Research Paper Volume 10, Issue 8 pp 1989—2000

Relevance of XPD polymorphisms to neuroblastoma risk in Chinese children: a four-center case-control study

Jiwen Cheng1, *,, Zhenjian Zhuo2, *,, Yijuan Xin3, *,, Pu Zhao4, , Weili Yang1, , Haixia Zhou5, , Jiao Zhang6, , Ya Gao1, , Jing He7, , Peng Li1, ,

  • 1 Department of Pediatric Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China
  • 2 School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
  • 3 Clinical Laboratory Medicine Center of PLA, Xijing Hospital, Air Force Medical University, Xi'an 710032, Shaanxi, China
  • 4 Department of Neonatology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China
  • 5 Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
  • 6 Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
  • 7 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
* Equal contribution

Received: June 21, 2018       Accepted: August 6, 2018       Published: August 8, 2018      

https://doi.org/10.18632/aging.101522
How to Cite

Copyright: Cheng et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Neuroblastoma is a lethal tumor that commonly occurs in children. Polymorphisms in XPD reportedly influence risk for several types of cancer, though their roles in neuroblastoma remain unclear. Here we endeavored to determine the relevance of XPD gene polymorphisms and neuroblastoma susceptibility in Chinese children genotyping three XPD polymorphisms (rs3810366, rs13181 and rs238406) in 505 cases and 1070 controls and assessing their contributions to neuroblastoma risk. Overall, we detected no significant association between any single XPD genotype and neuroblastoma risk. When risk genotypes were combined, however, we found that patients with 2-3 risk genotypes were more likely to develop neuroblastoma (adjusted odds ratio =1.31; 95% confidence interval =1.06-1.62, P=0.013) than those with 0-1 risk genotypes. Stratification analysis of rs3810366 revealed significant relationships between the subgroups age ≤18 months and clinical stage I+II+4s and neuroblastoma risk. Moreover, the presence of 2-3 risk genotypes was significantly associated with increased neuroblastoma risk in the subgroups age ≤18 months, male, tumor originated from others, and clinical stage I+II+4s. Our findings provide novel insight into the genetic underpinnings of neuroblastoma and demonstrate that XPD polymorphisms may have a cumulative effect on neuroblastoma risk.

Introduction

Neuroblastoma, a solid tumor of the sympathetic nervous system, remains the most commonly occurring lethal cancer among children [1], accounting for 7%-10% of all cancers in children under 15 years of age [2,3]. The prevalence of neuroblastoma in the United States is about 1 in 7000 [4], but is only about 1 in 13,000 in China [5]. Neuroblastomas have been classified into low-risk, intermediate-risk and high-risk groups [6]. Among them, the high-risk group accounts for 50% of all neuroblastoma patients. The 5-year survival rate among this high-risk group remains less than 35%, despite administration of intense multimodal therapy [7,8]. This low cure rate may be attributable to the presence of widespread tumor metastasis at the time of diagnosis [9].

About 1% of neuroblastoma patients present with hereditary disease [10]. The etiology of familial neuroblastoma is mainly explained by germline mutations in PHOX2B [11,12] and ALK [13,14]. Although, there is as yet no explicit description of the causes of sporadic neuroblastoma, there is growing evidence suggesting genetic and genetic-environmental factors affect ones susceptibility to neuroblastoma [15,16]. Recent genome-wide association studies identified DNA alleles that contribute significantly to the risk of neuroblastoma, including BARD1 [17], TP53 [18], HACE1 [19], LIN28B [19], and MMP20 [20]. Moreover, candidate gene approaches also associated NEFL [21] and CDKN1B [22] polymorphisms with neuroblastoma susceptibility.

The integrity and stability of the human genome is maintained primarily by DNA repair systems [23], among which the nucleotide excision repair (NER) pathway is essential in eliminating DNA damage caused by both exogenous and endogenous factors [24]. Dysfunction of the NER pathway could lead to failure to repair genomic defects, thereby increasing cancer risk [2527]. Several critical genes (ERCC1, XPA, XPB, XPC, XPD, XPE, XPF and XPG) participate in the NER process and coordinately function to maintain genomic integrity [28]. XPD (xeroderma pigmentosum complementary group D), also known as ERCC2 (excision repair cross-complementation group 2), encodes an evolutionarily conserved ATP-dependent helicase [29]. This helicase forms a complex with the transcription factor TFIIH to function in basal transcription and nucleotide excision repair [30]. The importance of XPD to the NER pathway has prompted several case-control studies to assess the effect of XPD polymorphisms on the risk of such cancers as nasopharyngeal carcinoma [31], renal cell carcinoma [32], prostate cancer [33], esophageal squamous cell carcinoma [34], and breast cancer [35]. However, the effect of XPD polymorphisms on neuroblastoma risk has not yet been studied. To address that issue, we conducted a four-center case-control study analyzing the relationship between three XPD polymorphisms and neuroblastoma risk in the Chinese population.

