XRCC1 Gene Polymorphisms and the Risk of Differentiated Thyroid Carcinoma (DTC): A Meta-Analysis of Case-Control Studies
et al. (2013) XRCC1 Gene Polymorphisms and the Risk of Differentiated Thyroid Carcinoma (DTC): A Meta-
Analysis of Case-Control Studies. PLoS ONE 8(5): e64851. doi:10.1371/journal.pone.0064851
XRCC1 Gene Polymorphisms and the Risk of Differentiated Thyroid Carcinoma (DTC): A Meta-Analysis of Case-Control Studies
Yong-Quan Shi 0
Yi Bao 0
Lei Jiang 0
Jue-Yu Zhou 0
Jun-Jie Zou 0
Jiao-Yang Zheng 0
Xiang-Fang Chen 0
Zhi-Min Liu 0
Olga Y. Gorlova, The University of Texas M. D. Anderson Cancer Center, United States of America
0 1 Department of Endocrinology, Changzheng Hospital, Second Military Medical University , Shanghai , China , 2 Department of Neurosurgery, Changzheng Hospital, Second Military Medical University , Shanghai , China , 3 Institute of Genetic Engineering, Southern Medical University , Guangzhou , China
Background: Previous studies investigating the association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and thyroid cancer risk have yielded inconsistent results. This meta-analysis was performed to derive a more precise estimation of the relationship between three XRCC1 polymorphisms and thyroid cancer risk. Methods/Principal Findings: PubMed and EMBASE database were systematically searched to identify relevant studies. 10 publications were selected for this meta-analysis, including 11 studies for Arg399Gln polymorphism (1726 cases and 3774 controls), 7 studies for Arg194Trp polymorphism (1037 cases and 2487 controls) and 8 studies for Arg280His polymorphism (1432 cases and 3356 controls). The results in total population did not show any significant association between these three polymorphisms and the risk of DTC for all genetic models. However, when stratified by ethnicity, the results showed that Arg280His polymorphism was associated with an increased risk of DTC among Caucasians (Arg/His vs. Arg/Arg: OR = 1.45, 95% CI = 1.09-1.93; dominant model: OR = 1.43, 95% CI = 1.08-1.89; additive model: OR = 1.38, 95% CI = 1.05-1.80), whereas individuals carrying Arg/His genotype have a significantly reduced risk of DTC among Asians (Arg/His vs. Arg/Arg: OR = 0.71, 95% CI = 0.51-0.98). We also detected that 399Gln variant allele carriers might presented an overall decreased risk of DTC in mixed population. Furthermore, subgroup analyses by histological subtype revealed that Arg194Trp polymorphism was significantly associated with reduced risk for papillary thyroid carcinoma (PTC) (dominant model: OR = 0.71, 95% CI = 0.500.99). Conclusions: This meta-analysis suggests that Arg280His polymorphism might contribute to the susceptibility of DTC among Caucasians, whereas it might provide protective effects in Asians against the risk of DTC. Additionally, our results support the protective role of Arg194Trp polymorphism in developing PTC, and show evidence of an association between Arg399Gln polymorphism and decreased risk of DTC in mixed population.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
Thyroid cancer is the most prevalent endocrine malignancy
with increasing incidence rates in recent years [1,2]. It can be
classified into four forms (papillary, follicular, medullary and
anaplastic) based on different histopathological characteristics.
Pathologically, papillary thyroid carcinoma (PTC) and follicular
thyroid carcinoma (FTC) are termed differentiated thyroid
carcinoma (DTC), accounting for approximately 90% of all
thyroid malignancies. Although the exact etiology of thyroid
cancer remains unknown, exposure to ionizing radiation is the
only verified cause of thyroid carcinogenesis, especially radiation
exposure during childhood or as a young adult [3,4]. However,
not all of those who have been exposed to ionizing radiation will
develop thyroid cancer, and most patients do not have the history
of radiation exposure, suggesting that host factors, including
genetic polymorphisms, may have an impact on an individuals
susceptibility to thyroid cancer.
