Journal of Cancer Research and Therapeutics

REVIEW ARTICLE
Year
: 2013  |  Volume : 9  |  Issue : 2  |  Page : 187--192

Genetic polymorphisms of xeroderma pigmentosum group D and prostate cancer risk: A meta-analysis


Hongcheng Zhu1, Songyu Cao2, Yun Liu3, Xiangxiang Ding3, Qianqian Wu3, Hongxia Ma2,  
1 Department of Epidemiology and Biostatistics, Ministry of Education Key Lab for Modern Toxicology, School of Public Health; The First Clinical Medical College, Nanjing Medical University, Nanjing 210029, China
2 Department of Epidemiology and Biostatistics, Ministry of Education Key Lab for Modern Toxicology, School of Public Health, Nanjing, China
3 The First Clinical Medical College, Nanjing Medical University, Nanjing 210029, China

Correspondence Address:
Hongxia Ma
Department of Epidemiology and Biostatistics, School of public health, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029
China

Abstract

Introduction: The Xeroderma pigmentosum group D (XPD, also referred to as excision repair cross complementing gene 2, ERCC2) is one of key genes involved in nucleotide excision repair and two potentially functional polymorphisms of XPD (Asp312Asn and Lys751Gln) have been widely investigated in various cancers including prostate cancer. However, the results were conflicting rather than conclusive. Aims: Thus, we conducted a meta-analysis to evaluate the associations between these two polymorphisms of XPD and the risk of prostate cancer. Materials and Methods: An electronic search of PubMed and Embase was conducted to select relevant studies. Studies containing available genotype frequencies of XPD Asp312Asn and Lys751Gln were chosen, and the associations were assessed by pooled odds ratios with 95% confidence intervals. Results: According to PubMed and Embase databases, we identified seven eligible studies from six articles, including 2641 cases and 3259 controls for Asp312Asn and nine eligible studies from eight articles, including 3255 cases and 3654 controls for Lys751Gln. The meta-analysis showed that no overall association was observed between XPD Asp312Asn and prostate cancer risk. However, the significantly increased risk of 312Asp allele was found among Asians and Africans, but it seemed to be protective in Caucasians when stratified by ethnicity. For XPD Lys751Gln, overall findings had implicated null effects. Conclusion: These findings indicated that the Asn allele of XPD Asp312Asn might be a risk-factor for developing prostate cancer among Asian and African men but protective for Caucasian population.



How to cite this article:
Zhu H, Cao S, Liu Y, Ding X, Wu Q, Ma H. Genetic polymorphisms of xeroderma pigmentosum group D and prostate cancer risk: A meta-analysis.J Can Res Ther 2013;9:187-192


How to cite this URL:
Zhu H, Cao S, Liu Y, Ding X, Wu Q, Ma H. Genetic polymorphisms of xeroderma pigmentosum group D and prostate cancer risk: A meta-analysis. J Can Res Ther [serial online] 2013 [cited 2020 Apr 1 ];9:187-192
Available from: http://www.cancerjournal.net/text.asp?2013/9/2/187/113345


Full Text

 Introduction



Prostate cancer (PCa) is one of the most common non-cutaneous cancers in the world, accounting for 10% cancer-related death among men. [1] The etiology of PCa is still not fully understood, while both genetic and environmental factors may contribute to the risk of this disease. [2] Studies have shown that endogenous (e.g., inflammation, androgens) and exogenous (e.g., fat, environmental toxins) compounds can damage DNA and induce the instability of genome, [3],[4],[5],[6] but DNA repair mechanisms protect the genome from DNA damage caused by such agents. Accumulating evidence indicates that genetic variants, such as single nucleotide polymorphisms (SNPs) in the DNA repair genes may affect the DNA repair capacity (DRC) and risk of cancers. [7]