Results

Correlation between XPD polymorphisms and neuroblastoma susceptibility

A total of 505 patients and 1070 healthy controls were successfully genotyped in our study. The demographic characteristics of the tested subjects can be found in our previously published articles [3639] and in Supplemental Table 1. The genotype frequencies for the three selected XPD polymorphisms (rs3810366, rs13181, rs238406) in all subjects and in selected subject groups and their contributions to neuroblastoma risk are summarized in Table 1 and Supplemental Table 2. No single XPD polymorphism was significantly associated with neuroblastoma risk in any genetic model evaluated. On the other hand, participants harboring 2 or 3 risk genotypes were more likely to develop neuroblastoma (adjusted OR=1.31; 95% CI=1.06-1.62, P=0.013) than those with 0 or 1 risk genotype.

Table 1. Logistic regression analysis of the correlation between XPD polymorphisms and neuroblastoma risk.

GenotypeCases
(N=505)
Controls
(N=1070)
PaCrude OR
(95% CI)
PAdjusted OR
(95% CI) b
Pb
rs3810366 (HWE=0.143)
GG118 (23.37)285 (26.64)1.001.00
GC261 (51.68)511 (47.76)1.23 (0.95-1.60)0.1151.23 (0.95-1.60)0.120
CC126 (24.95)274 (25.61)1.11 (0.82-1.50)0.4941.11 (0.82-1.50)0.502
Additive0.2771.05 (0.91-1.22)0.4981.05 (0.91-1.22)0.506
Dominant387 (76.63)785 (73.36)0.1651.19 (0.93-1.52)0.1661.19 (0.93-1.52)0.171
Recessive379 (75.05)796 (74.39)0.7800.97 (0.76-1.23)0.7810.97 (0.76-1.23)0.778
rs13181 (HWE=0.971)
TT424 (83.96)905 (84.58)1.001.00
TG75 (14.85)158 (14.77)1.01 (0.75-1.37)0.9311.01 (0.75-1.36)0.943
GG6 (1.19)7 (0.65)1.83 (0.61-5.48)0.2801.84 (0.61-5.50)0.278
Additive0.5481.08 (0.83-1.41)0.5861.08 (0.82-1.40)0.594
Dominant81 (16.04)165 (15.42)0.7521.05 (0.78-1.40)0.7511.05 (0.78-1.40)0.762
Recessive499 (98.81)1063 (99.35)0.2741.83 (0.61-5.46)0.2811.83 (0.61-5.49)0.279
rs238406 (HWE=0.325)
GG133 (26.34)317 (29.63)1.001.00
GT264 (52.28)516 (48.22)1.22 (0.95-1.57)0.1211.22 (0.95-1.57)0.119
TT108 (21.39)237 (22.15)1.09 (0.80-1.47)0.5951.09 (0.80-1.48)0.578
Additive0.2821.05 (0.91-1.22)0.5081.05 (0.91-1.22)0.492
Dominant372 (73.66)753 (70.37)0.1771.18 (0.93-1.49)0.1781.18 (0.93-1.50)0.172
Recessive397 (78.61)833 (77.85)0.7320.96 (0.74-1.24)0.7340.96 (0.74-1.24)0.749
Combined effect of risk genotypes c
0-1247 (48.91)595 (55.61)1.001.00
2-3258 (51.09)475 (44.39)0.0131.31 (1.06-1.62)0.0131.31 (1.06-1.62)0.013
aχ2 test for genotype distributions between neuroblastoma patients and cancer-free controls. b Adjusted for age and gender. c Risk genotypes were rs3810366 GC/GG, rs13181 GG and rs238406 GT/TT.

Stratification analysis of XPD polymorphisms and neuroblastoma susceptibility

To assess the correlations between XPD polymorphisms and neuroblastoma risk in particular subgroups of healthy individuals and neuroblastoma patients, we conducted analyses after stratifying based on age, gender, sites of origin, and clinical stages. We found a significant association between the rs3810366 GC/CC genotypes and neuroblastoma risk in participants under age ≤18 months (adjusted OR=1.66, 95% CI=1.10-2.49, P=0.015) and in the clinical stage I+II+4s subgroup (adjusted OR=1.50, 95% CI=1.06-1.11, P=0.021) (Table 2). After combining the risk genotypes (Table 2), we observed that patients in the following subgroups with 2-3 risk genotypes were more likely to develop a tumor: age ≤18 months (adjusted OR=1.43, 95% CI=1.02-2.02, P=0.041), male (adjusted OR=1.33, 95% CI=1.01-1.76, P=0.046), tumor originated from others (adjusted OR=2.29, 95% CI=1.20-4.36, P=0.012), and clinical stage I+II+4s (adjusted OR=1.53, 95% CI=1.16-2.01, P=0.003). We then performed haplotype analysis to determine whether any haplotype carriers were more likely to develop neuroblastoma (Table 3). However, no XPD haplotype was associated with neuroblastoma susceptibility when the most common haplotype (GTG) was used as the reference.

