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American Journal of Translational Research logoLink to American Journal of Translational Research
. 2019 Feb 15;11(2):1020–1029.

XPG Asp1104His polymorphism increases colorectal cancer risk especially in Asians

Jinsong Su 1, Ying Zhu 2, Baiyun Dai 3, Weitang Yuan 1, Junmin Song 1
PMCID: PMC6413257  PMID: 30899401

Abstract

Xeroderma pigmentosum group G (XPG) protein is a pivotal element of the nucleotide excision repair pathway. XPG gene single nucleotide polymorphisms (SNPs) have been shown to confer colorectal cancer (CRC) susceptibility. In this study, we further investigated the role of Asp1104His (rs17655 G > C) in XPG on CRC risk. We genotyped the rs17655 G > C polymorphism in Chinese population comprising 1019 CRC cases and 1036 cancer-free controls. We also performed a meta-analysis to further assess the association. Overall, no significant association was detected between the rs17655 G > C and the risk of CRC. Stratified analysis also revealed no significant association. To further elucidate the association of the rs17655 with CRC susceptibility, we conducted a meta-analysis by including qualified publications and the current study. The meta-analysis results demonstrated that rs17655 G > C was associated with an increased CRC risk (CG vs. GG: OR = 1.14, 95% CI = 1.01-1.28; CC/CG vs. GG: OR = 1.12, 95% CI = 1.01-1.24; C vs. G: OR = 1.06, 95% CI = 1.01-1.11). In subgroup analysis, the significant association between the rs17655 C allele and CRC risk was found in Asians and hospital-based subgroups. Taken together, our results suggested that the XPG rs17655 G > C polymorphism is a low-penetrance susceptibility locus for CRC. Further studies are warranted to validate these findings.

Keywords: Colorectal cancer, XPG, Asp1104His, polymorphism, susceptibility

Introduction

Colorectal cancer (CRC) is considered as the third most common cancer and the fourth leading cause of cancer-related death in the world [1]. In China, CRC ranks the top five both in new cancer cases and the cancer-related cause death [2]. The etiology of CRC is highly complicated, involving the interaction between genetic and environmental factors [3]. The discovery of risk factors would help to identify high-risk individuals and develop prevention strategies. Previous epidemiological studies have led to the findings of numerous polymorphisms predisposing to CRC.

DNA repair systems play an indispensable role in protecting genome from endogenous and exogenous damages [4]. Nucleotide excision repair (NER) is the most versatile DNA repair mechanism among the five known DNA repair systems [5,6], which mainly takes the responsibility to get rid of bulky DNA adducts and UV-induced DNA damage [7]. Aberrant function of NER pathway is tightly associated with Xeroderma pigmentosum (XP), an unusual autosomal recessive disease; affected individuals are extremely vulnerable to sunlight-induced skin cancer [8]. NER pathway is composed of a number of core protein molecules, including XPA to XPG [9]. XPG [alias excision repair cross-complementation group 5 (ERCC5)] [10] is mapped to chromosome 13q22-q23 and encodes a protein of 1186-amino acid residues. XPG protein participates in the initial step of DNA repair process by recognizing the DNA damage loci [11-13]. XPG also mediates mutagenesis and cell death by influencing RNA transcription [14,15].

Single nucleotide polymorphisms (SNPs) in the XPG gene are reported to predispose to the susceptibility of several cancers, including gastric cancer [16-18], prostate cancer [19], breast cancer [20], as well as colorectal cancer [21]. Among cancer predisposing XPG SNPs, the Asp1104His polymorphism (rs17655 G > C) is most frequently investigated [22,23]. Asp1104His polymorphism is a nonsynonymous polymorphism commonly regarded as a tagger. It can result in an amino acid alteration within the protein sequence. Several studies have been performed to investigate the association between the XPG rs17655 G > C polymorphism and CRC risk, but yielded conflicting results. Therefore, further replication studies are needed to solve these discrepancies. Here, we conducted a case-control study, followed by a meta-analysis, to provide a precise evaluation of the association of interest.

