X-Ray Repair Cross-Complementing Group 1 (XRCC1) Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis
Zhao D (2012) X-Ray Repair Cross-Complementing Group 1 (XRCC1) Genetic Polymorphisms and Risk of Childhood Acute
Lymphoblastic Leukemia: A Meta-Analysis. PLoS ONE 7(4): e34897. doi:10.1371/journal.pone.0034897
X-Ray Repair Cross-Complementing Group 1 (XRCC1 ) Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis
Libing Wang 0
Fan Yin 0
Xia Xu 0
Xiaoxia Hu 0
Dongbao Zhao 0
Rui Medeiros, IPO, Inst Port Oncology, Portugal
0 1 Department of Hematology, Second Military Medical University, Changhai Hospital , Shanghai , China , 2 Department of Rheumatology and Immunology, Second Military Medical University, Changhai Hospital , Shanghai , China
Background: Recently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk. Methods: A meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used. Results: Significant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (ORadditive model = 1.501, 95% CI 1.112-2.026, POR = 0.008; ORdominant model = 1.316, 95% CI = 1.104-1.569, POR = 0.002) and Asian subgroup analyses (ORadditive model = 2.338, 95%CI = 1.254-4.359, POR = 0.008; ORdominant model = 2.108, 95%CI = 1.498-2.967, POR = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found. Conclusions: The meta-analysis results suggested that XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population.
Funding: This work was financially supported by Young Scholar Grant from National Natural Science Foundation of China (Grant Number: 30800488) and
Excellent Young Scholarship from Shanghai Health Bureau(XYQ2011007). The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
While survival rates for childhood acute lymphoblastic leukemia
(ALL) have been improved significantly over the past 50 years,
ALL is still the most common pediatric cancer in developed
countries with high incidence and mortality .
As a complex and multifactorial process, leukemogenesis is still
not fully understood. It is widely known that dysregulated immune
response to infection may be a cause of childhood ALL .
Although the role of environmental exposure is still currently
undefined, it is likely that the environmental carcinogenesis
exposure is influenced by co-inheritance of multiple low-risk
variants, such as single nucleotide polymorphisms (SNPs) in
susceptible genes . These variants can be identified by
comparing the frequency of polymorphic genotypes in cases and
To date, the candidates for childhood ALL susceptibility genes
have been categorized into those coding for carcinogen
metabolism enzymes, folate metabolism enzymes, DNA repair proteins,
and others . The DNA repair system plays an important role in
maintaining the genome integrity and stability through the
reversal of DNA damage. If accumulated mutations are occurred
in corresponding DNA repair genes, their reversal capacity could
be damaged, substantially increasing the risk of cancer. SNPs in
common DNA repair genes have been identified and
demonstrated to be linked to several sporadic carcinogenesis [5,6].
X-ray repair cross-complementing group 1 (XRCC1), located on
chromosome 19q13.213.3, with 33 kilobases in length, is one of
the most important proteins in base excision repair (BER) .
BER is also the predominant DNA damage repair pathway for the
processing of small base lesions derived from oxidation and
alkylation damage . There have been more than 300 validated
SNPs in the XRCC1 gene reported in the dbSNP database (http://
www.ncbi.nlm.nih.gov/SNP). Nevertheless, only three genetic
changes have been extensively studied including Arg194Trp on
exon 6 (rs1799782 in dbSNP, C/T), Arg280His on exon 9
(rs25489 in dbSNP, G/A), and Arg399Gln on exon 10 (rs25487 in
dbSNP, G/A). There have been a number of studies on the
association between XRCC1 polymorphisms and childhood ALL
risk . However, these inconsistent results fail to clarify this
complicated genetic relationship because of the small sample size
and its low statistical power. To reliably demonstrate the effect of
XRCC1 variants (Arg399Gln, Arg280His, and Arg194Trp) on
childhood ALL risk, we conduct a meta-analysis of all eligible
studies to resolve this pivotal issue.