Table 2. Stratification analysis of associations between XPD genotypes and neuroblastoma susceptibility.

Variablesrs3810366
(case/control)
Adjusted ORaPars13181
(case/control)
Adjusted ORaPars238406
(case/control)
Adjusted ORaPaRisk genotypes
(case/control)
Adjusted ORaPa
GGGC/CC(95% CI)TTTG/GG(95% CI)GGGT/TT(95% CI)0-12-3(95% CI)
Age, month
≤1840/130149/2951.66 (1.10-2.49)0.015156/36133/641.19 (0.75-1.88)0.46455/124134/3011.00 (0.69-1.46)0.99794/24995/1761.43 (1.02-2.02)0.041
>1878/155238/4900.96 (0.70-1.32)0.804268/54448/1010.96 (0.66-1.40)0.82978/193238/4521.31 (0.96-1.78)0.085153/346163/2991.24 (0.94-1.62)0.125
Gender
Female46/109167/3391.17 (0.79-1.73)0.440182/37331/750.85 (0.54-1.34)0.47861/142152/3061.16 (0.81-1.65)0.427106/250107/1981.27 (0.92-1.77)0.147
Male72/176220/4461.20 (0.87-1.65)0.270242/53250/901.22 (0.84-1.78)0.30572/175220/4471.20 (0.87-1.65)0.258141/345151/2771.33 (1.01-1.76)0.046
Sites of origin
Adrenal gland38/285135/7851.27 (0.86-1.86)0.231149/90524/1650.86 (0.54-1.37)0.52948/317125/7531.12 (0.78-1.61)0.53486/59587/4751.28 (0.92-1.76)0.140
Retroperitoneal41/285106/7850.96 (0.65-1.42)0.850126/90521/1650.93 (0.57-1.53)0.78535/317112/7531.32 (0.88-1.98)0.17574/59573/4751.24 (0.87-1.75)0.227
Mediastinum32/285103/7851.16 (0.76-1.77)0.489107/90528/1651.44 (0.92-2.25)0.11342/31793/7530.94 (0.64-1.39)0.76872/59563/4751.11 (0.77-1.58)0.586
Others7/28535/7851.89 (0.83-4.30)0.13236/9056/1650.92 (0.38-2.22)0.8548/31734/7531.77 (0.81-3.86)0.15315/59527/4752.29 (1.20-4.36)0.012
Clinical stage
I+II+4s49/285201/7851.50 (1.06-2.11)0.021215/90535/1650.90 (0.61-1.33)0.58965/317185/7531.20 (0.88-1.64)0.253113/595137/4751.53 (1.16-2.01)0.003
III+IV62/285170/7850.96 (0.70-1.33)0.823196/90536/1650.98 (0.66-1.46)0.92066/317166/7531.08 (0.79-1.48)0.642126/595106/4751.04 (0.78-1.39)0.768
a Adjusted for age and gender, omitting the corresponding stratification factor.

Table 3. Association between inferred XPD haplotypes and neuroblastoma susceptibility.

Haplotypes aCases
(n=1010)
Controls
(n=2140)
Crude OR
(95% CI)
PAdjusted OR b
(95% CI)
Pb
GTG267 (26.44)553 (25.84)1.001.00
GTT203 (20.10)470 (21.96)0.90 (0.72-1.12)0.3210.90 (0.72-1.12)0.340
GGG6 (0.59)7 (0.33)1.78 (0.59-5.33)0.3071.80 (0.60-5.42)0.295
GGT21 (2.08)51 (2.38)0.85 (0.50-1.45)0.5550.85 (0.50-1.44)0.544
CTG230 (22.77)527 (24.63)0.90 (0.73-1.12)0.3520.91 (0.73-1.12)0.357
CTT223 (22.08)418 (19.53)1.11 (0.89-1.38)0.3711.11 (0.89-1.38)0.370
CGG27 (2.67)63 (2.94)0.89 (0.55-1.43)0.6220.88 (0.55-1.42)0.602
CGT33 (3.27)51 (2.38)1.34 (0.85-2.13)0.2141.35 (0.85-2.14)0.202
a The haplotype order was rs3810366, rs13181, and rs238406. b Adjusted for age and gender.

Discussion

To identify XPD polymorphisms influencing neuroblastoma tumorigenesis, we performed a hospital-based case-control study involving a total of 505 neuroblastoma patients and 1070 healthy control subjects. All participants were Chinese. To our knowledge, this study is the first investigation assessing the association between XPD polymorphisms and neuroblastoma risk in Chinese children.