Among four main DNA repair pathways, nucleotide excision repair (NER) is an important one, which is responsible for removing bulky lesions and simple base modifications. [8] The xeroderma pigmentosum group D (XPD, also referred to as excision repair cross complementing gene 2, ERCC2) gene, is a vital subunit of the general transcription factor II H (TFIIH), which is not only involved in transcription but is also an essential component of the NER pathway. [9],[10] Studies have shown that different mutations in the XPD gene diminish the helicase activity and evidently result in a defect in NER and transcription activities. [11],[12],[13] A lot of molecular epidemiological studies have explored the associations between SNPs in XPD gene and cancer risk, including PCa. Among them, Asp312Asn (rs1799793, mapped at exon 10, G > A) and Lys751Gln (rs13181, mapped at exon 23, A > C) had been most widely investigated. Studies have shown these two SNPs may be potentially functional and associated with decreased DRC, increased frequency of p53 mutations, and increased tumor risks. [14],[15],[16],[17],[18],[19],[20],[21],[22] For the associations between XPD Asp312Asn polymorphisms and PCa risk, the results were inconclusive. For example, Rybicki et al., first reported that XPD 312Asn allele exerted a modest positive effect on increasing PCa risk through a family-based case-control study in the United States. Bau et al., and Mandal et al., also found that 312Asn was associated with the increased risk of PCa in Asians . [7],[23],[24] However, some other studied [25],[26],[27] found no association between this SNP and PCa risk. For XPD Lys751Gln polymorphisms, all eligible articles reported that there was no significant association between this SNP and PCa risk, but the evidence was not strong enough in each single study because of a relative small sample size. [7],[23],[24],[26],[27],[28],[29],[30]

Therefore, we performed a comprehensive meta-analysis including all the eligible studies on these two SNPs and PCa risk to derive a more precise estimation for the associations of the both polymorphisms (XPD Asp312Asn and Lys751Gln) with PCa risk.

 Materials and Methods



Literature search strategy

Eligible studies were identified by searching the PubMed and Embase databases for relevant reports before March 6 th 2012 using the following search terms: "DNA repair gene or XPD or ERCC2", "polymorphism or polymorphisms" and "prostate cancer (PCa)". Besides, additional studies were identified from references of the original articles. Studies meeting all of the following criteria were included in our meta-analysis: (1) published in English, (2) case-control study design, (3) detailed Asp312Asn or Lys751Gln genotype information, (4) the most recent study was chosen if studies had overlapping patients or controls. Meeting abstracts, unpublished reports, and review articles were not considered. Finally, nine articles were eligible, including 2641 cases and 3259 controls for Asp312Asn and 3255 cases and 3654 controls for Lys751Gln.

Data extraction

To improve the reliability of data, information was extracted from all eligible publications by two investigators independently according to the following characteristics : f0 irst author's name, year of publication, distribution area, ethnicity, source of controls and number of genotyped patients and controls. The frequencies of the Asn allele for XPD codon 312 and Gln allele for XPD codon 751 were calculated for patients and controls from the corresponding genotype distributions. When articles included subjects of more than one ethnicity, data was extracted separately for future subgroup analysis.