Materials and Methods
Study identification and selection
Computer searches of PubMed, EMBASE, Medline, Google
Scholar and Cochrane Library were performed by two authors
independently using the following key words (childhood acute
lymphoblastic leukemia or childhood ALL)and(XRCC1 or
X-ray repair cross-complementation group 1), covering all papers
published before November 30, 2011. All eligible articles were
retrieved and their references were searched simultaneously to find
other relevant articles. Inclusion criteria was defined as follows: (1)
case-control studies evaluating the association between XRCC1
polymorphisms and childhood ALL risk; (2) studies based on
unrelated individuals; (3) sufficient published data available to
estimate an odds ratio (OR) with 95% confidence interval (CI). We
excluded studies that were not full-length publications articles or
letters in peer-reviewed English journals. When the same patient
population was included in different articles, the one with the largest
population of participants or the most recent one was selected.
The following information was extracted from each study by
two authors independently: first author, publication year,
ethnicity, area, mean age of the study subjects, gender component,
matching criteria, genotyping method, numbers of cases and
controls, and genotype frequency of cases and controls. The two
authors achieved a consensus at last.
The strength of XRCC1 polymorphisms and childhood ALL risk
was assessed by odds ratios (ORs) with the corresponding 95% CI for
each study. The OR and its 95% CI in each comparison were
assessed in additive (aa versus AA; a was for the minor allele and A
was for the major allele), dominant (aa+Aa versus AA), and recessive
(aa versus Aa+AA) genetic models. Heterogeneity among studies
was tested by chi-square-based Q test, and I2 statistics was calculated
to quantify the proportion of the total variation due to heterogeneity
. The pooled ORs were calculated by a fixed-effects model (the
Mantel-Haenszel 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 . The source of heterogeneity was explored in a
metaregression model. The significance of pooled ORs was determined
by Z test (P,0.05 was considered statistically significant). The
potential publication bias was examined visually in a funnel plot of
log[OR] against its standard error (SE), and the degree of
asymmetry was tested by Eggers test (P,0.05 was considered a
significant publication bias) . In the control populations, Hardy
Weinberg equilibrium (HWE) was tested. In addition, subgroup
analysis for ethnicity (Asian, Caucasian, Mestizo, and Mixed
population) was conducted, and influence analysis was performed
by omitting each study to find potential outliers . The two
authors inputted the data in the statistic software programs STATA
version 11.0 to perform the statistical analysis independently and got
the same results.
Extraction process and study characteristics
With our search criterion, a total of eleven full-text articles [4,9
15,2123] were preliminarily identified for further detailed
evaluation (Fig. 1). Two studies that not focused on childhood
ALL risk were excluded after title review. One study  was
excluded as another included study  was based on the same
population, and one was a systematic review. At last, seven
casecontrol studies  were selected, including a total of 880 cases
and 1311 controls originally. A list of characteristics of these
included studies was provided in Table 1. There were 7 studies with
a total of 880 cases and 1311 controls for Arg399Gln polymorphism,
3 studies with a total of 345 cases and 554 controls for Arg280His
polymorphism, and 6 studies with a total of 783 cases and 1180
controls for Arg194Trp polymorphism. Genotype distributions in
the controls of all studies were in agreement with HWE except one
Table 2 listed the main results of the meta-analysis. The
results of the associations between XRCC1 Arg399Gln
polymorphism and childhood ALL risk, and the heterogeneity
test were shown in Table 2. When all the eligible studies were
Source of controls
sex, age, ethnicity
sex, age, ethnicity
aHWE HardyWeinberg equilibrium.
bGenotype distributions of Arg194Trp in the controls were significantly deviated from HWE 399 Arg399Gln, 194 Arg194Trp, 280 Arg280His.