XPD is located on chromosome 19p13.3 [40] and is composed of 23 exons encoding an evolutionarily conserved ATP-dependent helicase. This helicase is responsible for DNA unwinding and transcription initiation. More than 100 mutations have been mapped in XPD [41], which could potentially affect the helicase activity of the encoded protein, thereby impeding normal NER function and leading to increased cancer risk [29,42]. Several XPD polymorphisms are reportedly associated with cancer risk [4345]. Among these, rs1799793 (Asp312Asn) and rs13181 (Lys751Gln) in the XPD coding region are the two most widely investigated. The rs13181 polymorphism at codon 751 in exon 23 is a non-synonymous A>C substitution, which results in an amino acid change from Lys to Gln. It has been demonstrated that this Lys751Gln polymorphism could decrease DNA repair capacity [46]. In a study conducted in Poland with 430 patients and 430 controls, Magdalena et al. [47] found that the Gln/Gln genotype of rs13181 is associated with an increased risk of ovarian cancer. In our earlier study investigation of the association between two XPD polymorphisms (rs238406 and rs13181) and esophageal squamous cell carcinomas risk, we found that rs238406, but not rs13181, was associated with elevated disease risk [34]. The results are somewhat inconclusive, however, since differing relationships between XPD polymorphisms and cancer risk have been reported. These discrepancies may reflect differences in the cancer types, sample sizes, population sources, selection criteria for subjects, and environmental exposures. It is therefore necessary to limit conclusions regarding the contributions of XPD polymorphisms to cancer risk to a particular population and cancer type.

Given the critical role of XPD polymorphisms in cancer risk and the lack of research on their contributions to neuroblastoma risk, we endeavored to assess the association between three XPD polymorphisms and neuroblastoma risk in Chinese children. Unexpectedly, we failed to detect any significant contribution by rs13181 or rs238406 to neuroblastoma risk in the overall analysis or in any of the selected subgroups after stratification. Several factors, including the relatively small sample size, low penetrance of a single polymorphism, and population bias may account for the null association. The etiology of neuroblastoma is complex and subject to heterogenetic influence by a variety of risk factors [15,48]. Although a single XPD polymorphism may have limited impact on neuroblastoma risk, it would be expected that the combined effects of several polymorphisms might bring about more significant findings. Indeed, in the present study, we observed that participants with two or more risk genotypes of these functional XPD polymorphisms were at significantly higher risk of neuroblastoma than those carrying one or fewer risk genotypes. This trend was also observed in earlier studies by ourselves and others [49,50]. These findings are biologically plausible, probably due to the joint effects of multiple functional polymorphisms.

While this study has its merits, it also has several limitations. First, inherent bias could not be excluded, as all the DNA samples were collected in hospitals. Second, although the sample size for the overall analysis was relatively large, after stratification some subgroups were less than 100, which inevitably diminished the statistical power. Third, the included subjects were restricted to unrelated Han Chinese; consequently, the results may not be applicable to other ethnicities. Fourth, only three XPD polymorphisms were selected and analyzed in this study. Other potentially functional XPD polymorphisms may also modify the activity of gene or the encoded helicase and thus should be involved in the ongoing study. Fifth, as neuroblastoma is a heterogeneous disease with a complex etiology, the genetic analysis in the present study only partially elucidated the etiology of neuroblastoma. Potentially important environmental factors such as diet, living environment, and parental exposures should be addressed in the future.

In summary, our findings provide insight into the potential role of XPD polymorphisms in neuroblastoma risk. Our results failed to detect a role for any single XPD polymorphism in neuroblastoma risk. It is anticipated that ongoing epidemiological studies with larger samples and more analysis of confounding factors will provide additional information on the contribution of XPD polymorphisms to neuroblastoma tumorigenesis.

Materials and Methods

Study subjects

A total of 505 cases and 1070 healthy controls were included in this study. Of those, 429 cases and 884 controls were described in our previous study [39]. The additional 76 cases and 186 controls were from the Second Affiliated Hospital of Xi'an Jiaotong University (Supplemental Table 1). The cases were individuals diagnosed with neuroblastoma, and the controls were recruited from the same hospitals between September 2009 and March 2018. The eligibility criteria for the included subjects were described previously [49,5153]. Written informed consent was provided by all subjects or their guardians. The study protocols were approved by the Institutional Review Board of each hospital.

