Genetic variation in DNA repair gene XRCC7 (G6721T) and susceptibility
to breast cancer
Meysam Nasiria, Iraj Saadata,b, Shahpour Omidvaric, Mostafa Saadata,b,⁎
aDepartment of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran
bInstitute of Biotechnology, Shiraz University, Shiraz, Iran
cDepartment of Chemotherapy, Shiraz University of Medical Sciences, Shiraz, Iran
a b s t r a c t a r t i c l ei n f o
Accepted 22 April 2012
Available online 24 May 2012
The human XRCC7 is a DNA double-strand break (DSBs) repair gene, involved in non-homologous end joining
(NHEJ). It is speculated that DNA DSBs repair have an important role during development of breast cancer.
The human XRCC7 is a NHEJ DSBs repair gene. Genetic variation G6721T of XRCC7 (rs7003908) is located in
the intron 8 of the gene. This polymorphism may regulate splicing and cause mRNA instability. In the present
study, we specifically investigated whether common G6721T genetic variant of XRCC7 was associated with an
altered risk of breast cancer. The present study included 362 females with breast cancer. Age frequency-
matched controls (362 persons) were randomly selected from the healthy female blood donors, according
to the age distribution of the cases. Using RFLP-PCR based method, the polymorphism of XRCC7 was deter-
mined. The TG (OR=1.20, 95% CI: 0.83–1.74, P=0.320) and TT (OR=1.01, 95% CI: 0.67–1.53, P=0.933)
genotypes had no significant effect on risk of breast cancer, in comparison with the GG genotype. Our present
findings indicate that the TT and TG genotypes were not associated with an altered breast cancer risk.
© 2012 Elsevier B.V. All rights reserved.
It is well established that the capacity of cells to maintain their
genomic stability, by means of a variety of DNA repair pathways, is
essential in the prevention of tumor initiation and progression. DNA
double-strand breaks (DSBs) may result in genetic instability and
ultimately may enhance the rate of cancer development. There are
two pathways for DNA DSBs repair, homologous recombination
(HR) and non-homologous end joining (NHEJ) pathways. HR entails
copying the missing information from an undamaged homologous
chromosome. HR acts during S to G2 phases of the mammalian cell
cycle. In NHEJ, the broken DNA termini are first processed to make
them compatible and then sealed by a ligation step. NHEJ acts during
all phases of the mammalian cell cycle. Therefore, HR and NHEJ are
error-free and error-prone pathways, respectively. It should be noted
that NHEJ is the major pathway for DSB repair in human cells (Valerie
and Povirk, 2003).
The human XRCC7 (MIM: 600899; GenBank accession no: NM_
001469) is a NHEJ DSBs repair gene. This gene encodes the catalytic
subunit of DNA-activated protein kinase (DNA-PKcs), involved in
NHEJ repair pathway (Blunt et al., 1995). DNA-PKcs is recruited to
the site of DSBs by the KU70/KU80 heterodimer to form an active
DNA-PK complex that is essential for the progression of the NHEJ
pathway (Sipley et al., 1995). Deficiencies in DNA-PK activity are clin-
ically significant. Mice with inactivated components of DNA-PK show
severe combined immunodeficiency as well as ionizing radiation
hypersensitivity (Ferguson et al., 2000; Singleton et al., 1997).
Genetic variation G6721T of XRCC7 (rs.7003908) is located in the
intron 8 of the gene. It is speculated that this polymorphism, may
regulate splicing and cause mRNA instability (Sipley et al., 1995).
Although NHEJ is the major pathway for DSB repair in human cells
(Valerie and Povirk, 2003), only a few studies on the G6721T poly-
morphism of XRCC7 associated with several types of cancers have
been published with conflicting results (Gangwar et al., 2009; Hirata
et al., 2006, 2007; Liu et al., 2007; Mandal et al., 2010; Wang et al.,
To the best of our knowledge, there is no report on the association
between this polymorphism and breast cancer risk. Therefore the
present study was done.
2. Materials and methods
The present case–control study consisted of 362 females with path-
ologically confirmed primary adenocarcinoma of breast who were
recruited from chemotherapy department of Nemazi hospital in Shiraz
Gene 505 (2012) 195–197
Abbreviations: DNA-PKcs, DNA-activated protein kinase; DSBs, double-strand break;
NHEJ, non-homologous end joining; RFLP-PCR, restriction fragment length polymorphism-
polymerase chain reaction; XRCC7, DNA-dependent protein kinase, catalytic subunit.
⁎ Correspondingauthor at: Departmentof Biology,College of Sciences, Shiraz University,
Shiraz 71454, Iran.
E-mail addresses: firstname.lastname@example.org, email@example.com (M. Saadat).
0378-1119/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
Contents lists available at SciVerse ScienceDirect
journal homepage: www.elsevier.com/locate/gene
(south of Iran). Age frequency-matched controls (362 persons) were
randomly selected from the healthy female blood donors. Exclusion
criteria for controlsincludedanypreviouscancer historyand diagnosed
psychiatric diseases. The mean age (SD; min–max) of the patients and
the controls were 45.4 (9.8; 23–74) and 44.2 (8.6; 24–72) years,
Because Iranian population is one of the most heterogeneous
populations (Bazrgar et al., 2008; Mohamadynejad and Saadat,
2008; Rafiee et al., 2010), we selected our patients and controls
from Persian (Caucasians) Muslims living in Fars province. Informed
consent was obtained from each subject before the study.