Materials and methods

Study population

We recruited 1019 cases with histologically confirmed CRC in the Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University in the last four year. We also enrolled 1036 cancer-free controls in the same region during the same period. All the enrolled participants were unrelated ethnic Han Chinese population. Each participant provided a written informed consent. The demographic characteristics were obtained from the participants by using a self-administered questionnaire. Each participant donated 5 ml of venous blood sample on a voluntary basis. The study was approved by the Institutional Review Board of The First Affiliated Hospital of Zhengzhou University.

Genotyping

We first adopted the Qiagen Blood DNA Mini Kit (Qiagen Inc., Valencia, CA) to extract genomic DNA, according to the standard procedures. Then Taqman assay was chosen for genotyping with Applied Biosystems (Foster City, CA). We also set four duplicated positive controls and four negative controls (without DNA) in each of 384-well plates for quality control. Moreover, 10% of the samples were randomly chosen to be analyzed for a second time, and 100% concordant results were obtained.

Statistical analysis

Differences in demographic characteristics among cases and controls were tested using chi-square test. Goodness-of-fit X2 test was applied to check whether the genotype frequency distribution of rs17655 G > C in controls was deviated from Hardy-Weinberg equilibrium (HWE). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from multivariate logistic regression, and then used to estimate the associations between rs17655 G > C and CRC risk. We also performed stratification analysis by age, gender, body mass index (BMI), smoking status, pack-years, drinking status, tumor location, and Duke stage. All statistical analysis was performed using SAS system (version 9.1; SAS Institute, Cary, NC). Statistical significance was set on the basis of two-sided P-values < 0.05.

Meta-analysis

We further evaluated the association between rs17655 G > C and CRC risk using meta-analysis. PubMed, EMBASE, and MEDLINE databases were used to conduct systematic literature searches. The search terms were as follows: “colorectal cancer or colorectal tumor or colorectal carcinoma or colorectal neoplasm or CRC”, “Xeroderma pigmentosum group G or XPG or rs17655 or Asp1104His”, and “polymorphism or SNP or variant or variation”. Literature searches were updated to July 1, 2018. Between-study heterogeneity was determined by a chi-square-based Q-Test. The random-effects model (the DerSimonian and Laird method) would be performed in the presence of heterogeneity, whereas the fixed-effects model (the Mantel-Haenszel method) would be performed [23-25]. The funnel plot and the Egger’s linear regression test were used to assess publication bias. In addition, sensitivity analysis was also applied to assess the strength of the study. The meta-analysis was conducted using STATA version 11.0 (Stata Corporation, College Station, TX, USA).

Results

Population characteristics

The demographic characteristics of 1019 CRC patients and 1036 cancer-free controls were shown in Table 1. No significant difference was observed in the distributions of age (P = 0.508) and gender (P = 0.230) between the cases and controls. The percentage of ever smokers (28.75%) were significantly lower in cases than in controls (45.46%). Significant difference was also detected in pack-years between cases and controls. Moreover, cases were less likely to be drinkers than controls. As to the location of tumor, 46.81% of lesions (477 cases) occurred in colon, while 53.19% of lesions (542 cases) in rectum. In term of tumor stage, 46 (4.51%), 314 (30.81%), 380 (37.29%), and 279 cases (27.38%) were diagnosed with Duke’s stage A, B, C, and D diseases, respectively.

Table 1.

Demographic characteristics of the colorectal cancer patients and controls

Variables Cases (n = 1019) Controls (n = 1036) Pa
No. % No. %
Age range, year 23-87 24-85 0.508
Mean ± SD 56.58 ± 12.69 57.25 ± 11.82
    ≤ 58 546 53.58 650 52.12
    > 58 473 46.42 496 47.88
Gender 0.230
    Female 389 38.17 369 35.62
    Male 630 61.83 667 64.38
BMI < 0.0001
    < 18.0 90 8.83 9 0.87
    18-24.9 717 70.36 606 58.49
    25.0-29.9 193 18.94 362 34.94
    > 30.0 19 1.86 59 5.69
Smoking status < 0.0001
    Never 726 71.25 565 54.54
    Ever 293 28.75 471 45.46
Pack-year < 0.0001
    0 726 71.25 565 54.54
    ≤ 30 151 14.82 294 28.38
    > 30 142 13.94 177 17.08
Drinking status < 0.0001
    No 847 83.12 763 73.65
    Yes 172 16.88 273 26.35
Tumor locations
    Colon 477 46.81 / /
    Rectal 542 53.19 / /
Duke stages
    A 46 4.51 / /
    B 314 30.81 / /
    C 380 37.29 / /
    D 279 27.38 / /
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SD, standard deviation; BMI, body mass index.

a

Two-sided Chi-square test for the distributions between patients and controls.