Polymorphism selection and genotyping

In brief, we searched for potentially functional candidate SNPs located in the 5’- flanking region, 5’ untranslated region, 3’ untranslated region, and exon of XPD. The potentially functional XPD polymorphisms were screened from the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP) and SNPinfo (https://snpinfo.niehs.nih.gov/snpinfo/snpfunc.html) using previously described criteria [54]. Three polymorphisms (rs3810366 G>C, rs13181 T>G, and rs238406 G>T) in the XPD gene were ultimately selected: rs3810366 G>C, which is located within transcription factor binding sites; rs13181 T>G and rs238406 G>T, which may affect splicing regulation activity; and rs13181 T>G, which may also lead to Lys751Gln alteration. As shown in Supplementary Figure 1, there was no significant LD (R2<0.8) between rs13181 and rs238406 (R2=0.026) or between rs13181 and rs3810366 (R2=0.001). However, there was a little LD between rs238406 and rs3810366 (R2=0.891).

For genotyping, DNA samples were mainly purified from venous blood using a TIANamp Blood DNA Kit (TianGen Biotech Co. Ltd., Beijing, China). Following standard methods, we used TaqMan real-time PCR to genotype the selected polymorphisms. Details of the genotyping protocol are provided elsewhere [5457]. To control for result quality, approximately 10% of the samples were randomly selected to perform duplicate analyses. We obtained a concordance rate of 100% for all duplicate sets.

Statistical analysis

We first used a goodness-of-fit χ2 test to assess whether the selected polymorphisms were in Hardy-Weinberg equilibrium in the controls. The demographic variables and allele frequencies were compared between the cases and controls using a two-sided χ2 test. The association between XPD polymorphisms and neuroblastoma risk was estimated using logistic regression analysis providing odds ratios (ORs) and 95% confidence intervals (CIs). Values of P<0.05 were considered significant. All statistical analyses were performed using the SAS statistical package (version 9.1, SAS Institute, Cary, NC).

Conflicts of Interest

No competing interests to declare.

Funding

This study was funded by grants from the Youth Science and Technology New Star Project of Shaanxi Province (No: 2018KJXX-050), Basic Scientific Research fee of Xi'an Jiaotong University (No: 1191329829 and No: YJ(ZD)201704), and the Pearl River S&T Nova Program of Guangzhou (No: 201710010086).

