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. 2024 Jun 30;36(3):298–305. doi: 10.21147/j.issn.1000-9604.2024.03.06

Nucleotide excision repair gene polymorphisms and hepatoblastoma susceptibility in Eastern Chinese children: A five-center case-control study

Huimin Yin 1,*, Xianqiang Wang 2,*, Shouhua Zhang 3,*, Shaohua He 4, Wenli Zhang 1, Hongting Lu 5, Yizhen Wang 6, Jing He 1,*, Chunlei Zhou 7,*
PMCID: PMC11230887  PMID: 38988482

Abstract

Objective

Nucleotide excision repair (NER) plays a vital role in maintaining genome stability, and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation. This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children.

Methods

In this five-center case-control study, we enrolled 966 subjects from East China (193 hepatoblastoma patients and 773 healthy controls). The TaqMan method was used to genotype 19 single nucleotide polymorphisms (SNPs) in NER pathway genes, including ERCC1, XPA, XPC, XPD, XPF, and XPG. Then, multivariate logistic regression analysis was performed, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to assess the strength of associations.

Results

Three SNPs were related to hepatoblastoma risk. XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model (adjusted OR=1.49, 95% CI=1.07−2.08, P=0.019; adjusted OR=1.66, 95% CI=1.12−2.45, P=0.012, respectively). However, XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model (adjusted OR=0.68, 95% CI=0.49−0.95; P=0.024). Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups. Moreover, there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) analysis.

Conclusions

In summary, NER pathway gene polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) are significantly associated with hepatoblastoma risk, and further research is required to verify these findings.

Keywords: Nucleotide excision repair, polymorphisms, hepatoblastoma, susceptibility

Introduction

Hepatoblastoma, an embryonal solid tumor, is the most common primary pediatric liver malignancy and accounts for more than 60% of all malignant liver neoplasms (1). Hepatoblastoma mostly occurs prior to age 5 and is more common in males (2,3). Treatment for hepatoblastoma includes surgical resection, chemotherapy, and liver transplantation. Although advances in multimodal therapies have improved survival rates, patients with high-risk hepatoblastoma still have a dismal prognosis, and survivors may suffer from long-term treatment-related complications, including second malignancies and hearing loss (4,5). The etiology of hepatoblastoma has not yet been clarified. Although most cases of hepatoblastoma are sporadic, it is believed that premature birth or low birth weight and inherited syndromes such as Beckwith-Wiedemann syndrome can be risk factors for developing hepatoblastoma (6,7). Hence, a deeper grasp of tumor biology would enable us to make progress in the prevention, treatment, and prognosis of this disease.

Nucleotide excision repair (NER), one of the most important DNA repair mechanisms, can remove diverse bulky DNA lesions formed by radiation, environmental mutagens, or other chemical adducts, such as cyclobutene-pyrimidine dimers (CPDs), 6-4 pyrimidine-pyrimidone photoproducts (6-4PPs), and various aromatic amines (8,9). NER includes two subpathways: transcription-coupled NER (TC-NER) and global genome NER (GG-NER). The two pathways differ only in the step of recognizing DNA lesions (8,10). Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) within NER pathway genes are associated with susceptibility to cancers, such as colorectal cancer (11), neuroblastoma (12), Wilms tumor (13), and ovarian cancer (14).

Our group previously conducted a seven-center case-control study, and to the best of our knowledge, we are the first to provide evidence that NER gene polymorphisms could predispose patients to hepatoblastoma risk in the Chinese pediatric population. However, only one study to date has investigated the role of NER pathway gene SNPs in hepatoblastoma risk, and the results need to be validated in another independent study. Therefore, we performed this five-center case-control study to assess this association in Eastern Chinese Han children.

Materials and methods

Study subjects

A total of 193 patients with hepatoblastoma and 773 healthy controls (Supplementary Table S1) were recruited from five hospitals in Jiangsu, Anhui, Fujian, Shandong, and Jiangxi provinces. The recruitment details of the subjects were described in our previous study (15). Written informed consent was obtained from the subjects’ parents or legal guardians before this study started. This study complied with the Declaration of Helsinki and was approved by the Institutional Review Board of the Children’s Hospital of Nanjing Medical University (No: 202402008-1).

Table S1. Frequency distribution of selected variables in hepatoblastoma patients and cancer-free controls from East China.