pooled into the meta-analysis, elevated childhood ALL risk was
revealed in additive model (OR = 1.501, 95% CI 1.1122.026,
POR = 0.008, P = 0.384 for heterogeneity)(Fig. 2a). We also found
a significant association with childhood ALL risk in the dominant
model (OR = 1.316, 95% CI = 1.1041.569, POR = 0.002,
P = 0.016 for heterogeneity) (Fig. 2b). No significant association
was found in the recessive model (OR = 1.324, 95% CI = 0.998
1.757, P = 0.628 for heterogeneity). In subgroup analysis by
ethnicity, the results revealed significant associations between the
XRCC1 Arg399Gln polymorphism and childhood ALL in Asian
population (Additive model: OR = 2.338, 95%CI = 1.2544.359,
POR = 0.008, P = 0.903 for heterogeneity; Dominant model:
OR = 2.108, 95%CI = 1.4982.967, POR = 0.000 P = 0.821 for
heterogeneity). We did not observe any significant association in
any genetic model among other subgroups. Moreover,
metaregression analysis revealed that ethnicity was a significant source
of between-study heterogeneity (P = 0.007).
Additive model(aa vs AA)
Recessive model (aa vs AA+Aa)
OR Odds ratio; 95% CI 95% confidence interval.
a:minor allele; A:major allele.
Figure 2. Meta-analysis of XRCC1 Arg399Gln polymorphism in childhood ALL. a Additive model, b Dominant model.
There was no statistical difference in all contrasts of genotypes for
Arg280His polymorphism (Additive model: OR = 1.251, 95%CI
0.3714.220, POR = 0.709; Dominant model: OR = 1.125, 95% CI
0.8051.574, POR = 0.490; Recessive model: OR = 1.203, 95%CI
0.3574.055, POR = 0.765) and Arg194Trp polymorphism(Additive
model: OR = 0.806, 95% CI 0.4511.438, POR = 0.465; Dominant
model OR = 1.056, 95% CI 0.8501.312, POR = 0.625; Recessive
model = 0.797, 95% CI 0.4451.426, P OR = 0.444). Subgroup
analysis based on ethnicity also showed no significant association
between the two SNPs and childhood ALL risk.
Tests of heterogeneity
We have found heterogeneities in four studies: Arg399Gln
polymorphism dominant model (p = 0.016, I2 = 61.6%); Arg194Trp
polymorphism additive model (p = 0.041, I2 = 56.9%), dominant
model (p = 0.059, I2 = 53%), recessive model (p = 0.070, I2 = 50.9%)
(Table 2). A random-effects model was employed in these studies.
Influence analysis was performed to assess the influence of each
individual study on the pooled OR by sequential omission of
individual studies. The results suggested that no individual study
significantly affected the pooled ORs (Fig. 3).
Publication bias was examined by Funnel plot and Eggers
regression test. The shapes of the funnel plot did not indicate any
evidence of obvious asymmetry in additive model (Fig. 4) and the
Eggers test suggested the absence of publication bias (P = 0.810).
XRCC1 plays an important role in the DNA damage repair
pathway for the processing of small base lesions, which has been
thought of as the predominant DNA-damage repair pathway for
the processing of small base lesions derived from oxidation and
alkylation damage . It is widely accepted that alterations in
DNA repair genes play roles in the process associated with the
etiology of cancers. In some of the previous studies, it has been
reported that carriers of the variant allele were at higher risk of
lung cancer , breast cancer , and prostate cancer among
Asians , whereas the result was controversial in gastric cancer
, as well as in bladder caner . In this meta-analysis, we
focused on XRCC1 genetic polymorphisms and provide the most
comprehensive assessment of its association with childhood ALL
risk. By critically reviewing 7 studies on XRCC1 Arg399Gln
polymorphism (a total of 880 cases and 1311 controls), 3 studies on
XRCC1 Arg280His polymorphism (a total of 345 cases and 554
controls), and 6 studies on Arg194Trp polymorphism (a total of
783 cases and 1180 controls), we performed a meta-analysis to
indicate that the polymorphisms in XRCC1 Arg399Gln was
significantly associated with risk of childhood ALL. However, we
did not observe associations of XRCC1 Arg280His polymorphism
and Arg194Trp polymorphism with childhood ALL risk.