References

  • 1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007; 369:2106–20. https://doi.org/10.1016/S0140-6736(07)60983-0 [PubMed]
  • 2. Campbell K, Gastier-Foster JM, Mann M, Naranjo AH, Van Ryn C, Bagatell R, Matthay KK, London WB, Irwin MS, Shimada H, Granger MM, Hogarty MD, Park JR, DuBois SG. Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children’s Oncology Group. Cancer. 2017; 123:4224–35. https://doi.org/10.1002/cncr.30873 [PubMed]
  • 3. Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, Scott RH, Asgharzadeh S, Attiyeh EF, Diskin SJ, Laudenslager M, Winter C, Cole KA, Glessner JT, et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008; 358:2585–93. https://doi.org/10.1056/NEJMoa0708698 [PubMed]
  • 4. Gurney JG, Ross JA, Wall DA, Bleyer WA, Severson RK, Robison LL. Infant cancer in the U.S.: histology-specific incidence and trends, 1973 to 1992. J Pediatr Hematol Oncol. 1997; 19:428–32. https://doi.org/10.1097/00043426-199709000-00004 [PubMed]
  • 5. Bao PP, Li K, Wu CX, Huang ZZ, Wang CF, Xiang YM, Peng P, Gong YM, Xiao XM, Zheng Y. [Recent incidences and trends of childhood malignant solid tumors in Shanghai, 2002-2010]. Zhonghua Er Ke Za Zhi. 2013; 51:288–94. [PubMed]
  • 6. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A, et al, and INRG Task Force. The international Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009; 27:289–97. https://doi.org/10.1200/JCO.2008.16.6785 [PubMed]
  • 7. Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, Klingebiel T, Kremens B, Schilling FH, Schrappe M, Simon T, Hero B. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol. 2005; 6:649–58. https://doi.org/10.1016/S1470-2045(05)70291-6 [PubMed]
  • 8. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP, and Children’s Cancer Group. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med. 1999; 341:1165–73. https://doi.org/10.1056/NEJM199910143411601 [PubMed]
  • 9. Deyell RJ, Attiyeh EF. Advances in the understanding of constitutional and somatic genomic alterations in neuroblastoma. Cancer Genet. 2011; 204:113–21. https://doi.org/10.1016/j.cancergen.2011.03.001 [PubMed]
  • 10. Cheung NK, Dyer MA. Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 2013; 13:397–411. https://doi.org/10.1038/nrc3526 [PubMed]
  • 11. Bourdeaut F, Trochet D, Janoueix-Lerosey I, Ribeiro A, Deville A, Coz C, Michiels JF, Lyonnet S, Amiel J, Delattre O. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Cancer Lett. 2005; 228:51–58. https://doi.org/10.1016/j.canlet.2005.01.055 [PubMed]
  • 12. Mosse YP, Laudenslager M, Khazi D, Carlisle AJ, Winter CL, Rappaport E, Maris JM. Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet. 2004; 75:727–30. https://doi.org/10.1086/424530 [PubMed]
  • 13. Janoueix-Lerosey I, Lequin D, Brugières L, Ribeiro A, de Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008; 455:967–70. https://doi.org/10.1038/nature07398 [PubMed]
  • 14. Devoto M, Specchia C, Laudenslager M, Longo L, Hakonarson H, Maris J, Mossé Y. Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma. Hum Hered. 2011; 71:135–39. https://doi.org/10.1159/000324843 [PubMed]
  • 15. McDaniel LD, Conkrite KL, Chang X, Capasso M, Vaksman Z, Oldridge DA, Zachariou A, Horn M, Diamond M, Hou C, Iolascon A, Hakonarson H, Rahman N, et al. Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma. PLoS Genet. 2017; 13:e1006787. https://doi.org/10.1371/journal.pgen.1006787 [PubMed]
  • 16. Zhu S, Zhang X, Weichert-Leahey N, Dong Z, Zhang C, Lopez G, Tao T, He S, Wood AC, Oldridge D, Ung CY, van Ree JH, Khan A, et al. LMO1 synergizes with MYCN to promote Neuroblastoma initiation and metastasis. Cancer Cell. 2017; 32:310–323.e5. https://doi.org/10.1016/j.ccell.2017.08.002 [PubMed]
  • 17. Capasso M, Devoto M, Hou C, Asgharzadeh S, Glessner JT, Attiyeh EF, Mosse YP, Kim C, Diskin SJ, Cole KA, Bosse K, Diamond M, Laudenslager M, et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet. 2009; 41:718–23. https://doi.org/10.1038/ng.374 [PubMed]
  • 18. Diskin SJ, Capasso M, Diamond M, Oldridge DA, Conkrite K, Bosse KR, Russell MR, Iolascon A, Hakonarson H, Devoto M, Maris JM. Rare variants in TP53 and susceptibility to neuroblastoma. J Natl Cancer Inst. 2014; 106:dju047. https://doi.org/10.1093/jnci/dju047 [PubMed]
  • 19. Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, Diamond M, Carpenter EL, Winter C, Lee H, Jagannathan J, Latorre V, Iolascon A, et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet. 2012; 44:1126–30. https://doi.org/10.1038/ng.2387 [PubMed]