DNA damage, caused by ionizing radiation, environmental
toxins, and metabolic chemicals, can lead to gene mutations and
genomic instability, which in turn may contribute to
tumorigenesis. There are four major DNA repair pathways in mammals,
including base excision repair (BER), nucleotide excision repair
(NER), mismatch repair (MMR) and double strand break repair
(DSBR) . Among them, BER is the predominant DNA damage
repair pathway for the processing of endogenous DNA lesions as
well as damages produced during episodes of inflammation and
exposures to ionizing radiation or a variety of chemical
carcinogens . At least 20 proteins are involved in BER pathway,
including X-ray repair cross-complementing group 1 (XRCC1),
apurinic/apyrimidinic endonuclease 1 (APE1), 8-oxoguanine
DNA glycosylase 1 (OGG1), etc . The mutations and
singlenucleotide polymorphisms (SNPs) in corresponding genes may
impair their repair or reversal capacity and increase the risk of
XRCC1 gene is an important component of the BER pathway
encoding a scaffolding protein, which functions as a facilitator or
coordinator in this pathway by directly interacting with poly
(ADP-ribose) polymerase (PARP), DNA polymerase beta, and
DNA ligase III [8,9,10]. Although numerous validated SNPs in
XRCC1 gene have been identified in the dbSNP database (http://
www.ncbi.nlm.nih.gov/SNP), only three of which are most widely
investigated including Arg194Trp on exon 6 (rs1799782, C/T),
Arg280His on exon 9 (rs25489, G/A), and Arg399Gln on exon 10
(rs25487, G/A) . These XRCC1 polymorphisms may affect
DNA repair capacity by changing interactions between XRCC1
protein and other proteins in BER pathway, and a large number of
studies have focused on the relationship between XRCC1
polymorphisms and development of cancer in humans
Over the past decade, several epidemiological studies have
reported the association regarding XRCC1 polymorphisms and
thyroid cancer risk [16,17,18,19,20,21,22,23,24,25,26]. However,
the results are to some extent divergent, but nevertheless
intriguing. And majority of studies involved no more than a few
hundred thyroid cancer cases, which may have been
underpowered to detect a slight effect or may have generated a fluctuated
risk estimate. So far, no quantitative summary of the evidence has
ever been performed. To clarify the effect of XRCC1
polymorphisms (Arg399Gln, Arg280His, and Arg194Trp) on thyroid
cancer risk, we carried out a meta-analysis of all eligible
Materials and Methods
Identification and selection of relevant studies
A comprehensive literature search was performed using the
PubMed and EMBASE database to identify studies that evaluated
the association between XRCC1 polymorphisms and the risk of
thyroid cancer up to December 18, 2012 with the following terms
and keywords: (XRCC1 or X-ray repair cross-complementation
group 1 or DNA repair gene), (thyroid cancer or thyroid
carcinoma) and (polymorphism or variant or variation). The
search was limited to human studies. In addition, references cited
in the retrieved articles were reviewed to trace additional relevant
studies missed by the searching.
The following inclusion criteria were used to select literatures
for the meta-analysis: 1) a casecontrol study evaluating at least
one polymorphism in the XRCC1 gene; 2) studies with full text
articles; 3) sufficient data for estimating an odds ratio (OR) with
95% confidence interval (CI); 4) no overlapping data. If studies
had the same or overlapping data, only the largest study should be
included in the final analysis.
Two investigators reviewed and extracted information from all
eligible publications independently, according to the inclusion
criteria listed above. For conflicting evaluation, a consensus was
reached by discussion. The following data were collected from
each study: first author, year of publication, country, ethnicity
(categorized as Asian, Caucasian, or mixed descent), source of
controls (population-based [PB] or hospital-based [HB] controls),
genotyping method, numbers of cases and controls, genotype
frequency of cases and controls, and the results of Hardy
Weinberg equilibrium (HWE) test.