XPG gene rs17655 G > C polymorphism and colorectal cancer risk

The genotype distribution of the XPG gene rs17655 G > C and the association results were summarized in Table 2. The frequency distribution of rs17655 G > C was consistent with HWE in the control subjects (P = 0.854). We observed no significant association between rs17655 G > C and CRC risk.

Table 2.

Association between XPG rs17655 G > C polymorphism and colorectal cancer risk

Genotype Cases Controls P a OR (95% CI) P AOR (95% CI)b P b
No. % No. %
rs17655 (HWE = 0.854)
    GG 248 24.34 265 25.58 1.00 1.00
    CG 510 50.05 515 49.71 1.06 (0.86-1.31) 0.601 0.99 (0.79-1.24) 0.947
    CC 261 25.61 256 24.71 1.09 (0.85-1.39) 0.492 1.10 (0.85-1.43) 0.461
Additive 0.781 1.04 (0.92-1.18) 0.493 1.05 (0.92-1.20) 0.459
    Dominant 771 75.66 771 74.42 0.515 1.07 (0.88-1.31) 0.516 1.03 (0.83-1.27) 0.797
    Recessive 758 74.39 780 75.29 0.637 1.05 (0.86-1.28) 0.637 1.11 (0.90-1.37) 0.342
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OR, odds ratio; CI, confidence interval; AOR, adjusted odds ratio; HWE, Hardy-Weinberg equilibrium.

a

Chi-square test for genotype distributions between patients and controls.

b

Adjusted for age, gender, BMI, smoking and drinking status.

Stratification analysis

The stratified study was performed to explore the association between rs17655 G > C polymorphism and CRC risk by age, gender, BMI, smoking status, pack-year, drinking status, tumor location, and Duke stage. However, we did not find any significant association (Table 3).

Table 3.

Stratification analysis for the association between XPG rs17655 G > C polymorphism and colorectal cancer risk

Variables GG CG/CC OR (95% CI) P AOR (95% CI)a P a
Cases/controls
Age, median
    ≤ 58 124/125 422/415 1.03 (0.77-1.36) 0.864 1.01 (0.75-1.35) 0.964
    > 58 124/140 349/356 1.11 (0.83-1.47) 0.483 1.04 (0.77-1.42) 0.789
Gender
    Females 92/90 297/279 1.04 (0.75-1.45) 0.812 1.06 (0.74-1.51) 0.764
    Males 156/175 474/492 1.08 (0.84-1.39) 0.543 1.02 (0.78-1.32) 0.910
BMI
    < 18.0 19/6 71/3 7.47 (1.71-32.68) 0.008 13.58 (2.33-79.11) 0.004
    18-24.9 171/150 546/456 1.05 (0.82-1.35) 0.702 1.04 (0.80-1.34) 0.788
    25.0-29.9 53/93 140/269 0.91 (0.62-1.36) 0.652 0.87 (0.58-1.32) 0.512
    > 30.0 5/16 14/43 1.04 (0.32-3.36) 0.946 1.09 (0.33-3.66) 0.887
Smoking status
    Never 174/134 552/431 0.99 (0.76-1.28) 0.917 0.93 (0.71-1.22) 0.579
    Ever 74/131 219/340 1.14 (0.82-1.59) 0.438 1.15 (0.81-1.64) 0.425
Pack-year
    0 174/134 552/431 0.99 (0.76-1.28) 0.917 0.94 (0.72-1.24) 0.676
    ≤ 30 34/82 117/212 1.33 (0.84-2.11) 0.222 1.26 (0.77-2.05) 0.361
    > 30 40/49 102/128 0.98 (0.60-1.60) 0.923 0.75 (0.43-1.33) 0.324
Drinking status
    Never 205/180 642/583 0.97 (0.77-1.22) 0.774 0.95 (0.75-1.21) 0.677
    Ever 43/85 129/188 1.36 (0.88-2.09) 0.165 1.29 (0.82-2.02) 0.271
Tumor locations
    Colon 117/265 360/771 1.06 (0.82-1.36) 0.664 1.00 (0.76-1.30) 0.969
    Rectal 131/265 411/771 1.08 (0.85-1.37) 0.540 1.07 (0.83-1.38) 0.607
Duke stages
    A + B 90/265 270/771 1.03 (0.78-1.36) 0.829 1.04 (0.78-1.39) 0.783
    C + D 158/265 501/771 1.09 (0.87-1.37) 0.457 1.02 (0.80-1.30) 0.859
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OR, odds ratio; CI, confidence interval; AOR, adjusted odds ratio; BMI, body mass index.

