Association of X-Ray Repair Cross-Complementing Group 1 Arg194Trp, Arg399Gln and Arg280His Polymorphisms with Head and Neck Cancer Susceptibility: A Meta-Analysis
Association of X-Ray Repair Cross-Complementing Group 1 Arg194Trp, Arg399Gln and Arg280His Polymorphisms with Head and Neck Cancer Susceptibility: A Meta- Analysis
Wei Wu 0
Lu Liu 0
Zhihua Yin 0
Peng Guan 0
Xuelian Li 0
Baosen Zhou 0
Xifeng Wu, MD Anderson Cancer Center, United States of America
0 1 Department of Epidemiology, School of Public Health, China Medical University , Shenyang , China , 2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province , Shenyang , China , 3 Department of Preventive Dentistry, School of Stomatology, China Medical University , Shenyang , China
Background: Previous studies on the association of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg399Gln, and Arg280His polymorphisms with head and neck cancer (HNC) have produced inconsistent results. The aim of the present study was to evaluate the effects of these three polymorphic variants on HNC risk. Methods: The PubMed and EMBASE databases were searched for genetic association studies on the XRCC1 Arg194Trp, Arg399Gln, and Arg280His polymorphisms and HNC risk. (The most recent search was conducted on 20 August, 2013.) Twenty-six studies were identified and meta-analysis was performed to evaluate the association between the polymorphism and HNC by calculating combined odds ratios and 95% confidence intervals. Results: No significant association was found under the allelic, homozygous, heterozygote, and dominant genetic models in the overall comparison. Further, no significant association between the XRCC1 Arg399Gln and Arg280His polymorphisms and HNC risk was detected under the four genetic models in subgroup analyses based on ethnicity, cancer site, and whether or not the studies had been adjusted for cigarette smoking and alcohol. However, in stratified analyses based on cancer site, a significant association was found between the XRCC1 Arg194Trp polymorphism and oral cancer under the allelic, heterozygote, and dominant models. The XRCC1 Arg194Trp polymorphism was significantly associated with HNC risk in studies that were adjusted for smoking and alcohol under the homozygous and heterozygote models. Conclusion: The meta-analysis results suggest that the XRCC1 Arg399Gln and Arg280His polymorphisms are probably not associated with the risk of HNC, but the XRCC1 Arg194Trp polymorphism was associated with increased risk of HNC in the subgroup analysis of studies adjusted for smoking and alcohol and with increased risk of oral cancer in the stratified analyses based on cancer site. Further studies with larger samples are needed to confirm these findings.
Head and neck cancer (HNC), including cancers in the oral
cavity, pharynx (other than nasopharynx), and larynx, is the sixth
most common cancer in the world . Approximately 540,000
new cases and 271,000 deaths are reported annually worldwide,
indicating a mortality of approximately 50% . HNC is
considered to be a complex disease because both genetic and
environmental risk factors contribute to its etiology . The
principal risk factors for HNC include tobacco and alcohol use,
and exposure to the human papillomavirus (HPV), which together
contribute to the development of at least 90% of squamous cell
carcinoma of the head and neck cases . Furthermore, many
recent studies have provided evidence that genetic factors
including family history  and polymorphisms in genes 
play important roles in the development of HNC.
Recent evidence indicates that DNA repair genes may
determine individual susceptibility to HNC [9,10]. Polymorphisms
in the repair genes that encode enzymes may increase or decrease
DNA repair capacity. The DNA repair pathway involves the
direct reversal pathway, the excision repair pathway, and the
postreplication/bypass pathway. The excision repair pathway includes
base excision repair (BER), nucleotide excision repair, and
mismatch repair . X-ray repair cross-complementing group
1 (XRCC1) is an important DNA repair protein in the BER
pathway . In vitro and vivo studies have shown that XRCC1
plays a role either directly during the repair of single-strand breaks
or indirectly during BER. Loss of XRCC1 activity resulted in
decreased genetic stability, including the increased frequency of
spontaneous and/or induced chromosome translocations and
deletions . Although more than 200 single nucleotide
polymorphisms (SNPs) have been identified in XRCC1, only three
common SNPs have been widely investigated in cancer risk. They
are Arg194Trp (rs1799782), Arg280His (rs25489), and Arg399Gln
(rs25487), located in exons 6, 9, and 10, respectively, of the
XRCC1 gene . In HapMap (http://snp.cshl.org/cgi-perl/
gbrowse/hapmap24_B36/), the minor allele frequency (MAF) of
Arg194Trp is 0.09 for Caucasians and 0.26 for Asians; the MAF of
Arg399Gln is 0.37 for Caucasians and 0.26 for Asians; and the
MAF of Arg280His is 0.04 for Caucasians and 0.09 for Asians.