We first assessed HWE in the controls for each study using a
(http://ihg2.helmholtz-muenchen.de/cgibin/hw/hwa1.pl) and a P,0.05 was considered as significant
disequilibrium. The strength of association between these three
XRCC1 polymorphisms (Arg399Gln, Arg194Trp and Arg280His)
and thyroid cancer risk was measured by ORs with 95% CIs. The
pooled ORs were performed for dominant model (aa+Aa vs. AA, a
was for the minor allele and A was for the major allele), recessive
model (aa vs. Aa+AA), codominant model (aa vs. AA, Aa vs. AA)
and additive model (a vs. A), respectively. Heterogeneity
assumption was checked by a chi-square-based Q test , and
I2 statistics was calculated to quantify the proportion of the total
variation across studies due to heterogeneity . The pooled
ORs were calculated by a fixed-effects model (the
MantelHaenszel method) when the P value.0.05 for the Q test which
indicated a lack of heterogeneity among the studies .
Otherwise, a random-effects model (DerSimonian-Laird method)
was used . To explore the effect of heterogeneity among the
studies on the conclusions of this meta-analysis, subgroup analyses
were performed by ethnicity and histological subtype (papillary
thyroid carcinoma and follicular thyroid carcinoma). Sensitivity
analysis was performed by omitting each study in turn to assess the
stability of results. The publication bias was diagnosed by the
funnel plot, in which the standard error of log (OR) of each study
was plotted against its log (OR). Funnel plot asymmetry was
further assessed by the method of Eggers linear regression test
(P,0.05 was considered a significant publication bias) . All of
the statistical analyses used in our meta-analysis were performed
by STATA version 11.0 (Stata, College Station, TX, USA).
A total of eleven publications were preliminarily retrieved based
on the inclusion criteria for risks of thyroid cancer related to the
XRCC1 polymorphisms [16,17,18,19,20,21,22,23,24,25,26].
Among which, one was excluded because the data of genotyping
distribution was missing , two separated casecontrol studies
were included from the publication of Akulevich et al.  and
were considered separately. And part of the data were analyzed
only in dominant genetic model because the publication of
Sigurdson et al.  only provide the limited genotyping
information for two XRCC1 polymorphisms (Arg194Trp and
Arg280His). Hence, there were 11 studies for Arg399Gln
polymorphism (1726 cases and 3774 controls), 7 studies for
Arg194Trp polymorphism (1037 cases and 2487 controls) and 8
studies for Arg280His polymorphism (1432 cases and 3356
controls). Our initial search and the process of study selection
were summarized in Figure 1, while the main characteristics of
included studies were listed in Table 1. And the study for Iran
population was considered as Caucasian descent, but not Asian
descent since the genotype distribution and allele frequency of
controls of XRCC1 among Iran population seems more similar as
Caucasians, as shown in the Table 2. Therefore, there were 5
studies of Caucasians [19,22,24,25], 4 studies of Asians
[16,17,18,23] and 2 studies of mixed population [20,21]. In
addition, some of the studies provided genotype data for specific
histological subtypes of thyroid cancer, such as PTC and FTC.
Among them, six studies focused on PTC [16,18,19,21,23], and
only the study by Santos et al.  on both PTC and FTC. The
distribution of genotypes in the controls of each study was in
agreement with HardyWeinberg equilibrium except for two
studies (only for the Arg399Gln polymorphism) [21,23]. Among
these studies, 10 were hospital-based and only one was
populationbased. Most of the cases were confirmed histologically or
Table 3 summarized the main results of the meta-analysis for
XRCC1 polymorphisms. For Arg399Gln polymorphism, there
was no statistically significant difference between this
polymorphism and the risk of DTC in all genetic models when all eligible
studies were pooled together. Similarly, the combined results did
not showed any association between Arg194Trp/Arg280His
polymorphisms and the risk of DTC for all genetic models.
