCC1

(399Arg/Gln_Gln/Gln)/APE1(148Asp/Asp) (OR: 2.9;

95% CI: 1.4 - 6.1) genotypes have higher risk for PC [9].

However, another study reported reduced PC risk for

men who carry 1 or 2 copies of the variant alleles at the

XRCC1 codons 194 and 399 compared with those who

were homozygous for the common allele (OR: 0.8; 95%

CI: 0.4 - 1.8 and OR_0.8; 95% CI, 0.5 - 1.3), respectively

[19].

We also examined the combined effect of XPC

Lys939Gln and XRCC1 Arg399Gln on prostate cancer

risk, and the resultant ORs for XPC Lys939Gln (Lys/Lys

+ Lys/Gln) + XRCC1 Arg399Gln (Arg/Arg + Arg/Gln)

were 0.370. We found a decreased prostatic cancer risk

when the previous genotypes were combined. In a study

conducted by Hirata et al. [23], the results showed that

an additional effect was not observed in the combined

analysis compared to XPC Lys939Gln (Lys/Lys + Lys/

Gln). This was considered to be due to the increased fre-

quencies of the XPC Lys allele.

5. Conclusion

In conclusion, our results suggested that there is no asso-

ciation between XPC Lys939Gln, XRCC1 Arg399Gln

and PC risk. Although the combined effect of XPC

Lys/Lys + Lys/Gln and XRCC1 Arg/Arg + Arg/Gln de-

creased PC risk, it didn’t reach a statistically significant

level. To our knowledge, this is the first report on the

studies of XPC Lys939Gln and XRCC1 Arg399Gln

polymorphisms in a sample of Egyptian prostatic cancer

patients. Further studies with a larger sample size and

other DNA repair polymorphisms that may play a role in

the pathogenesis of PC and the inclusion of other envi-

ronmental factors as smoking are necessary to confirm

these findings.

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