Statistical analysis

The risks of PCa associated with the XPD Asp312Asn and Lys751Gln were estimated by odds ratios (ORs), with the corresponding 95% CIs. Pearson's goodness-of-fit χ2 test with 1° of freedom was used in the control groups of each study to check the frequencies of genotypes. [31] For XPD Asp312Asn polymorphisms, we estimated the effect of variant homozygote (Asn/Asn or AA) and heterozygote (Asp/Asn or GA) compared with the wild-type homozygote (Asp/Asp or GG). Moreover, the pooled ORs were performed for dominant model (AA/GA vs. GG) and recessive model (AA vs. GA/GG), respectively. For the Lys751Gln polymorphisms, similar estimations were done : t0 he variant homozygote (Gln/Gln or CC) versus the wild-type homozygote (Lys/Lys or AA), the heterozygote (Lys/Gln or AC) versus the wild-type homozygote (Lys/Lys or AA), the dominant model (CC/AC vs. AA) and the recessive model (CC vs. CC + CA). The χ2 -based Q statistic test was used for the assessment of heterogeneity, and it was considered significant for P < 0.10. Fixed-effects model and the random-effects model based on the Mantel-Haenszel method and the DerSimonian and Laird method were respectively used to combine values from a single study. [32] When the effects were assumed to be homogenous, the fixed-effects model was used; otherwise, the random-effects model was more appropriate. Publication bias was diagnosed graphically by using funnel plots and assessed statistically using the Egger's test (P < 0.05 was considered representative of statistically significant publication bias). [33] In addition to the comparisons of all the subjects, subgroup analyses were performed by ethnicity. All the statistical tests were performed with STATA version 11.0 (Stata Corporation, College Station, TX, USA). All P values are two-sided.

 Results



Characteristics of eligible studies

Nine articles were finally included in the meta-analysis. The races of all the subjects included Caucasians, Asians and Africans. In the study of Rybicki et al.,[23] the genotyping distributions of Caucasians, Asians and Africans were not given, so it was considered as the mixed population in subgroup analyses by ethnicity. Furthermore, another study by Agalliu et al., provided the genotyping distributions in both Caucasians and Africans, and thus it was divided into two studies in subgroup analysis by ethnicity. [26] For XPD Asp312Asn, seven studies from six eligible articles including 2641 cases and 3259 controls explored the association of this SNP with PCa risk. [7],[23],[24],[25],[26],[27] For XPD Lys751Gln, nine studies from eight articles with 3255 cases and 3654 controls were included in the analysis [Table 1]. [7],[23],[24],[26],[27],[28],[29],[30]{Table 1}

Quantitative synthesis

[Table 2] lists the main results of the meta-analysis for XPD Asp312Asn, and PCa risk. Overall, no significant association was found between this genetic polymorphism and PCa risk. However, when evaluating the effects of the Asp312Asn polymorphism on PCa risk among subgroups by ethnicity, a significantly increased risk was observed in both Asians (Asn/Asn vs. Asp/Asp: odds ratio (OR) = 2.09, 95% confidence interval (CI) = 1.39 3.15, P = 0.38 for heterogeneity test; dominant model: OR = 1.49, 95% CI = 1.12 - 1.98, P = 0.19 for heterogeneity test; recessive model: OR = 1.93, 95% CI = 1.31 - 2.84, P = 0.13 for heterogeneity test) and Africans (Asn/Asn vs. Asp/Asp: OR = 2.80, 95% CI = 1.01, 7.74, P = 0.63 for heterogeneity test), but a decreased risk for Caucasians (Asn/Asn vs. Asp/Asp: OR = 0.71, 95% CI = 0.55 - 0.92, P = 0.62 for heterogeneity test; recessive model: OR = 0.69, 95% CI = 0.54 - 0.88, P = 0.58 for heterogeneity test).{Table 2}

[Figure 1] shows the main results of the meta-analysis of XPD Lys751Gln and prostate cancer. However, no significant association was found between this genetic polymorphism and PCa risk in either overall and subgroup analysis.{Figure 1}

Sensitivity analysis

Substantial heterogeneity was found among different studies for XPD Asp312Asn (Asn/Asn versus Asp/Asp: χ2 = 27.14, df = 5, P < 0.001 and I2 = 81.6% for heterogeneity test) but not among the studies for XPD Lys751Gln (Gln/Gln versus Lys/Lys: χ2 = 5.73, df = 7, P = 0.57 and I2 = 0.0% for heterogeneity test). Therefore, we only assessed the source of heterogeneity for Asn/Asn genotype (Asn/Asn versus Asp/Asp) by ethnicity (P < 0.001). However, the results showed that the observed heterogeneity was not mainly induced by the difference of ethnicity, which only explained 4.58% of the heterogeneity between studies.