Some studies reported the association of the Arg194Trp [8,17],
Arg280His [17,18], and Arg399Gln [19,20] polymorphisms with
risk of various cancers.
Lately, a number of studies have reported the association
between XRCC1 polymorphisms and HNC risk, but the results
are inconsistent. Tea et al.  and Ramachandran et al. 
found that the Arg194Trp polymorphism might increase the HNC
risk, while Matullo et al.  reported the opposite finding. The
function of the Arg280His polymorphism is still not fully
understood. Chuang et al.  conducted a pooled analysis and
found that rare XRCC1 Arg280His homozygotes were associated
with HNC risk after adjustment for cigarette smoking and alcohol
consumption, while, in other studies, no such association was
found [9,2325]. For the Arg399Gln polymorphism, the results
are still controversial [10,11,24]. Therefore, we performed a
metaanalysis to assess the association between the XRCC1 Arg194Trp,
Arg280His and Arg399Gln polymorphisms and HNC risk.
Materials and Methods
We searched PubMed and EMBASE databases for all genetic
association studies on XRCC1 and HNC risk. (The most recent
search was conducted on 20 August, 2013). Various combinations
of the following terms were used in the search: head and neck
cancer, oral cancer, oropharyngeal cancer, laryngeal
cancer, pharyngeal cancer, XRCC1, X-ray
cross-complementing group 1, base excision repair, BER, SNP, single
nucleotide polymorphism, polymorphism and variant. Only
English language papers were included in the search. The
references cited in the original studies or review articles concerning
the relevant topic were retrieved to potentially broaden the search
for additional relevant publications.
Inclusion and Exclusion Criteria
The following criteria were used to select the articles for the
meta-analysis: (a) case-control study or cohort study methodology
was used; (b) association of HNC with the XRCC1 Arg194Trp or
Arg399Gln or Arg280His polymorphisms was explored; and (c)
sufficient data of genotypes presented with estimated odds ratios
(ORs) and 95% confidence intervals (CIs) were available. The
exclusion criteria used were: (a) the control population included
malignant tumor patients or the study had no controls; (b)
insufficient information was available about genotype frequency or
number; (c) duplicate publications or publications that contained
Information was extracted from all eligible publications
carefully and independently by two investigators (Wei Wu and
Lu Liu) using a standard protocol and data-collecting form based
on the inclusion criteria. The original extraction data were
checked by another investigator (Zhihua Yin), and disagreements
were resolved by discussion among the three investigators. The
following data were extracted: name of first author, year of
publication, ethnicity of studied populations, site of cancer,
genotyping method, source of controls, matching criteria, adjusted
variables, and cases and controls with different genotypes.
The Hardy-Weinberg equilibrium (HWE) test  was
conducted on the control groups to evaluate the genetic
equilibrium of each study. A P value.0.05 was taken to indicate
no significant disequilibrium. To avoid the inclusion of unknown
heterogeneities, studies in which the distribution of the genotypes
of the XRCC1 gene polymorphisms in the control groups not
consistent with the HWE were excluded in the subsequent
analysis. The MAF was computed in the control groups. MAF is
an estimate of the frequency at which the less common allele
occurs in a given population. The strength of the association
between an XRCC1 polymorphism and HNC risk was assessed by
combined odds ratios (ORs) with 95% confidence interval (CIs).