Variables n (%) Pa
Cases (N=193) Controls (N=773)
NA, not available. a, two-sided χ2 test for distributions between hepatoblastoma cases and cancer-free controls.
Age (month) 0.097
Range 0.03−156.00 0.001−156.00
　Inline graphic 23.95±23.22 27.54±24.10
　<17 105 (54.40) 369 (47.74)
　≥17 88 (45.60) 404 (52.26)
Sex 0.730
　Female 78 (40.41) 323 (41.79)
　Male 115 (59.59) 450 (58.21)
Clinical stages −
　I 49 (25.39) −
　II 61 (31.61) −
　III 39 (20.21) −
　IV 22 (11.40) −
　NA 22 (11.40) −
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SNP selection and genotyping

Based on the standard criteria described previously, the potentially functional SNPs were selected using the dbSNP database (https://www.ncbi.nlm.nih.gov/snp) and SNPinfo (https://snpinfo.niehs.nih.gov/snpinfo/snpfunc.html) (12,16-18). The minor allele frequencies should be greater than 5% in the Chinese Han population, and no significant linkage disequilibrium (LD) existed among these selected SNPs (R2<0.8). Total genomic DNA was extracted from paraffin-embedded tissues and peripheral blood samples using a QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, CA) and a TIANGEN Blood DNA Extraction Kit (TianGen Biotech, Beijing), respectively, according to the manufacturers’ protocols. Then, the qualified DNA samples were diluted into 96-well plates. Genotyping was performed by the TaqMan method, as we described previously (19). Four positive controls and four negative controls were included in each 384-well plate. In addition, 10% of the DNA samples were randomly chosen for repeated genotyping, and the results were 100% consistent.

Statistical analysis

Differences in clinical variables between patients and controls were analyzed by two-sided χ2 tests. The goodness-of-fit χ2 test was adopted to estimate the Hardy-Weinberg equilibrium (HWE) in the controls. To explore the association between NER gene polymorphisms and hepatoblastoma risk, we used multivariate logistic regression analysis to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Further stratified analysis was conducted by age, sex, and clinical stage. Moreover, we conducted expression quantitative trait locus (eQTL) and splicing quantitative trait locus (sQTL) analyses using the Genotype-Tissue Expression (GTEx) database (https://gtexportal.org/home/) to assess the potential biological effects of the significant SNPs. A two-sided P<0.05 was considered to indicate statistical significance. All the statistical analyses were carried out using SAS software (Version 10.0; SAS Institute Inc., Cary, NC, USA).

Results

Participants’ characteristics

The frequency distributions of selected variables of all participants are shown in Supplementary Table S1. No significant differences in age (P=0.097) or sex (P=0.730) were observed between the hepatoblastoma patients and controls. Among the patients, 25.39% were classified as clinical stage I, 31.61% as stage II, 20.21% as stage III, 11.40% as stage IV, and 11.40% could not be classified.

NER pathway gene SNPs and hepatoblastoma susceptibility

A total of 193 patients and 773 controls were successfully genotyped. Detailed information on the relationship between polymorphisms in NER pathway genes and hepatoblastoma risk is listed in Table 1. Only three SNPs associated with hepatoblastoma risk were detected. XPC rs2229090 and XPD rs3810366 were significantly related to increased hepatoblastoma risk according to the dominant model (adjusted OR=1.49, 95% CI=1.07−2.08, P=0.019; adjusted OR=1.66, 95% CI=1.12−2.45, P=0.012, respectively), whereas XPD rs238406 was significantly related to decreased hepatoblastoma risk (dominant model: adjusted OR=0.68, 95% CI=0.49−0.95, P=0.024).

Table 1. Association between polymorphisms in NER pathway genes and hepatoblastoma risk in Eastern Chinese children.