Additionally, two [7],[23] of the studies was not consistent with Hardy-Weinberg equilibrium (HWE P value < 0.05), so we evaluated the results when excluding these two studies. The overall result showed that the results for Asn/Asn versus Asp/Asp model had no significant change after the exclusion (Total: OR = 1.42, 95% CI = 0.61 - 3.35; P < 0.001 for heterogeneity test; Caucasian: OR = 0.71, 95% CI=0.55 - 0.92; P = 0.62 for heterogeneity test; African: OR = 2.80, 95% CI=1.01 - 7.74, P = 0.64 for heterogeneity test).

Publication bias

Publication bias of literatures was assessed by Begg's funnel plot and Egger's test. The shape of the funnel plots of the two SNPs did not reveal any evidence of asymmetry [Figure 2] and [Figure 3]. Egger's test was further used to provide statistical evidence for the funnel plot symmetry. [33] We observed that publication biases might not have had a significant influence on the results of the XPD Asp312Asn genotype (t = 2.24, P = 0.09) and the XPD Lys751Gln genotype (t = 1.79, P = 0.12).{Figure 2}{Figure 3}

 Discussion



In this meta-analysis, we pooled seven eligible studies from six literatures, including 2641 cases and 3259 controls for Asp312Asn and nine eligible studies from eight literatures, including 3255 cases and 3654 controls for Lys751Gln to investigate the associations between polymorphisms of XPD and prostate cancer risk. When stratified by ethnicity, significantly increased risk of 312Asp allele of XPD Asp312Asn was found among Asians and Africans while it seemed to a protective factor in Caucasians.

The XPD gene is mapped to chromosome 19q13.3, and spans over 20 kb, containing 23 exons and encoding a 761-amino acid protein. [34] The XPD protein is a kind of DNA helicase involved in transcriptions and NER. [35] Studies have showed that two potentially functional polymorphisms of XPD (Asp → Asn at position of 312 and Lys → Gln at position 751) may result in complete changes of the configuration of the amino acid and thus affect interactions of XPD protein and its helicase activator. [36] Furthermore, these two polymorphisms had been widely investigated and reported the association with various cancers. There were also several studies conducted to examine the association between these two SNPs and the susceptibility to prostate cancer, but the results remain controversial rather than consistent. [7],[23],[24],[25],[26],[27],[28],[29],[30] Meta-analysis have shown that these two SNPs are associated with the risk of lung cancer, esophageal cancer and bladder cancer but have no association with breast cancer, colorectal cancer, et al. [34],[37],[38],[39],[40],[41] However, no explicit results of meta-analysis of the two SNPs and prostate cancer risk existed. So in this study, we performed a meta-analysis by pooling nine articles and indicated that XPD Asp312Asn may play the different role in the PCa risk in different populations. For example, XPD Asp312Asn polymorphism seemed to increase PCa risk in both Asians and African subjects but decrease the risk in Caucasians. Additionally, the heterogeneity test also indicated a significant heterogeneity in different ethnic groups. The possible reasons may be the difference in genetic background or the environment they lived in. However, because there were only seven studies included in our meta-analysis, results still need the validation from other larger studies. For XPD Lys751Gln polymorphism, it still showed that no significant association was observed between this SNP and PCa risk, suggesting that this SNP might not be associated with the risk of PCa risk.

Our meta-analyses also had some limitations. First, relatively small samples were included for the assessment, partly due to the limited original articles and limited English publications. Second, the controls were not uniformly defined. For example, one study [26] used healthy population as the reference group; three studies [7],[25],[27] selected hospital patients without organic prostate cancer, and another study [23] recruited controls from the brothers of cases. Furthermore, the other two studies did not provide the explicit source of controls. Third, no test for gene-environment interactions was done in the analysis due to the lack of sufficient information. Thus, larger and well-designed studies are essential to further evaluate the association between these two SNPs and PCa risk.