The significance of the combined ORs was determined by a Z test
and two-sided P values,0.05 were considered significant. The
chisquare-based Q statistical test was used for heterogeneity analysis
. In this study, P values,0.05 were taken to indicate
significant heterogeneity among studies. The random-effects
model was used when heterogeneity was significant ;
otherwise, the fixed-effects model was used . Heterogeneity
across studies was detected using an I2 test. I2 values of ,25%
were considered low, I2 values of 25% to 75% were considered
moderate, and I2 values of .75% were considered high . We
calculated the OR using four different genetic models: allelic
model (B vs. A), homozygous model (BB vs. AA), heterozygote
model (AB vs. AA), and dominant model (BB+AB vs. AA), where
A represents the major allele and B represents the minor allele.
Stratified analyses of each study by ethnicity, cancer site, and
whether the data had been adjusted for smoking and alcohol were
also conducted using the four genetic models, to identify the
relationship between the XRCC1 polymorphism and HNC risk.
Whenever possible, adjusted ORs in a logistic model were used to
compute combined OR and 95% CI for studies adjusted for
smoking and alcohol. Furthermore, sensitivity analyses were
conducted to confirm the stability and reliability of our results
. Visual inspection of Beggs funnel plot and Eggers test were
used to evaluate the publication bias in the meta-analysis and P
values,0.05 were considered statistically significant [32,33]. All
statistical tests were performed with the software Stata version 12.0
(Stata Corporation, College Station, TX, USA).
A total of 168 potentially relevant studies were retrieved after a
comprehensive search of the PubMed and EMBASE databases
(Figure 1), and 125 of these studies were excluded as not relevant
to HNC or the XRCC1 Arg194Trp, Arg280His, and Arg399Gln
polymorphisms. A further 17 studies were excluded including
three reviews, three meta-analyses, seven studies with missing data,
one study with no controls, and three studies relevant to cell lines.
Consequently, 26 studies [911,21,2325,3452] of the
association of the XRCC1 Arg194Trp, Arg280His, and Arg399Gln
polymorphisms with the risk of HNC were included in the
metaanalysis. Twenty-one of the studies were about XRCC1
Arg194Trp, 25 were about XRCC1 Arg399Gln, and nine were
about XRCC1 Arg280His (Figure 1).
The characteristics of the 26 eligible studies, including year of
publication, ethnicity of studied populations, site of cancer,
method of genotyping, source of controls, matching criteria,
adjusted variables, cases and controls with different genotypes,
HWE in controls, and MAF in controls for the XRCC1
Arg194Trp, Arg399Gln, and Arg280His polymorphisms are listed
in Tables 13 respectively. All the studies were published between
1999 and 2013. The most commonly used genotyping method was
polymerase chain reaction (PCR)-restriction fragment length
polymorphism. The distribution of the genotypes of the XRCC1
Arg194Trp, Arg280His, and Arg399Gln polymorphisms in the
control groups was consistent with the HWE, except in three of the
studies. Two of these studies were related to the Arg194Trp
polymorphism [37,43], and one was related to the Arg399Gln
polymorphism . These studies were excluded from the
subsequent analyses. Finally, to analyze the association of the
three XRCC1 polymorphisms with the risk of HNC, 19 studies
were selected for Arg194Trp, 24 studies were selected for
Arg399Gln, and nine studies were selected for Arg280His.