Gene Polymorphism n AOR (95% CI)a Pa AOR (95% CI)b Pb HWE
Allele Cases (N=193) Controls (N=773)
W M WW WM MM WW WM MM
NER, nucleotide excision repair; AOR, adjusted odds ratio; 95% CI, 95% confidence interval; HWE, Hardy-Weinberg equilibrium. a, adjusted for age and sex for dominant model; b, adjusted for age and sex for recessive model.
ERCC1 rs2298881 C A 79 73 41 284 342 146 0.85 (0.62−1.18) 0.339 1.15 (0.78−1.69) 0.491 0.019
ERCC1 rs3212986 C A 88 89 16 368 323 81 1.09 (0.80−1.50) 0.581 0.76 (0.43−1.33) 0.329 0.420
ERCC1 rs11615 G A 102 78 13 441 291 40 1.20 (0.87−1.65) 0.260 1.29 (0.67−2.47) 0.443 0.367
XPA rs1800975 T C 39 107 47 199 383 191 1.39 (0.94−2.05) 0.096 0.99 (0.68−1.43) 0.945 0.803
XPA rs3176752 G T 156 35 2 602 160 11 0.82 (0.55−1.23) 0.340 0.70 (0.15−3.18) 0.643 0.921
XPC rs2228001 A C 79 92 22 300 369 104 0.91 (0.66−1.26) 0.580 0.82 (0.50−1.34) 0.425 0.572
XPC rs2228000 C T 81 93 19 364 319 90 1.24 (0.90−1.71) 0.190 0.84 (0.50−1.41) 0.504 0.119
XPC rs2607775 C G 175 17 2 715 56 2 1.28 (0.74−2.23) 0.381 1.84 (0.17−20.39) 0.621 0.420
XPC rs1870134 G C 108 72 13 418 307 48 0.92 (0.67−1.27) 0.628 1.06 (0.56−2.01) 0.857 0.398
XPC rs2229090 G C 64 103 26 328 331 114 1.49 (1.07−2.08) 0.019 0.90 (0.57−1.43) 0.655 0.044
XPD rs3810366 G C 37 116 40 214 370 188 1.66 (1.12−2.45) 0.012 0.81 (0.55−1.20) 0.292 0.262
XPD rs238406 G T 72 83 38 224 370 178 0.68 (0.49−0.95) 0.024 0.80 (0.54−1.19) 0.266 0.291
XPD rs13181 T G 162 29 2 646 119 7 0.98 (0.64−1.51) 0.937 1.13 (0.23−5.50) 0.883 0.561
XPF rs2276466 C G 114 71 8 496 245 31 1.24 (0.90−1.72) 0.188 1.01 (0.45−2.23) 0.988 0.914
XPG rs2094258 C T 68 91 31 308 339 126 1.20 (0.86−1.67) 0.275 1.01 (0.66−1.56) 0.958 0.047
XPG rs751402 C T 92 74 24 328 371 74 0.78 (0.57−1.08) 0.132 1.34 (0.82−2.20) 0.241 0.034
XPG rs2296147 T C 125 56 9 484 261 28 0.86 (0.61−1.20) 0.368 1.31 (0.61−2.83) 0.492 0.321
XPG rs1047768 T C 107 69 14 393 325 55 0.80 (0.58−1.10) 0.169 1.02 (0.55−1.87) 0.958 0.270
XPG rs873601 G A 63 94 33 218 374 181 0.78 (0.55−1.09) 0.145 0.68 (0.45−1.02) 0.064 0.402
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Stratification analysis

We then conducted stratified analyses for the three significant polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) by age, sex, and clinical stage (Table 2). We found that XPC rs2229090 GC/CC had enhanced effects on hepatoblastoma risk in children aged ≥17 months (adjusted OR=1.95, 95% CI=1.18−3.22, P=0.010), females (adjusted OR=1.84, 95% CI=1.07−3.17, P=0.027), and patients with clinical stage I+II (adjusted OR=1.65, 95% CI=1.07−2.54, P=0.022) subgroups. Similarly, XPD rs3810366 GC/CC was significantly related to increased hepatoblastoma risk in participants aged <17 months (adjusted OR=1.77, 95% CI=1.04−2.99, P=0.034), males (adjusted OR=2.17, 95% CI=1.26−3.75, P=0.005), and patients with clinical stage I+II disease (adjusted OR=1.78, 95% CI=1.07−2.98, P=0.027). Moreover, XPD rs238406 GT/TT was strongly associated with a reduced risk of hepatoblastoma in children at clinical I+II stages (adjusted OR=0.61, 95% CI=0.40−0.92; P=0.020).

Table 2. Stratification analysis for association of XPC and XPD genotypes with hepatoblastoma susceptibility in Eastern Chinese children.