This study showed that the mean frequency of the XRCC1
variant 399Gln allele was 28.99% (Table S1). Previous
investigations found that the frequency distribution of 399Gln allele
significantly varied in different ethnicities. Among Asian
population, 22%,28% had at least one copy of the variant allele XRCC1
399Gln [910,2930], while among Caucasian, Turkish, and
other ethnic populations, the frequencies were 28%,43%
[11,13,3133]. This may lead to XRCC1 Arg399Gln
polymorphism genotype distribution disequilibrium when all ethnic
populations were pooled together. Ethnicity was significantly
associated with childhood ALL risk and it was considered as a
significant source of heterogeneity in the meta-regression model. It
was essential to conduct a subgroup analysis based on ethnicities.
In this meta-analysis, all subjects were classified into four ethnic
groups (Caucasian, Asian, Metizo and mixed populations). No
association was detected in Caucasians, Metizo and mixed
populations, while increased risk was found in Asian population
carrying variant 399Gln allele homozygote, and it should be
further investigated in large scale Asian populations.
Despite lots of investigations in many aspects of childhood ALL,
little attention has been paid to its pathogenesis, particularly with
respect to genetic susceptibility. Several reports have demonstrated
the association between some DNA repair gene variants and
childhood ALL, so the possible relationship between polymorphisms
of DNA repair genes and childhood ALL may be helpful in
understanding the pathogenesis of childhood ALL and the
prevention of this disease. Our results suggest that the risk of
childhood ALL may be associated with DNA repair mechanisms.
XRCC1 polymorphisms may be used as an important predictive
factor, and ethnic background might have an impact on the results in
the studies of its polymorphisms in childhood ALL. Analysis of these
polymorphisms, particularly XRCC1 codon 399 Arg/Gln may help
in identifying individuals at risk of developing ALL and providing an
essential information source for future improvement of ALL
Although our result is suggestive, there are still some limitations
in this meta-analysis. First, heterogeneity among the studies,
resulting from different sources of controls, matching criteria of
age and gender or some other factors, may influence the results of
this analysis. The matching criteria of the control group, such as
age, gender, and environment exposures, are different between
studies. Furthermore, childhood ALL is heterogeneous considering
its underlying cellular and molecular biology, so subtypes of B- or
T-cell precursor ALL may not be suspected to share a common
etiology. To date none of the studies have examined the
relationship between XRCC1 variants and risk by subtype. Second,
specific environmental and lifestyle factors may alter those
associations between gene polymorphisms and cancer risk.
Figure 4. Funnel plot of XRCC1 Arg399Gln polymorphism and childhood ALL risk for publication bias.
Evidence supports that there is no association between Gln/Gln
genotype of Arg399Gln and bladder cancer risk in total
population, but it is associated with a decreased risk of bladder
cancer among ever smokers [34,35]. The relationship between
XRCC1 gene polymorphism and childhood ALL risk was analyzed
without consideration of genegene and gene-environment
interactions because of the lack of sufficient data, which should
be further investigated. Third, the Funnel plot did not reveal any
evidence of obvious publication bias, while there is still a possibility
that our meta-analysis was biased toward a positive result since
negative findings were likely to be unreported.
In summary, it is a worthy and meaningful enterprise to search
for polymorphic variants influencing the risk of childhood ALL.
This meta-analysis suggests that XRCC1 399Gln might be a
susceptibility allele for childhood ALL. However, we could not
observe any association of XRCC1 Arg194Trp and Arg280His
with childhood ALL. We have searched as many publications as
we could by means of various searching approaches,
comprehensively assessed publication biases and pinpointed the potential
sources of heterogeneity via subgroup and sensitivity analysis.
However, these results may be biased by the relatively small
number of subjects, and therefore need to be validated by larger
studies and subsequent update of the current meta-analysis. In
order to understand the mechanisms underlying childhood ALL
better, future research should be considered and investigated.
Table S1 Frequencies of XRCC1 Arg194Trp, Arg280His
and Arg399Gln allele among control population in
Conceived and designed the experiments: LW FY DZ. Performed the
experiments: LW FY. Analyzed the data: LW FY. Contributed reagents/
materials/analysis tools: LW FY. Wrote the paper: FY XH XX.