 Acknowledgement



This work was supported by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

References

1Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96.
2Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer - Analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343:78-85.
3Pathak SK, Sharma RA, Steward WP, Mellon JK, Griffiths TR, Gescher AJ. Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: Targets for chemopreventive strategies. Eur J Cancer 2005;41:61-70.
4Khandrika L, Kumar B, Koul S, Maroni P, Koul HK. Oxidative stress in prostate cancer. Cancer Lett 2009;282:125-36.
5Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB J 2003;17:1195-214.
6Sikka SC. Role of oxidative stress response elements and antioxidants in prostate cancer pathobiology and chemoprevention - A mechanistic approach. Curr Med Chem 2003;10:2679-92.
7Bau DT, Wu HC, Chiu CF, Lin CC, Hsu CM, Wang CL, et al. Association of XPD polymorphisms with prostate cancer in Taiwanese patients. Anticancer Res 2007;27:2893-6.
8Christmann M, Tomicic MT, Roos WP, Kaina B. Mechanisms of human DNA repair: An update. Toxicology 2003;193:3-34.
9Benhamou S, Sarasin A. ERCC2 /XPD gene polymorphisms and lung cancer: A HuGE review. Am J Epidemiol 2005;161:1-14.
10Fuss JO, Tainer JA. XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase. DNA Repair (Amst) 2011;10:697-713.
11Wang Z, Svejstrup JQ, Feaver WJ, Wu X, Kornberg RD, Friedberg EC. Transcription factor b (TFIIH) is required during nucleotide-excision repair in yeast. Nature 1994;368:74-6.
12Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, et al. Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. Nature 1994;368:769-72.
13Taylor EM, Broughton BC, Botta E, Stefanini M, Sarasin A, Jaspers NG, et al. Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. Proc Natl Acad Sci U S A 1997;94:8658-63.
14Rzeszowska-Wolny J, Polanska J, Pietrowska M, Palyvoda O, Jaworska J, Butkiewicz D, et al. 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.
15Affatato AA, Wolfe KJ, Lopez MS, Hallberg C, Ammenheuser MM, Abdel-Rahman SZ. Effect of XPD/ERCC2 polymorphisms on chromosome aberration frequencies in smokers and on sensitivity to the mutagenic tobacco-specific nitrosamine NNK. Environ Mol Mutagen 2004;44:65-73.
16Mechanic LE, Marrogi AJ, Welsh JA, Bowman ED, Khan MA, Enewold L, et al. Polymorphisms in XPD and TP53 and mutation in human lung cancer. Carcinogenesis 2005;26:597-604.
17Stern MC, Conway K, Li Y, Mistry K, Taylor JA. DNA repair gene polymorphisms and probability of p53 mutation in bladder cancer. Mol Carcinog 2006;45:715-9.
18Suárez-Martínez EB, Ruiz A, Matías J, Morales L, Cruz A, Vázquez D, et al. Early-onset of sporadic basal-cell carcinoma: Germline mutations in the TP53, PTCH, and XPD genes. P R Health Sci J 2007;26:349-54.
19Wang F, Chang D, Hu FL, Sui H, Han B, Li DD, et al. DNA repair gene XPD polymorphisms and cancer risk: A meta-analysis based on 56 case-control studies. Cancer Epidemiol Biomarkers Prev 2008;17:507-17.
20Stern MC, Johnson LR, Bell DA, Taylor JA. XPD codon 751 polymorphism, metabolism genes, smoking, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:1004-11.
21Sreeja L, Syamala VS, Syamala V, Hariharan S, Raveendran PB, Vijayalekshmi RV, et al. Prognostic importance of DNA repair gene polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln in lung cancer patients from India. J Cancer Res Clin Oncol 2008;134:645-52.