Variables XPC rs2229090
(case/control) (n)		 AOR
(95% CI)a 		Pa XPD rs3810366
(case/control) (n)		 AOR
(95% CI)a 		Pa XPD
rs238406
(case/control) (n)		 AOR
(95% CI)a 		Pa
GG GC/CC GG GC/CC GG GT/TT
AOR, adjusted odds ratio; 95% CI, 95% confidence interval. a, adjusted for age and sex, omitting the corresponding stratify factor.
Age (month)
　<17 39/152 66/217 1.19 (0.76−1.86) 0.455 21/113 84/256 1.77 (1.04−2.99) 0.034 38/106 67/263 0.71 (0.45−1.12) 0.143
　≥17 25/176 63/228 1.95 (1.18−3.22) 0.010 16/101 72/302 1.49 (0.83−2.69) 0.180 34/118 54/285 0.66 (0.41−1.06) 0.085
Sex
　Female 22/136 56/187 1.84 (1.07−3.17) 0.027 19/88 59/234 1.19 (0.67−2.10) 0.562 29/96 49/226 0.71 (0.42−1.20) 0.199
　Male 42/192 73/258 1.30 (0.85−1.99) 0.222 18/126 97/324 2.17 (1.26−3.75) 0.005 43/128 72/322 0.67 (0.43−1.02) 0.063
Clinical stages
　I+II 34/328 76/445 1.65 (1.07−2.54) 0.022 20/214 90/558 1.78 (1.07−2.98) 0.027 44/224 66/548 0.61 (0.40−0.92) 0.020
　III+IV 18/328 43/445 1.76 (1.00−3.10) 0.052 13/214 48/558 1.41 (0.75−2.66) 0.289 20/224 41/548 0.84 (0.48−1.47) 0.538
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Genotype-based mRNA expression analysis

We further explored the biological effects of the three significant SNPs using eQTL and sQTL analyses. The eQTL results showed that the rs2229090 C allele was significantly associated with increased XPC mRNA expression in cultured fibroblasts (Figure 1). Furthermore, the sQTL results showed that the rs2229090 C allele significantly reduced alternative splicing of XPC mRNA in whole blood (Figure 2A) and cultured fibroblasts (Figure 2B). We also found that the rs3810366 C allele was significantly associated with an increase in PPP1R13L mRNA expression in cultured fibroblasts (Figure 3A) and a decrease in ERCC2 mRNA expression in the pancreas (Figure 3B), and the rs238406 T allele was significantly associated with a decrease in PPP1R13L mRNA expression in cultured fibroblasts (Figure 3C) and an increase in ERCC2 mRNA expression in the pancreas (Figure 3D).

Figure 1.

Figure 1

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eQTL analysis for XPC rs2229090 G>C. The XPC rs2229090 C allele was significantly associated with increased XPC mRNA expression in cultured fibroblasts (P=1.64e−9). eQTL, expression quantitative trait locus.

Figure 2.

Figure 2

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sQTL analysis for XPC rs2229090 G>C. The XPC rs2229090 C allele significantly reduced alternative splicing of XPC mRNA in whole blood (P=4.65e−7) (A) and cultured fibroblasts (P=7.82e−7) (B). sQTL, splicing quantitative trait locus.

Figure 3.

Figure 3

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eQTL analysis for XPD rs3810366 G>C and XPD rs238406 G>T. The XPD rs3810366 C allele was significantly associated with increased PPP1R13L mRNA expression in cultured fibroblasts (P=2.28e−10) (A) and decreased ERCC2 mRNA expression in the pancreas (P=1.84e−9) (B). The XPD rs238406 T allele was significantly associated with decreased PPP1R13L mRNA expression in cultured fibroblasts (P=2.3e−8) (C) and increased ERCC2 mRNA expression in the pancreas (P=3.65e−13) (D). eQTL, expression quantitative trait locus.

Discussion

The NER pathway is an essential mechanism for removing DNA damage induced by both exogenous and endogenous factors (8). Many efforts have previously been made to investigate the role of NER pathway gene polymorphisms in the development of cancer. Here, we found that XPC rs2229090, XPD rs3810366, and XPD rs238406 were significantly related to hepatoblastoma risk by conducting a five-center case-control study, and the association remained significant in stratified analyses.