a

Adjusted for age, gender, BMI, smoking and drinking status.

Meta-analysis results

Meta-analysis was also carried out to further explore the association of rs17655 G > C polymorphism with CRC risk by combining qualified publications and our data. Overall, 14 eligible case-control studies were pooled together to evaluate such association [26-37] (Table 4). As shown in Table 5 and Figure 1, pooled results indicated that rs17655 G > C polymorphism was associated with an increased CRC susceptibility (CG vs. GG: OR = 1.14, 95% CI = 1.01-1.28; CC/CG vs. GG: OR = 1.12, 95% CI = 1.01-1.24; C vs. G: OR = 1.06, 95% CI = 1.01-1.11). Stratified analysis by ethnicity revealed significant association between rs17655 G > C genotype and CRC risk among Asian (CC vs. GG: OR = 1.18, 95% CI = 1.04-1.35; CG vs. GG: OR = 1.25, 95% CI = 1.00-1.54; CC/CG vs. GG: OR = 1.23, 95% CI = 1.03-1.47; C vs. G: OR = 1.10, 95% CI = 1.03-1.17), but not among Caucasians or Africans (Figure 2). Regarding source of controls (Figure 3), significant association was detected between rs17655 G > C and an increased CRC risk in hospital-based studies (CC vs. GG: OR = 1.14, 95% CI = 1.01-1.29; CG vs. GG: OR = 1.26, 95% CI = 1.11-1.44; CC/CG vs. GG: OR = 1.24, 95% CI = 1.11-1.37; C vs. G: OR = 1.11, 95% CI = 1.05-1.17). Regarding HWE (Figure 4), significant association was only detected between rs17655 G > C and an increased CRC risk in HWE ≤ 0.05 studies (CC/CG vs. GG: OR = 1.13, 95% CI = 1.00-1.28). Leave-one-out sensitivity analysis result demonstrated that no removal of any single study could lead to substantial change in pooled results. Moreover, no evidence of obvious asymmetry in Begg’s funnel plots was found.

Table 4.

Main characteristics of included studies for the final meta-analysis

Name Year Region Ethnicity Design Genotype Case Control MAF HWE
Method GG CG CC All GG CG CC All
Bigler 2005 USA Caucasian PB Taqman 440 237 36 713 353 226 37 616 0.24 0.917
Huang 2006 USA Caucasian PB Sequencing 407 243 29 679 403 265 29 697 0.23 0.073
Pardini 2008 Czech Caucasian HB PCR-RFLP 334 177 21 532 356 153 23 532 0.19 0.211
Joshi 2009 USA Caucasian FB Taqman 183 114 11 308 213 137 11 361 0.22 0.046
Canbay 2011 Turkey Caucasian PB PCR-RFLP 43 34 2 79 148 83 16 247 0.23 0.352
Gil 2012 Poland Caucasian PB PCR-RFLP 86 35 11 132 64 31 5 100 0.21 0.625
Liu 2012 China Asian HB PCR-RFLP 233 603 192 1028 329 537 219 1085 0.45 0.996
Du 2014 China Asian HB TaqMan 286 459 133 878 355 405 124 884 0.37 0.623
Steck 2014 USA Caucasian PB MassARRAY 183 100 15 298 335 170 27 532 0.21 0.372
Steck 2014 USA African PB MassARRAY 65 120 39 224 100 151 66 317 0.45 0.519
Paszkowska-Szczur 2015 Poland Caucasian HB Taqman 429 272 32 733 869 404 85 1358 0.21 0.0001
Sun 2015 China Asian HB PCR-RFLP 216 476 198 890 227 497 186 910 0.48 0.004
Kabzinski 2015 Poland Caucasian HB QPCR 36 171 27 234 43 175 20 238 0.45 < 0.001
Su Current China Asian HB Taqman 248 510 261 1019 265 515 256 1036 0.50 0.854
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MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium; PB, population based; HB, hospital based; FB, family based; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism.