  • 20. Chang X, Zhao Y, Hou C, Glessner J, McDaniel L, Diamond MA, Thomas K, Li J, Wei Z, Liu Y, Guo Y, Mentch FD, Qiu H, et al. Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk. Nat Commun. 2017; 8:569. https://doi.org/10.1038/s41467-017-00408-8 [PubMed]
  • 21. Capasso M, Diskin S, Cimmino F, Acierno G, Totaro F, Petrosino G, Pezone L, Diamond M, McDaniel L, Hakonarson H, Iolascon A, Devoto M, Maris JM. Common genetic variants in NEFL influence gene expression and neuroblastoma risk. Cancer Res. 2014; 74:6913–24. https://doi.org/10.1158/0008-5472.CAN-14-0431 [PubMed]
  • 22. Capasso M, McDaniel LD, Cimmino F, Cirino A, Formicola D, Russell MR, Raman P, Cole KA, Diskin SJ. The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma. J Cell Mol Med. 2017; 21:3224–30. https://doi.org/10.1111/jcmm.13226 [PubMed]
  • 23. Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Science. 2001; 291:1284–89. https://doi.org/10.1126/science.1056154 [PubMed]
  • 24. Gillet LC, Schärer OD. Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem Rev. 2006; 106:253–76. https://doi.org/10.1021/cr040483f [PubMed]
  • 25. Li YL, Wei F, Li YP, Zhang LH, Bai YZ. A case-control study on association of nucleotide excision repair polymorphisms and its interaction with environment factors with the susceptibility to non-melanoma skin cancer. Oncotarget. 2017; 8:80994–1000. [PubMed]
  • 26. McWilliams RR, Bamlet WR, de Andrade M, Rider DN, Cunningham JM, Petersen GM. Nucleotide excision repair pathway polymorphisms and pancreatic cancer risk: evidence for role of MMS19L. Cancer Epidemiol Biomarkers Prev. 2009; 18:1295–302. https://doi.org/10.1158/1055-9965.EPI-08-1109 [PubMed]
  • 27. Hua RX, Zhuo ZJ, Zhu J, Zhang SD, Xue WQ, Zhang JB, Xu HM, Li XZ, Zhang PF, He J, Jia WH. XPG gene polymorphisms contribute to colorectal cancer susceptibility: a two-stage case-control study. J Cancer. 2016; 7:1731–39. https://doi.org/10.7150/jca.15602 [PubMed]
  • 28. Cleaver JE. Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmentosum. J Dermatol Sci. 2000; 23:1–11. https://doi.org/10.1016/S0923-1811(99)00088-2 [PubMed]
  • 29. Houten BV, Kuper J, Kisker C. Role of XPD in cellular functions: to TFIIH and beyond. DNA Repair (Amst). 2016; 44:136–42. https://doi.org/10.1016/j.dnarep.2016.05.019 [PubMed]
  • 30. Compe E, Egly JM. Nucleotide excision repair and transcriptional regulation: TFIIH and beyond. Annu Rev Biochem. 2016; 85:265–90. https://doi.org/10.1146/annurev-biochem-060815-014857 [PubMed]
  • 31. Ban EZ, Lye MS, Chong PP, Yap YY, Lim SY, Abdul Rahman H. Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia. PLoS One. 2017; 12:e0187200. https://doi.org/10.1371/journal.pone.0187200 [PubMed]
  • 32. Loghin A, Bănescu C, Nechifor-Boila A, Chibelean C, Orsolya M, Nechifor-Boila A, Tripon F, Voidazan S, Borda A. XRCC3 Thr241Met and XPD Lys751Gln gene polymorphisms and risk of clear cell renal cell carcinoma. Cancer Biomark. 2016; 16:211–17. https://doi.org/10.3233/CBM-150558 [PubMed]
  • 33. Mirecka A, Paszkowska-Szczur K, Scott RJ, Górski B, van de Wetering T, Wokołorczyk D, Gromowski T, Serrano-Fernandez P, Cybulski C, Kashyap A, Gupta S, Gołąb A, Słojewski M, et al. Common variants of xeroderma pigmentosum genes and prostate cancer risk. Gene. 2014; 546:156–61. https://doi.org/10.1016/j.gene.2014.06.026 [PubMed]
  • 34. Zhu ML, He J, Wang M, Sun MH, Jin L, Wang X, Yang YJ, Wang JC, Zheng L, Xiang JQ, Wei QY. Potentially functional polymorphisms in the ERCC2 gene and risk of esophageal squamous cell carcinoma in Chinese populations. Sci Rep. 2014; 4:6281. https://doi.org/10.1038/srep06281 [PubMed]
  • 35. Shore RE, Zeleniuch-Jacquotte A, Currie D, Mohrenweiser H, Afanasyeva Y, Koenig KL, Arslan AA, Toniolo P, Wirgin I. Polymorphisms in XPC and ERCC2 genes, smoking and breast cancer risk. Int J Cancer. 2008; 122:2101–05. https://doi.org/10.1002/ijc.23361 [PubMed]
  • 36. He J, Zou Y, Liu X, Zhu J, Zhang J, Zhang R, Yang T, Xia H. Association of common genetic variants in pre-microRNAs and Neuroblastoma susceptibility: a two-center study in Chinese children. Mol Ther Nucleic Acids. 2018; 11:1–8. https://doi.org/10.1016/j.omtn.2018.01.003 [PubMed]
  • 37. Zhang Z, Chang Y, Jia W, Zhang J, Zhang R, Zhu J, Yang T, Xia H, Zou Y, He J. LINC00673 rs11655237 C>T confers neuroblastoma susceptibility in Chinese population. Biosci Rep. 2018; 38:BSR20171667. https://doi.org/10.1042/BSR20171667 [PubMed]
  • 38. Zhuo ZJ, Liu W, Zhang J, Zhu J, Zhang R, Tang J, Yang T, Zou Y, He J, Xia H. Functional polymorphisms at ERCC1/XPF genes confer neuroblastoma risk in Chinese children. EBioMedicine. 2018; 30:113–19. https://doi.org/10.1016/j.ebiom.2018.03.003 [PubMed]