As a key initiator of the GG-NER pathway, XPC plays an essential role in the recognition of damaged DNA by binding to HR23B to form the XPC-HR23B complex (20,21). XPC gene polymorphisms are involved in different types of cancer. A previous study revealed that the XPC intron 11 C>A polymorphism could contribute to an increased risk of prostate cancer in a Japanese population (22). In addition, Zhang et al. (23) reported that the XPC rs2229090 GC/CC genotype could increase the risk of glioma in certain subgroups, while Zheng et al. (24) failed to detect any significant contribution of the rs2229090 polymorphism to neuroblastoma risk in Chinese children. XPD, also known as ERCC2, encodes a DNA helicase (25). XPD is a part of the transcription factor II H complex and participates in the unwinding of DNA, which is one of the main NER steps (26,27). XPD polymorphisms have been reported to be linked to the risk of cancer, such as lung cancer (28), cutaneous melanoma (29), and colorectal cancer (30). A recent meta-analysis showed that XPD rs238406 was closely linked to skin cancer risk (31). Our previous study revealed that the XPD rs3810366 and rs238406 polymorphisms were significantly associated with the risk of neuroblastoma (12) and Wilms tumor (13). However, Yin et al. (32) suggested that rs238406 was not associated with breast cancer susceptibility among nonsmoking Chinese individuals. The different roles of these SNPs in different cancer types may be attributed to differences in sample sizes, population sources, and environmental factors. Therefore, it is essential to validate the exact role of NER gene polymorphisms in particular cancer types in specific populations.

In our previous study, significant associations with hepatoblastoma susceptibility were shown for XPC rs2607775 and XPC rs1870134. Interestingly, the current analysis revealed that XPC rs2229090, XPD rs3810366, and XPD rs238406 were significantly related to hepatoblastoma risk. We speculated that this might be due to differences in geography and environment. However, XPC rs2229090 did not exactly obey HWE in controls (HWE=0.044), and replication studies are required to verify these findings. We further performed eQTL and sQTL analyses to explore the possible mechanism by which rs2229090, rs3810366, and rs238406 affect hepatoblastoma risk. The eQTL results showed that the rs2229090 C allele increased the expression of XPC mRNA in cultured fibroblasts, and the sQTL revealed that the rs2229090 C allele reduced alternative splicing of XPC mRNA in whole blood and cultured fibroblasts. As a DNA repair factor, XPC plays an important role in tumorigenesis. Rezvani et al. (33) revealed that XPC silencing could lead to the tumorigenic transformation of normal keratinocytes. Wang and coworkers also found that the expression of XPC was significantly lower in lung adenocarcinoma cancer tissues than in paracancerous tissues and could affect the proliferation and migration of lung cancer cells (34). Alternative splicing is a crucial posttranscriptional regulatory mechanism, and splicing repair events have been observed in the onset and progression of cancers, including neuroblastoma (35,36). In addition, Jin et al. (37) reported that the rs156697 variant could impact the risk of non-small cell lung cancer by altering GSTO2 splicing. However, more studies are needed to determine the important role of the XPC gene in hepatoblastoma. We also found that the rs3810366 C allele and rs238406 T allele were significantly associated with PPP1R13L gene expression levels. PPP1R13L expression is generally believed to be elevated in multiple cancers (38,39). Laska et al. (40) provided evidence that increased levels of PPP1R13L could increase tumorigenesis and progression, suggesting that PPP1R13L could function as an oncoprotein. Xue et al. (41) also reported that a high expression level of PPP1R13L was associated with poor clinical prognosis in lung cancer patients, indicating its potential oncogenic role in lung cancer. These findings suggest that the functional effects of rs2229090, rs3810366, and rs238406 on local or distant genes may influence the risk of hepatoblastoma. However, further experiments are needed to verify our results.

Several limitations should be mentioned in this study. First, the participants involved in this study were all Han Chinese, and the findings may not be applicable to people of other ethnicities. Furthermore, given insufficient sample information, environmental factors were not included. Additionally, false-positive results may occur without rigorous correction, and a larger sample size is needed to validate our results. Finally, the specific mechanism of NER gene polymorphisms in hepatoblastoma susceptibility is unclear, and further biological experiments should be performed to elucidate this mechanism.

Conclusions

We found a significant association between NER pathway gene polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) and hepatoblastoma susceptibility in Eastern Chinese children. Further replication studies and biological experiments are required to verify these findings.

SUPPLEMENTARY DATA

Supplementary data to this article can be found online.

cjcr-36-3-298-S1.pdf (97.5KB, pdf)

Acknowledgements

This study was supported by grants from the Innovation and Cultivation Fund Project of the Seventh Medical Center, PLA General Hospital (No. QZX-2023-7); Postdoctoral Science Foundation of China (No. 2021M691649) and Postdoctoral Science Foundation of Jiangsu Province (No. 2021K524C).

Acknowledgments

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Contributor Information

Jing He, Email: hejing198374@gmail.com.

Chunlei Zhou, Email: chunlei1064@sina.cn.

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