Quantitative Data Synthesis
XRCC1 Arg194Trp: In the overall comparison, the Arg194Trp
polymorphism was not significantly associated with HNC risk
under the four different genetic models (Figure 2). Further, in the
subgroup analyses based on ethnicity, the Arg194Trp
polymorphism was found to be a risk factor in Asians while it was a
protective factor in Caucasians under all genetic models; however,
the association of the Arg194Trp polymorphism with HNC risk in
Asians and in Caucasians was not significant (Table 4). In the
stratified analyses based on cancer site, the Arg194Trp
polymorphism was significantly associated with oral cancer using the
allelic, heterozygote, and dominant models (allelic model:
OR = 1.35, 95%CI = 1.001.82, I2 = 63.5%, Pheterogeneity = 0.02;
heterozygote model: OR = 1.40, 95%CI = 1.131.73, I2 = 28.5%,
Pheterogeneity = 0.22; dominant model: OR = 1.40, 95%CI = 1.14
1.72, I2 = 53.1%, Pheterogeneity = 0.06), but not significantly associated
with oral cancer using the homozygous model. The Arg194Trp
polymorphism was not significantly associated with larynx cancer
under all four genetic models (Table 4). In the analyses of studies
adjusted for smoking and alcohol, the Arg194Trp polymorphism
was significantly associated with HNC risk under the homozygous
and heterozygote models (homozygous model: OR = 2.21,
95%CI = 1.443.38, I2 = 0.0%, Pheterogeneity = 0.50; heterozygote
model: OR = 1.65, 95%CI = 1.152.38, I2 = 50.0%, Pheterogeneity =
0.01), but the association was not significant under the
dominant model. When the studies were not adjusted for
smoking and alcohol, the Arg194Trp polymorphism was not
significantly associated with HNC risk using any of the four
genetic models (Table 4).
XRCC1 Arg399Gln: In the overall comparison, the Arg399Gln
polymorphism was not significantly associated with HNC risk
under the four different genetic models (Figure 3). Further, in the
subgroup analyses based on ethnicity, the Arg399Gln
polymorphism was not significantly associated with HNC risk in Asians or
Caucasians (Table 4). In the stratified analyses based on cancer
site, the Arg399Gln polymorphism was not significantly associated
with oral cancer or larynx cancer (Table 4). When studies either
adjusted or unadjusted for smoking and alcohol were analyzed, the
Arg399Gln polymorphism was not significantly associated with
HNC risk (Table 4).
XRCC1 Arg280His: In the overall comparison, the Arg280His
polymorphism was not significantly associated with HNC risk
under the four different genetic models (Figure 4). Further, in the
subgroup analyses based on ethnicity, the Arg280His
polymorphism was not significantly associated with HNC risk in Asians or
Caucasians (Table 4). In the stratified analyses based on cancer
site, the Arg280His polymorphism was not significantly associated
with oral cancer (Table 4). When studies either adjusted or
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unadjusted for smoking and alcohol were analyzed, the Arg280His
polymorphism was not significantly associated with HNC risk
Evidence of heterogeneity between studies in this meta-analysis
was detected for XRCC1 Arg194Trp, and Arg399Gln, but the
reasons for the heterogeneity were unclear. In the subgroup
analyses, significant heterogeneity was found in the studies that
used Asian populations, but not in the studies that used
Caucasians, indicating that the publications that used Asians were
probably the main source of heterogeneity in our study. In
addition, significant heterogeneity was found in studies among oral
cancers but not larynx cancers, indicating that the publications
that focused on oral cancers were another probable source of
heterogeneity. HNC includes cancers from different sites and risk
factors for these cancers are different. Therefore, further studies
with larger sample sizes and different tumor sites are needed to
investigate the possible sources of the heterogeneity.
Sensitivity analyses were conducted to assess the influence of
individual studies on the combined ORs by omitting each study in
turn. For all three polymorphisms under all four genetic models,
the significance of the combined ORs was not materially altered
by the exclusion of any individual study (data not shown). This
result indicated that our results were statistically robust. Figure S1
shows the sensitivity analysis of XRCC1 Arg194Trp obtained
under the allelic model by deleting of one study at a time.