1. Schafer ES , Hunger SP ( 2011 ) Optimal therapy for acute lymphoblastic leukemia in adolescents and young adults . Nat Rev Clin Oncol . 8 : 417 - 424 .
2. Cardwell CR , McKinney PA , Patterson CC , Murray LJ ( 2008 ) Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records . Br J Cancer . 99 : 1529 - 1533 .
3. Mehta PA , Davies SM , Kumar A , Devidas M , Lee S , et al. ( 2006 ) Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group . Leukemia. 20 : 1539 - 1541 .
4. Vijayakrishnan J , Houlston RS ( 2010 ) Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and metaanalysis . Haematologica . 95 : 1405 - 1414 .
5. Roberts MR , Shields PG , Ambrosone CB , Nie J , Marian C , et al. ( 2011 ) Singlenucleotide polymorphisms in DNA repair genes and association with breast cancer risk in the web study . Carcinogenesis . 2011 32: 1223 - 1230 .
6. Shiraishi K , Kohno T , Tanai C , Goto Y , Kuchiba A , et al. ( 2010 ) Association of DNA repair gene polymorphisms with response to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer . J Clin Oncol . 28 : 4945 - 4952 .
7. Chou WC , Wang HC , Wong FH , Ding SL , Wu PE , et al. ( 2008 ) Chk2- dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair . EMBO J . 27 : 3140 - 3150 .
8. Lan L , Nakajima S , Oohata Y , Takao M , Okano S , et al. ( 2007 ) In situ analysis of repair processes for oxidative DNA damage in mammalian cells . Proc Natl Acad Sci U S A . 101 : 13738 - 13743 .
9. Joseph T , Kusumakumary P , Chacko P , Abraham A , Pillai MR ( 2005 ) DNA repair gene XRCC1 polymorphisms in childhood acute lymphoblastic leukemia . Cancer Lett . 217 : 17 - 24 .
10. Pakakasama S , Sirirat T , Kanchanachumpol S , Udomsubpayakul U , Mahasirimongkol S , et al. ( 2007 ) Genetic polymorphisms and haplotypes of DNA repair genes in childhood acute lymphoblastic leukemia . Pediatr Blood Cancer . 48 : 16 - 20 .
11. Batar B , Guven M , Baris S, Celkan T , Yildiz I ( 2009 ) DNA repair gene XPD and XRCC1 polymorphisms and the risk of childhood acute lymphoblastic leukemia . Leuk Res . 33 : 759 - 763 .
12. Meza-Espinoza JP , Peralta-Leal V , Gutierrez-Angulo M , Macias-Gomez N , Ayala-Madrigal ML , et al. ( 2009 ) XRCC1 polymorphisms and haplotypes in Mexican patients with acute lymphoblastic leukemia . Genet Mol Res . 8 : 1451 - 1458 .
13. Tumer TB , Yilmaz D , Tanrikut C , Sahin G , Ulusoy G , et al. ( 2010 ) DNA repair XRCC1 Arg399Gln polymorphism alone, and in combination with CYP2E1 polymorphisms significantly contribute to the risk of development of childhood acute lymphoblastic leukemia . Leuk Res . 34 : 1275 - 1281 .
14. Canalle R , Silveira VS , Scrideli CA , Queiroz RG , Lopes LF , et al. ( 2011 ) Impact of thymidylate synthase promoter and DNA repair gene polymorphisms on susceptibility to childhood acute lymphoblastic leukemia . Leuk Lymphoma . 52 : 1118 - 1126 .
15. Stanczyk M , Sliwinski T , Cuchra M , Zubowska M , Bielecka-Kowalska A , et al. ( 2011 ) The association of polymorphisms in DNA base excision repair genes XRCC1, OGG1 and MUTYH with the risk of childhood acute lymphoblastic leukemia . Mol Biol Rep . 30 : 445 - 451 .
16. Cochran WG ( 1954 ) The combination of estimates from different experiments . Biometrics . 10 : 101 - 129 .
17. Mantel N , Haenszel W ( 1959 ) Statistical aspects of the analysis of data from retrospective studies of disease . J Natl Cancer Inst . 22 : 719 - 748 .