  • 39. Wang J, Zhuo Z, Chen M, Zhu J, Zhao J, Zhang J, Chen S, He J, Zhou H. RAN/RANBP2 polymorphisms and neuroblastoma risk in Chinese children: a three-center case-control study. Aging (Albany NY). 2018; 10:808–18. [PubMed]
  • 40. Flejter WL, McDaniel LD, Johns D, Friedberg EC, Schultz RA. Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene. Proc Natl Acad Sci USA. 1992; 89:261–65. https://doi.org/10.1073/pnas.89.1.261 [PubMed]
  • 41. Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol. 2001; 44:891–924. https://doi.org/10.1067/mjd.2001.114294 [PubMed]
  • 42. Takayama K, Salazar EP, Lehmann A, Stefanini M, Thompson LH, Weber CA. Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D. Cancer Res. 1995; 55:5656–63. [PubMed]
  • 43. Lye MS, Visuvanathan S, Chong PP, Yap YY, Lim CC, Ban EZ. Homozygous Wildtype of XPD K751Q polymorphism is associated with increased risk of nasopharyngeal carcinoma in Malaysian population. PLoS One. 2015; 10:e0130530. https://doi.org/10.1371/journal.pone.0130530 [PubMed]
  • 44. Paszkowska-Szczur K, Scott RJ, Serrano-Fernandez P, Mirecka A, Gapska P, Górski B, Cybulski C, Maleszka R, Sulikowski M, Nagay L, Lubinski J, Dębniak T. Xeroderma pigmentosum genes and melanoma risk. Int J Cancer. 2013; 133:1094–100. https://doi.org/10.1002/ijc.28123 [PubMed]
  • 45. Chen S, Zhu JH, Wang F, Huang SY, Xue WQ, Cui Z, He J, Jia WH. Association of the Asp312Asn and Lys751Gln polymorphisms in the XPD gene with the risk of non-Hodgkin’s lymphoma: evidence from a meta-analysis. Chin J Cancer. 2015; 34:108–14. https://doi.org/10.1186/s40880-015-0001-2 [PubMed]
  • 46. Rzeszowska-Wolny J, Polanska J, Pietrowska M, Palyvoda O, Jaworska J, Butkiewicz D, Hancock R. Influence of polymorphisms in DNA repair genes XPD, XRCC1 and MGMT on DNA damage induced by gamma radiation and its repair in lymphocytes in vitro. Radiat Res. 2005; 164:132–40. https://doi.org/10.1667/RR3400 [PubMed]
  • 47. Michalska MM, Samulak D, Romanowicz H, Sobkowski M, Smolarz B. An association between Single Nucleotide Polymorphisms of Lys751Gln ERCC2 gene and ovarian cancer in polish women. Adv Med. 2015; 2015:109593. https://doi.org/10.1155/2015/109593 [PubMed]
  • 48. Capasso M, Diskin SJ. Genetics and genomics of neuroblastoma. Cancer Treat Res. 2010; 155:65–84. https://doi.org/10.1007/978-1-4419-6033-7_4 [PubMed]
  • 49. He J, Wang F, Zhu J, Zhang R, Yang T, Zou Y, Xia H. Association of potentially functional variants in the XPG gene with neuroblastoma risk in a Chinese population. J Cell Mol Med. 2016; 20:1481–90. https://doi.org/10.1111/jcmm.12836 [PubMed]
  • 50. Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, Guo Z, Lei L, Mohrenweiser H, Wei Q. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res. 2001; 61:1354–57. [PubMed]
  • 51. Zhang J, Lin H, Wang J, He J, Zhang D, Qin P, Yang L, Yan L. LMO1 polymorphisms reduce neuroblastoma risk in Chinese children: a two-center case-control study. Oncotarget. 2017; 8:65620–26. [PubMed]
  • 52. He J, Wang F, Zhu J, Zhang Z, Zou Y, Zhang R, Yang T, Xia H. The TP53 gene rs1042522 C>G polymorphism and neuroblastoma risk in Chinese children. Aging (Albany NY). 2017; 9:852–59. [PubMed]
  • 53. He J, Zou Y, Wang T, Zhang R, Yang T, Zhu J, Wang F, Xia H. Genetic variations of GWAS-identified genes and neuroblastoma susceptibility: a replication study in southern chinese children. Transl Oncol. 2017; 10:936–41. https://doi.org/10.1016/j.tranon.2017.09.008 [PubMed]
  • 54. He J, Qiu LX, Wang MY, Hua RX, Zhang RX, Yu HP, Wang YN, Sun MH, Zhou XY, Yang YJ, Wang JC, Jin L, Wei QY, Li J. Polymorphisms in the XPG gene and risk of gastric cancer in Chinese populations. Hum Genet. 2012; 131:1235–44. https://doi.org/10.1007/s00439-012-1152-8 [PubMed]
  • 55. Gong J, Tian J, Lou J, Wang X, Ke J, Li J, Yang Y, Gong Y, Zhu Y, Zou D, Peng X, Yang N, Mei S, et al. A polymorphic MYC response element in KBTBD11 influences colorectal cancer risk, especially in interaction with an MYC-regulated SNP rs6983267. Ann Oncol. 2018; 29:632–39. https://doi.org/10.1093/annonc/mdx789 [PubMed]
  • 56. Li J, Zou L, Zhou Y, Li L, Zhu Y, Yang Y, Gong Y, Lou J, Ke J, Zhang Y, Tian J, Zou D, Peng X, et al. A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population. Mol Carcinog. 2017; 56:1798–807. https://doi.org/10.1002/mc.22637 [PubMed]
  • 57. Lou J, Gong J, Ke J, Tian J, Zhang Y, Li J, Yang Y, Zhu Y, Gong Y, Li L, Chang J, Zhong R, Miao X. A functional polymorphism located at transcription factor binding sites, rs6695837 near LAMC1 gene, confers risk of colorectal cancer in Chinese populations. Carcinogenesis. 2017; 38:177–83. [PubMed]