However, when stratified by ethnicity, the results showed that
Arg/His genotype was associated with an increased risk of DTC
among Caucasians (Arg/His vs. Arg/Arg: OR = 1.45, 95%
CI = 1.091.93; dominant model: OR = 1.43, 95% CI = 1.08
1.89; additive model: OR = 1.38, 95% CI = 1.051.80), whereas
individuals carrying Arg/His genotype have a significantly
reduced risk of DTC among Asians (Arg/His vs. Arg/Arg:
OR = 0.71, 95% CI = 0.510.98). (Figure 2) And carriers of the
399Gln variant allele might have a decreased risk of DTC in
mixed population (dominant model: OR = 0.73, 95% CI = 0.55
0.97; recessive model: OR = 0.56, 95% CI = 0.340.93; Gln/Gln
vs. Arg/Arg: OR = 0.50, 95% CI = 0.300.85; additive model:
OR = 0.73, 95% CI = 0.590.92). We also detected that the Trp
allele of Arg194Trp polymorphism was significantly associated
with increased risk of DTC in mixed population (additive model:
OR = 1.49, 95% CI = 1.022.17). Furthermore, stratified analyses
by histological subtype showed that Arg194Trp polymorphism
was significantly associated with reduced risk for PTC in dominant
Abbreviations: RFLP, restriction fragment length polymorphism; TaqMan, real-time TaqMan analysis; iPLEX Assay: Increased Plexing Efficiency.
and Flexibility for MassARRAY platform; PB, population-based; HB, hospital-based.
Abbreviations: HWE, Hardy-Weinberg equilibrium; MAF, minor allele frequency; A, the major allele; a, the minor allele.
model (OR = 0.71, 95% CI = 0.500.99). (Figure 3) However, no
evidence of significant association between Arg399Gln/Arg280His
polymorphisms and the risk of PTC was found. In addition,
subgroup analysis by the source of controls was not performed due
to the limited data for population-based studies.
Test of heterogeneity and sensitivity analyses
Significant heterogeneity was detected for Arg194Trp
polymorphism (recessive model comparison, additive model comparison
and homozygote comparison), Arg399Gln polymorphism (additive
model comparison) and Arg280His polymorphism (heterozygote
comparison). To explore the potential sources of heterogeneity, we
assessed the pooled ORs under all comparisons via subgroup and
sensitivity analyses. We found that ethnicity (x2 = 10.90, df = 2,
P = 0.004 for Arg280His polymorphism; x2 = 9.01, df = 2,
P = 0.011 for Arg399Gln polymorphism) but not the source of
controls (x2 = 0.34, df = 1, P = 0.560 for Arg280His
polymorphism; x2 = 0.01, df = 1, P = 0.920 for Arg399Gln polymorphism)
contributed to substantial heterogeneity for Arg280His/
Arg399Gln polymorphisms. Although there were two studies
deviated from HWE for Arg399Gln polymorphism, the
corresponding pooled ORs were not materially altered by including or
not including these studies (data not shown). In addition, we
evaluated the influence of each individual study on the overall
ORs for Arg194Trp/Arg280His polymorphisms. And the results
showed the pooled ORs of these two polymorphisms were not
materially altered by the results of any individual study, suggesting
that the results of this meta-analysis are credible (data also not
We performed Beggs funnel plot and Eggers test to assess the
publication bias in this meta-analysis. The shapes of the funnel
plots did not reveal any evidence of obvious asymmetry (Figure 4).
The results of Eggers test did not suggest any evidence of
publication bias for Arg399Gln polymorphism (P = 0.602 for Gln/
Gln vs. Arg/Arg, P = 0.342 for Arg/Gln vs. Arg/Arg, P = 0.534
for dominant model, P = 0.473 for recessive model and P = 0.798
for additive model), Arg194Trp polymorphism (P = 0.818 for Trp/
Trp vs. Arg/Arg, P = 0.306 for Arg/Trp vs. Arg/Arg, P = 0.234
for dominant model, P = 0.754 for recessive model and P = 0.636
for additive model) and Arg280His polymorphism (P = 0.588 for
His/His vs. Arg/Arg, P = 0.992 for Arg/His vs. Arg/Arg,
P = 0.656 for dominant model, P = 0.236 for recessive model and
P = 0.821 for additive model), respectively.