Prior to blood sampling, all participants were asked about their
family history of breast cancer in first-degree relatives. Among pa-
tients and controls a woman with at least one first-degree relative
with breast cancer was considered to have a positive family history.
Considering that small numbers of control subjects have positive fam-
ily history of breast cancer, only subjects with negative family history
were included in the statistical analysis.
2.2. DNA extraction and genotyping analysis
Genomic DNAwas extracted from wholeblood samples. The G6721T
polymorphism of XRCC7 was determined using the PCR-RFLP method
with the primers as described previously (Wang et al., 2004).
For quality control, 15% of randomly selected samples were repeated
to verify genotyping results and 100% concordance was found.
2.3. Statistical analysis
Chi-square test was performed for the polymorphism to determine
if the control sample demonstrated Hardy–Weinberg equilibrium. The
associations between the genotypes of XRCC7 and breast cancer risk
were assessed by calculating odds ratios (ORs) and 95% confidence
intervals (CIs). Positive family history of breast cancer in first-degree
the patients were stratified by the family history of the participants
(negative and positive) and the data were reanalyzed.
3. Results and discussion
The general characteristics of breast cancer patients and control
group are summarized in Table 1. Family history significantly differed
between cases and controls (OR=6.06, 95% CI: 3.13–11.7, Pb0.001).
However, smoking habit, marital status, menopausal status, age of
menarche did not differ significantly between cases and controls
Table 2 shows the genotype distribution of the G6721T polymor-
phism of XRCC7 between the breast cancer cases and healthy controls.
The genotype frequencies of the polymorphism in healthy controls
(χ2=2.023, df=1, P=0.155) and patients (χ2=0.069, df=1,
P=0.799) were consistent with the Hardy–Weinberg equilibrium
The TG (OR=1.20, 95% CI: 0.83–1.74, P=0.320) and TT (OR=
1.01, 95% CI: 0.67–1.53, P=0.933) genotypes had no significant effect
on risk of breast cancer, in comparison with the GG genotype
(Table 2). It should be noted that after adjusting for age and marital
status, same results were observed (data not showed). Although the
association between breast cancer risk and XRCC7 G6721T polymor-
phism was not investigated, only a few studies on the G6721T poly-
morphism of XRCC7 associated with other types of cancers (such as
bladder cancer, prostate cancer and renal cell carcinoma) have been
published (Gangwar et al., 2009; Hirata et al., 2006, 2007; Liu et al.,
2007; Mandal et al., 2010; Wang et al., 2004, 2008). A majority of
the studies found no association between this polymorphism and
risk of cancers, which is similar to our finding.
Table 3 shows the profiles of XRCC7 polymorphism control and
cancerous groups among negative family history for breast cancer.
The reference group consisted of individuals with negative family
history and GG genotype. The TG (OR=1.19, 95% CI: 0.80–1.78,
P=0.374) and TT (OR=0.96, 95% CI: 0.62–1.50, P=0.873) geno-
types had no significant effect on risk of breast cancer, in comparison
with the GG genotype. If the age was included in the analysis as a
covariate, the same results were obtained.
Variations in low-penetrance genes may confer a small to modu-
late cancer risk to an individual (Rebbeck, 1999). DSBs may result in
genetic instability and ultimately may enhance the rate of cancer
development. Therefore common polymorphisms in genes involved
in DNA DSBs repair are good candidate for low-penetrance breast
cancer susceptibility. The XRCC7 gene is involved in the NHEJ path-
way, which is responsible for repairing most DSBs of DNA (Blunt
et al., 1995; Sipley et al., 1995; Valerie and Povirk, 2003). Mice with
inactivated components of DNA-PK show ionizing radiation hyper-
sensitivity (Ferguson et al., 2000). Therefore, polymorphisms of the
XRCC7, if functional, could be expected to have an effect on DSB re-
pair, and thus, on carcinogenesis.
Interestingly, the TT and TG genotypes were not associated with
an altered breast cancer risk. Larger studies with more detailed data
on environmental exposure are needed to verify this initial finding.
Conflict of interest statement
The authors have no conflict of interest in relation to this study.
Selected characteristics of participants of breast cancer study.
Age at diagnosis (years)
Age at menarche (years)
⁎P associated with either Student's t-test or chi-square test and Fisher's exact test.
⁎⁎Family history of breast cancer in the first-degree relatives.
Association between XRCC7 polymorphism and risk of breast cancer.
XRCC7 polymorphism ControlCaseOR 95% CI
Association between XRCC7 polymorphism and risk of breast cancer among partici-
pants with negative family history in their first relatives.
XRCC7 polymorphismControlCase OR95% CI
M. Nasiri et al. / Gene 505 (2012) 195–197
Acknowledgments Download full-text
The authors are indebted to the participants for their close cooper-
ation. This study was supported by Shiraz University.
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