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.
Received November 23rd, 2013; revised December 13th, 2013; accepted December 20th, 2013
Copyright © 2013 Amani Fouad Sorour et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
In accordance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the
intellectual property Amani Fouad Sorour et al. All Copyright © 2013 are guarded by law and by SCIRP as a guardian.
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)
T
T1 6 12.0
T2 20 40.0
T3 20 40.0
T4 4 8.0
N
N0 32 64.0
N1 13 26.0
Nx 5 10.0
M
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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1502
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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Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer 1504
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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