The DNA repair system plays a pivotal role in maintaining the
genome integrity and stability through the reversal of DNA
damage. Genetic variations in DNA repair genes are thought to
modify DNA repair capacity and suggested to be related to cancer
risk [32,33,34]. The XRCC1, encoding an important scaffolding
protein that participate in the BER pathway, has multiple roles in
repairing DNA base damage and single-strand DNA breaks. More
than 300 validated SNPs have been identified in this gene, of
which, Arg399Gln, Arg194Trp and Arg280His polymorphisms
were most extensively studied . These non-conservative amino
acid alterations may alter XRCC1 function and contribute to the
risk of cancers . To date, several studies have been conducted
to evaluate the association between XRCC1 polymorphisms and
thyroid cancer risk in different ethnic populations, but the results
remain conflicting rather than conclusive
Previously, two studies by Akulevich et al.  and Ho et al.
, respectively, reported that Arg399Gln polymorphism was
associated with decreased risk of DTC and PTC, whereas
Arg399Gln variant genotype carriers presented an increased risk
of PTC in a Chinese study . However, more studies did not
support an association between Arg399Gln polymorphism and
thyroid cancer risk [17,21,22,23,24,25]. Furthermore, Ho et al.
 reported that Arg194Trp variant homozygote genotype was
associated with increased risk of DTC, in agreement with the
conclusion by Chiang et al. . In contrast, it was reported that
the heterozygous genotype was significantly associated with a
decreased risk of PTC in a Korean population . And other
studies did not reveal statistically significant association regarding
this polymorphism and thyroid cancer [16,21,24,25]. As for
Arg280His polymorphism, Garcia-Quispes et al.  addressed
the variant genotype showed a highly increased risk for DTC
among Caucasian, while two studies by Akulevich et al.  and
Fard-Esfahani et al.  found similar trends toward having DTC,
but statistical significance was not attained. Moreover, another two
studies suggested that Arg280His heterozygous genotype might
provide protective effects against the risk of thyroid cancer among
Asians, but this also did not reach statistical significance [17,18].
The discrepancies across these studies motivated the present
More importantly, many systematic reviews and meta-analyses
have addressed the association of XRCC1 polymorphisms with
various cancers [36,37,38,39,40,41,42], but have not evaluated the
association between these polymorphisms and thyroid cancer. In
other words, this is the first meta-analysis undertaken so far of the
largest and most comprehensive assessment for the relationship
between XRCC1 polymorphisms and the susceptibility to thyroid
cancer. Our meta-analysis did not show any significant association
between these three polymorphisms (Arg399Gln, Arg194Trp, and
Arg280His) and the risk of DTC in the total population for all
genetic models. Interestingly, in the subgroup analysis by ethnicity,
the results indicated that Arg280His polymorphism was associated
with a significantly increased risk of DTC among Caucasians
under dominant genetic model, additive genetic model and
heterozygote comparison, whereas heterozygote Arg/His
genotype might provide protective effects in Asians against the risk of
DTC. We also detected that individuals harboring variant allele of
Arg399Gln polymorphism might have a decreased risk of DTC in
mixed population, but not in Caucasians or Asians. In contrast,
the Arg194Trp variant allele carriers might have an increased risk
of DTC in mixed population, but not in Caucasians or Asians.
Several factors may contribute to different roles of the same
polymorphism in cancer susceptibility among different ethnic
populations. Above all, cancer is a complicated multigenetic
disease, and different genetic backgrounds may contribute to the
discrepancy. Another explanation may be that the low penetrance
genetic effects of single polymorphism usually depends on
interaction with other polymorphisms and/or a particular
environmental exposure including tobacco smoke, ionizing
radiation, dietary and other lifestyles. Besides, other factors such as
selection bias and different matching criteria may also result in the
difference. However, our results for Arg194Trp polymorphism
should be interpreted with caution because only one study of
mixed population was included for the analysis of the additive
model. Considering the limited numbers of studies, in the future,
larger studies are warranted to validate possible ethnic differences
in the effect of these polymorphisms on the risk of thyroid cancer.