18. DerSimonian R , Laird N ( 1986 ) Meta-analysis in clinical trials . Control Clin Trials 7 : 177 - 188 .
19. Egger M , Davey SG , Schneider M , Minder C ( 1997 ) Bias in meta-analysis detected by a simple, graphical test . BMJ . 315 : 629 - 634 .
20. Tobias A ( 1999 ) Assessing the influence of a single study in the meta-analysis estimate . Stata Tecnol Bull . 8 : 15 - 17 .
21. Krajinovic M , Labuda D , Mathonnet G , Labuda M , Moghrabi A , et al. ( 2002 ) Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia . Clin Cancer Res . 8 : 802 - 810 .
22. da Silva Silveira V , Canalle R , Scrideli CA , Queiroz RG , Bettiol H , et al. ( 2009 ) Polymorphisms of xenobiotic metabolizing enzymes and DNA repair genes and outcome in childhood acute lymphoblastic leukemia . Leuk Res . 33 : 898 - 901 .
23. Tumer TB , Sahin G , Arinc E ( 2012 ) Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia . Arch Toxicol . 86 : 431 - 439 .
24. Kiyohara C , Takayama K , Nakanishi Y ( 2006 ) Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis . Lung Cancer . 54 : 267 - 283 .
25. Saadat M , Ansari-Lari M ( 2009 ) Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer, a meta-analysis of the literatures . Breast Cancer Res Treat . 115 : 137 - 144 .
26. Geng J , Zhang Q , Zhu C , Wang J , Chen L ( 2009 ) XRCC1 genetic polymorphism Arg399Gln and prostate cancer risk: a meta-analysis . Urology . 72 : 4648 - 4653 .
27. Xue H , Ni P , Lin B , Xu H , Huang G ( 2011 ) X-ray repair cross-complementing group 1 (XRCC1) genetic polymorphisms and gastric cancer risk: A HuGE review and meta-analysis . Am J Epidemiol . 173 : 363 - 375 .
28. Wang C , Sun Y , Han R ( 2008 ) XRCC1 genetic polymorphisms and bladder cancer susceptibility: a meta-analysis . Urology . 72 : 869 - 872 .
29. Xing D , Qi J , Miao X , Lu W , Tan W , et al. ( 2002 ) Polymorphisms of DNA repair Genes XRCC1 and XPD and their associations with risk of esophageal squamous cell carcinoma in a Chinese population . Int J Cancer . 100 : 600 - 605 .
30. Lee SG , Kim B , Choi J , Kim C , Lee I , et al. ( 2002 ) Genetic polymorphisms of XRCC1 and risk of gastric cancer . Cancer Lett . 187 : 53 - 60 .
31. Vural P , Degirmencioglu S, Dogru Abbasoglu S , Saral NY , Akgu l C , et al. ( 2009 ) Genetic polymorphisms in DNA repair gene APE1, XRCC1 and XPD and the risk of preeclampsia . Eur J Obstet Gynecol Reprod Biol . 146 : 160 - 164 .
32. Harth V , Schafer M , Abel J , Maintz L , Neuhaus T , et al. ( 2008 ) Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair . J Toxicol Environ Health A . 71 : 887 - 897 .
33. Coppede ` F, Migheli F , Lo Gerfo A , Fabbrizi MR , Carlesi C , et al. ( 2009 ) Association study between XRCC1 gene polymorphisms and sporadic amyotrophic lateral sclerosis . Amyotroph Lateral Scler . 25 : 1 - 3 .
34. Wang C , Sun Y , Han R ( 2008 ) XRCC1 genetic polymorphisms and bladder cancer susceptibility: a meta-analysis . Urology . 72 : 869 - 872 .
35. Lao T , Gu W , Huang Q ( 2008 ) A meta-analysis on XRCC1 R399Q and R194W polymorphisms, smoking and bladder cancer risk . Mutagenesis . 23 : 523 - 532 .