Table 5.

Meta-analysis of the association between XPG rs17655 G > C polymorphism and colorectal cancer risk

Variables No. of studies Cases/controls Homozygous Heterozygous Recessive Dominant Allele comparing
CC vs. GG CG vs. GG CC vs. CG/GG CC/CG vs. GG C vs. G
OR (95% CI) P het OR (95% CI) P het OR (95% CI) P het OR (95% CI) P het OR (95% CI) P het
All 14 7747/8913 1.09 (0.98-1.22) 0.584 1.14 (1.01-1.28) 0.002 0.99 (0.90-1.09) 0.593 1.12 (1.01-1.24) 0.013 1.06 (1.01-1.11) 0.477
    Ethnicity
        Caucasian 9 3708/4681 0.93 (0.76-1.15) 0.651 1.07 (0.93-1.23) 0.046 0.91 (0.75-1.12) 0.503 1.05 (0.94-1.18) 0.163 1.02 (0.95-1.10) 0.557
        Asian 4 3815/3915 1.18 (1.04-1.35) 0.716 1.25 (1.00-1.54) 0.006 1.03 (0.92-1.15) 0.572 1.23 (1.03-1.47) 0.025 1.10 (1.03-1.17) 0.394
        African 1 224/317 0.91 (0.55-1.51) / 1.22 (0.83-1.81) / 0.80 (0.52-1.24) / 1.13 (0.78-1.64) / 0.98 (0.77-1.25) /
    Source of control
        PB 6 2125/2509 0.91 (0.71-1.17) 0.757 0.97 (0.85-1.12) 0.330 0.89 (0.70-1.13) 0.639 0.95 (0.84-1.07) 0.544 0.95 (0.86-1.05) 0.806
        HB 7 5314/6043 1.14 (1.01-1.29) 0.395 1.26 (1.11-1.44) 0.041 1.01 (0.91-1.12) 0.336 1.24 (1.11-1.37) 0.148 1.11 (1.05-1.17) 0.804
        FB 1 308/361 1.16 (0.49-2.75) / 0.97 (0.71-1.33) / 1.18 (0.50-2.76) / 0.98 (0.72-1.34) / 1.00 (0.77-1.30) /
    HWE
        > 0.05 10 5582/6046 1.11 (0.98-1.26) 0.100 1.14 (0.98-1.33) 0.090 0.98 (0.88-1.09) 0.709 1.20 (0.98-1.28) 0.105 1.05 (0.98-1.13) 0.141
        ≤ 0.05 4 2165/2867 1.05 (0.81-1.37) 0.722 1.13 (0.94-1.36) 0.196 1.02 (0.75-1.38) 0.895 1.13 (1.00-1.28) 0.047 1.07 (0.98-1.17) 0.116
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OR, odds ratio; CI, confidence interval; PB, population based; HB, hospital based; FB, family based; HWE, Hardy-Weinberg equilibrium.

Figure 1.

Figure 1

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Forest plot for the CRC susceptibility associated with the rs17655 G > C polymorphism under allele comparison model. The horizontal lines represent the study-specific ORs and 95% CIs, respectively. The diamond represents the pooled results of OR and 95% CI.

Figure 2.

Figure 2

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Forest plot for the CRC susceptibility associated with the rs17655 G > C polymorphism stratified by ethnicities under allele comparison model. The horizontal lines represent the study-specific ORs and 95% CIs, respectively. The diamond represents the pooled results of OR and 95% CI.