22De Ruyck K, Szaumkessel M, De Rudder I, Dehoorne A, Vral A, Claes K, et al. Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk. Mutat Res 2007;631:101-10.
23Rybicki BA, Conti DV, Moreira A, Cicek M, Casey G, Witte JS. DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2004;13:23-9.
24Mandal RK, Gangwar R, Mandhani A, Mittal RD. DNA repair gene X-ray repair cross-complementing group 1 and xeroderma pigmentosum group D polymorphisms and risk of prostate cancer: A study from North India. DNA Cell Biol 2010;29:183-90.
25Dhillon VS, Yeoh E, Fenech M. DNA repair gene polymorphisms and prostate cancer risk in South Australia - Results of a pilot study. Urol Oncol 2011;29:641-6.
26Agalliu I, Kwon EM, Salinas CA, Koopmeiners JS, Ostrander EA, Stanford JL. Genetic variation in DNA repair genes and prostate cancer risk: Results from a population-based study. Cancer Causes Control 2010;21:289-300.
27Lavender NA, Komolafe OO, Benford M, Brock G, Moore JH, Vancleave TT, et al. No association between variant DNA repair genes and prostate cancer risk among men of African descent. Prostate 2010;70:113-9.
28Ritchey JD, Huang WY, Chokkalingam AP, Gao YT, Deng J, Levine P, et al. Genetic variants of DNA repair genes and prostate cancer: A population-based study. Cancer Epidemiol Biomarkers Prev 2005;14:1703-9.
29Gao R, Price DK, Dahut WL, Reed E, Figg WD. Genetic polymorphisms in XRCC1 associated with radiation therapy in prostate cancer. Cancer Biol Ther 2010;10:13-8.
30Sobti RC, Berhane N, Melese S, Mahdi SA, Gupta L, Thakur H, et al. Impact of XPD gene polymorphism on risk of prostate cancer on north Indian population. Mol Cell Biochem 2012;362:263-8.
31Schaid DJ, Jacobsen SJ. Biased tests of association: Comparisons of allele frequencies when departing from Hardy-Weinberg proportions. Am J Epidemiol 1999;149:706-11.
32Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48.
33Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
34Yuan L, Cui D, Zhao EJ, Jia CZ, Wang LD, Lu WQ. XPD Lys751Gln polymorphism and esophageal cancer risk: A meta-analysis involving 2288 cases and 4096 controls. World J Gastroenterol 2011;17:2343-8.
35Sung P, Bailly V, Weber C, Thompson LH, Prakash L, Prakash S. Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 1993;365:852-5.
36Pavanello S, Pulliero A, Siwinska E, Mielzynska D, Clonfero E. Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B a PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers. Carcinogenesis 2005;26:169-75.
37Zhang Y, Ding D, Wang X, Zhu Z, Huang M, He X. Lack of association between XPD Lys751Gln and Asp312Asn polymorphisms and colorectal cancer risk: A meta-analysis of case-control studies. Int J Colorectal Dis 2011;26:1257-64.
38Zhan P, Wang Q, Wei SZ, Wang J, Qian Q, Yu LK, et al. ERCC2/XPD Lys751Gln and Asp312Asn gene polymorphism and lung cancer risk: A meta-analysis involving 22 case-control studies. J Thorac Oncol 2010;5:1337-45.
39Zhang J, Qiu LX, Leaw SJ, Hu XC, Chang JH. The association between XPD Asp312Asn polymorphism and lung cancer risk: A meta-analysis including 16,949 subjects. Med Oncol 2011;28:655-60.
40Li C, Jiang Z, Liu X. XPD Lys(751)Gln and Asp (312)Asn polymorphisms and bladder cancer risk: A meta-analysis. Mol Biol Rep 2010;37:301-9.
41Pabalan N, Francisco-Pabalan O, Sung L, Jarjanazi H, Ozcelik H. Meta-analysis of two ERCC2 (XPD) polymorphisms, Asp312Asn and Lys751Gln, in breast cancer. Breast Cancer Res Treat 2010;124:531-41.