Beggs funnel plot and Eggers test were used to estimate the
publication bias in the literature. For all three polymorphisms, the
shapes of the Beggs funnel plots under all four genetic models
showed no obvious asymmetry. Figure S2 shows the shape of the
1.40c(0.932.10) 0.00 75.9 1.46c(0.952.24) 0.00 80.4
0.22 28.5 1.40(1.141.72)*
1.65c(1.152.38)* 0.01 50.0 1.41c(0.424.71) 0.00 90.4
1.07c(0.891.29) 0.01 49.0
1.03c(0.621.71) 0.00 73.6
0.98c(0.781.22) 0.03 58.5 1.00c(0.761.30) 0.00 74.3
0.24 19.6 1.07(0.981.19)
1.14c(0.602.19) 0.00 76.1
0.06 55.5 1.11c(0.791.57) 0.00 74.7
1.13c(0.811.56) 0.04 56.5
0.13 41.2 1.01(0.881.16)
18 0.96c(0.881.06) 0.02
0.90c(0.721.12) 0.02 46.7
1.01c(0.881.15) 0.04 39.7 1.03c(0.901.18) 0.00 55.8
1.66(0.2013.63) 0.62 0.0
1.59(0.0832.17) 0.02 82.5
0.10 51.7 0.98(0.521.86)
aNumber of comparisons;
bP-value for Q-test;
cThe random-effects model was used when the P-value for the Q-test for heterogeneity was ,0.05, otherwise the fixed-effects model was used.
*Statistically significant, P,0.05.
Beggs funnel plot for XRCC1 Arg399Gln under the dominant
model. Eggers test also did not reveal significant evidence of
publication bias for the three polymorphisms under all four genetic
models (data not shown); the one exception was for XRCC1
Arg280His under the heterozygote model (t = 22.56, P = 0.037).
Nevertheless, we found no significant difference between the
corrected OR and uncorrected OR in the trim and fill analysis,
which supported the robustness of our findings.
In the overall comparison, the
significant association between
meta-analysis detected no
the XRCC1 Arg194Trp,
Arg399Gln, and Arg280His polymorphisms and HNC risk under
all four genetic models. Further, in the subgroup analyses based on
ethnicity, cancer site, and whether adjusted or unadjusted for
smoking and alcohol, no significant association was found between
the XRCC1 Arg399Gln, and Arg280His polymorphisms and
HNC risk under the four genetic models. Nevertheless, in the
stratified analyses based on cancer site, significant association was
found between the XRCC1 Arg194Trp polymorphism and oral
cancer under the allelic, heterozygote, and dominant models.
When the studies adjusted for smoking and alcohol were analyzed,
significant association was found between the XRCC1 Arg194Trp
polymorphism and HNC risk under the homozygous and
heterozygote models. Our results indicated that, while the
XRCC1 Arg399Gln and Arg280His polymorphisms may not
increase or decrease the risk of HNC, when cigarette smoking and
alcohol consumption were taken into account, the XRCC1
Arg194Trp polymorphism was associated with increased risk of
HNC and also may modulate genetic susceptibility to oral cancer.
The XRCC1Arg194Trp polymorphism is located in the region of
the protein that separates the DNA polymerase-b and poly
(ADPribose) polymerase-interacting domains. Tae et al. reported a highly
significant association under the dominant genetic model of XRCC1
Arg194Trp with increased risk of squamous cell carcinoma of the
head and neck among Korean patients and normal controls .
However, most other studies have found no association of XRCC1
Arg194Trp with HNC risk [11,24,25,34,35,40,46,48]. In the present
study, an intriguing finding was that the Arg194Trp polymorphism
was a risk factor in Asians and a protective factor in Caucasians under
all four genetic models; however, these associations were not
statistically significant. This finding may have happened by chance,
or may have resulted from different gene frequencies in the different
populations; the MAF of XRCC1 Arg194Trp is 0.26 for Asians but
only 0.09 for Caucasians. A number of studies have reported the
association between the XRCC1 Arg194Trp polymorphism and oral
cancer risk [10,39,41,43,44,51]. It has been reported that the
XRCC1 Arg194Trp polymorphism may result in decreased repair
efficiency of DNA damage, and the repair deficit may eventually
increase an individuals susceptibility to oral cancer [53,54]. In our
subgroup meta-analysis, we also detected the association of XRCC1
Arg194Trp with oral cancer risk. We found that under the allelic
model. Trp allele carriers had a higher risk of oral cancer than Arg
allele carriers. We also found that individuals with the Arg/Trp
genotype had a higher risk of developing oral cancer under the
heterozygote model; however, this association was not detected under
the homozygous model. We speculate that the main reason for this
finding may be the low occurrence of the Trp/Trp genotype in the
study populations; indeed, in several studies, the number of Trp/Trp
genotype was reported to be zero. The low occurrence of the Trp/
Trp genotype will lead to poor statistical power. Under the dominant
model, when the Trp/Trp and Arg/Trp genotypes were analyzed
together, the association of the Arg/Trp genotype with oral cancer
was still statistically significant. This finding is in accordance with our
speculation that the heterozygote and homozygote models gave
different results because of the low occurrence of the Trp/Trp
genotype in the study population. However, this hypothesis needs to
be tested with larger sample sizes in future studies.