Figure 3.

Figure 3

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Forest plot for the CRC susceptibility associated with the rs17655 G > C polymorphism stratified by design under allele comparison model. The horizontal lines represent the study-specific ORs and 95% CIs, respectively. The diamond represents the pooled results of OR and 95% CI.

Figure 4.

Figure 4

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Forest plot for the CRC susceptibility associated with the rs17655 G > C polymorphism stratified by HWE under allele comparison model. The horizontal lines represent the study-specific ORs and 95% CIs, respectively. The diamond represents the pooled results of OR and 95% CI.

Discussion

In the present study, we further explored the predisposing role of XPG rs17655 G > C polymorphism in CRC. The results of our case-control study failed to provide supportive evidence of the association between the XPG gene rs17655 G > C polymorphism and CRC risk. However, the following meta-analysis demonstrated that the XPG rs17655 G > C polymorphism confers increased CRC risk.

XPG is an endonuclease responsible for a dual incision in NER pathway. XPG cut the DNA strand at the 3’ end of the lesion, and maintain the DNA repair complex in the damaged site with ERCC1/XPF complex by generating 5’ incision [38-41]. Genetic variations of XPG may impair the DNA repair capacity and genome integrity, consequently leading to the initiation of carcinogenesis. The association of XPG rs17655 G > C (Asp1104His) polymorphism with colorectal cancer risk has been widely investigated, and results are controversial. Paszkowska-Szczur et al. [35] failed to detect significant associations between XPG rs17655 G > C and CRC risk. Such null associations were also presented in a study conducted by Canbay et al. [31] in Turkish population with 79 CRC cases and 247 healthy controls. Opposite results regarding the association were also reported. In a Czech hospital-based case-control study including 532 cases and 532 controls, the XPG rs17655 G > C was shown to increase the risk of CRC [29]. Liu et al. [33] observed that heterozygotes and homozygotes of this variant were more likely to have CRC than wild controls, in a Chinese population study including 1028 CRC cases and 1085 controls. More recently, Du et al. [26] also verified the risk effect of XPG rs17655 G > C polymorphism on CRC in a Chinese population.

Replication study is a golden standard to validate a association. We performed this case-control study to further elucidate the contribution of XPG rs17655 G > C polymorphism to CRC susceptibility. We found that the XPG rs17655 G > C polymorphism was not significantly associated with CRC risk, either in the overall analysis or stratification analysis. The null association may be attributed to therelatively small sample size or the low-penetrance of this SNP. Therefore, we next conducted a meta-analysis to comprehensively evaluate this association. Our meta-analysis indicated that individuals with CG and CC/CG genotype were more likely to be susceptible to CRC. Stratified analysis by ethnicity showed that significant association was observed among Asians, but not Caucasians. A variety of reasons may help to explain the discrepant results, such as differences in linkage disequilibrium structure, allele frequency, and lifestyles as well as diversities of geography and living environments [42]. Moreover, different results from the current study and meta-analysis regarding the association between rs17655 G > C and CRC risk might be due to different sample size, ethnicity, allele frequency and histological type of tumor.

The sample size of this study is moderate with 1019 cases and 1036 controls. Moreover, this meta-analysis is by far the largest pooled study to investigate the association of interest. Therefore, the conclusion obtained is convincing. However, several limitations still exist. First, we only analyzed one SNP in this study, more potentially functional SNPs in the XPG gene should be explored in the future. Second, the environmental variables were not included, which might also affect the risk of CRC. Third, selection bias and information bias could not be ruled out since all the participants were enrolled from the same hospital. Fourth, the moderate sample size of this study might have no sufficient power to detect the weak impact of SNP. Fifth, our study was a case-control study with subjects from north China. The current findings may not well represent other nationality and ethnicities. Finally, functional studies should be performed to elucidate the mechanism underlying this association.

In conclusion, we found that XPG rs17655 G > C polymorphism was associated with CRC susceptibility in Asian populations. More case-control studies with larger sample size are warranted to confirm our findings.

Acknowledgements

This study was funded by the Institutional Fund of the First Affiliated Hospital of Zhengzhou University.

Disclosure of conflict of interest

None.

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