Strikingly, stratified analysis by histological classification of
thyroid cancer revealed that Arg194Trp polymorphism was
significantly associated with reduced risk for PTC in dominant
model. On the contrary, Arg399Gln and Arg280His
polymorphisms did not appear to have an overall influence on the
susceptibility to PTC. Actually, only four studies explored the
possible association between Arg194Trp polymorphism and the
risk of PTC. In line with our findings, Ryu et al.  reported that
Arg/Trp genotype carriers presented an overall decreased risk of
PTC, in Asians (OR = 0.55, 95% CI = 0.310.98). Similarly, other
three studies suggested that the Trp allele might provide protective
effects against developing PTC in different populations, but
statistical significance was not attained [16,21,25]. Although our
results strongly suggested its role in the development of PTC, it
should not be excluded that this effect could be related to sample
size. Thus, given the existence of etiologic heterogeneity within
different histological types of thyroid cancer, subtype-specific
studies including adequate numbers of cases are needed to verify
its potential usefulness as a predictive biomarker of genetic
susceptibility to different subtypes of thyroid cancer.
Although we have put considerable effort and resources into
testing possible association between XRCC1 polymorphisms and
thyroid cancer risk, there are still some limitations in this
metaanalysis. First, the number of published studies was not sufficiently
large for a comprehensive analysis, especially for subgroup
analyses by ethnicity and histological subtype. Stratified analyses
by histological subtype were only performed for PTC, but not for
FTC, because only one study  reported separate genotype
frequency for FTC. Second, genegene, geneenvironment, or
even different polymorphism loci of the XRCC1 gene interactions
were not examined in this meta-analysis because of the insufficient
data. Actually, several studies demonstrated the effect of gene-gene
interactions between XRCC1 polymorphisms and other genes in
DNA repair pathway on cancer risk [17,43,44,45]. Also, the
studies by Chiang et al.  and Ho et al.  found that multiple
haplotypes of XRCC1 polymorphisms were associated with a
significantly increased risk of DTC. Therefore, it is of particular
interest to elucidate the utility of XRCC1 haplotypes in predicting
the risk of thyroid cancer. Third, our results were based on
singlefactor estimates without adjustment for other risk factors such as
age, gender, radiation exposure dose, smoking status, drinking
consumption, obesity, or other variables, which might have caused
confounding bias. For instance, the genetic risk in the study by
Chiang et al.  was more predominant in DTC cases that
showed neck lymph node (LN) metastasis. Thus, a more precise
analysis should be conducted if detailed individual data are
available. Last but not the least, some inevitable publication bias
might exist in the results because only published studies were
retrieved although the funnel plot and Eggers test indicated no
remarkable publication bias.
In conclusion, this meta-analysis suggests that Arg280His
polymorphism might contribute to the susceptibility of DTC
among Caucasians, whereas it might provide protective effects in
Asians against the risk of DTC. Additionally, our results support
the protective role of Arg194Trp polymorphism in developing
PTC, and show evidence of an association between Arg399Gln
polymorphism and decreased risk of DTC in mixed population.
Nevertheless, large-scale, well-designed and population-based
studies are needed to investigate haplotypes, genegene, and
geneenvironment interactions on these polymorphisms and the
risk of thyroid cancer and its histological subtypes in an ethnicity
specific population, which may eventually lead to better
comprehensive understanding of the possible roles in thyroid
PRISMA 2009 Checklist for this Meta-analysis.
Conceived and designed the experiments: YB LJ YQS J.Y. Zhou.
Performed the experiments: YB LJ JJZ. Analyzed the data: YB LJ J.Y.
Zheng. Contributed reagents/materials/analysis tools: YB LJ J.Y. Zheng.
Wrote the paper: YB LJ JJZ. Revised manuscript: J.Y. Zhou XFC ZML
YQS J.Y. Zheng.
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