The XRCC1 Arg399Gln polymorphism is located in the zinc
finger domain area (PARP binding site) of the protein that detects
DNA strand breaks . The carriers of this variant were shown to
have a higher level of DNA adducts  and tobacco-related DNA
damage [46,5759]. XRCC1 Arg399Gln has been reported to be
significantly associated with risks of gastric , lung , and
colorectal  cancers. Ramachandran et al. found that the
XRCC1 Arg399Gln polymorphism was associated with increased
risk of oral cancer in an Indian population , while
KostrzewskaPoczekaj et al. found that XRCC1 Arg399Gln was a protective
factor for squamous cell carcinoma of the head and neck in young
adults . Most other studies have found no significant association
of XRCC1 Arg399Gln with HNC risk [9,25,34,39,42,43,50]. In the
present study, we also found no association between XRCC1
Arg399Gln and HNC risk under all four genetic models.
The XRCC1 Arg280His polymorphism is located in the
proliferating cell nuclear antigen binding region  in the
apurinic/apyrimidinic endonuclease (APE)-binding domain of the
protein [54,63]. The Arg280His polymorphism could potentially
alter the structure of XRCC1 and affect its ability to interact with
APE [54,64]. In a functional study, the XRCC1 protein carrying His
280 failed to rescue the single-strand break repair deficiency of
mutant cells when human XRCC1 variant proteins were
introduced into XRCC1 mutant Chinese hamster ovary cells .
Although functional studies revealed a possible mechanism for the
association of the XRCC1 Arg280His polymorphism with cancer
risk, our meta-analysis did not detect a significant association
between XRCC1 Arg280His and HNC risk. This null result may be
because of the limited number of studies that were included in our
analyses. Clearly, larger sample sizes are needed to clarify the
association of the XRCC1 Arg280His polymorphism with HNC risk.
Although we conducted a comprehensive analysis, our study has
a number of limitations. First, only a limited number of eligible
studies were found and so the sample size was relatively small.
Therefore, especially in the stratified analyses, the association
detected in our study may have occurred by chance. Second,
because almost all the studies that were selected for meta-analysis
were case-control studies, the patients were cancer survivors and
patients who did not survive were not included. As a result,
selection/survival bias could not be avoided.
In conclusion, the meta-analysis detected no association
between the XRCC1 Arg399Gln and Arg280His polymorphisms
and risk of HNC. However, in the subgroup analyses of studies
adjusted for smoking and alcohol, the XRCC1 Arg194Trp
polymorphism was associated with increased risk of HNC and,
in the stratified analyses based on cancer site, XRCC1 Arg194Trp
was associated with increased risk of oral cancer. Further studies
with larger samples are needed to further evaluate the association
between XRCC1 polymorphisms and HNC risk.
Figure S2 Beggs funnel plot of publication bias test for
XRCC1 Arg399Gln using the dominant model.
Conceived and designed the experiments: WW LL BSZ. Performed the
experiments: WW LL ZHY. Analyzed the data: WW ZHY PG XLL.
Contributed reagents/materials/analysis tools: LL PG XLL. Wrote the
paper: WW LL.
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