Introduction

Prostate cancer (PCa) is the most common male non-dermatological cancer in Europe and the USA, and the sixth leading cause of cancer related-deaths, accounting for 14% (903, 500) of total new diagnosed cancer cases and 6% (258, 400) of whole cancer deaths in males in 2008 [1]. Despite its high incidence and morbidity, the etiology of PCa remains largely unknown, only age, ethnicity, diet and a family history are established risk factors. It is well established that genetic factor also play an important role in pathogenesis of PCa [2], [3].

Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens, including ultraviolet (UV) light, cigarette smoke, dietary factors, reactive oxygen species, and carcinogens. Most of these alterations, if not repaired, can result in genetic instability, mutagenesis and cell death. Because DNA repair pathways (DRP) play a critical role in maintaining the genomic integrity in general and specialized functions of cell as well as in the prevention of carcinogenesis, therefore the defection of those genes in DRP can lead to highter susceptibility to multiple cancers [4], [5].

There are a number of DRP, each responsible for repairing a different type of DNA damage. Base excision repair (BER) removes simple base modifications, including single-strand breaks, oxidative DNA damage, and alkylation and nonbulky adducts [6]. Nucleotide excision repair (NER) removes larger lesions, which often result from environmental damage, including UV radiation and external carcinogens [7]. Alkyltransferases directly reverse DNA damage by transferring alkyl groups from damaged DNA onto the transferase enzyme [8]. Double-stranded DNA breaks are repaired through mechanisms including the homologous recombination repair pathway [9]. Sequence variants in DNA repair genes also are thought to modulate DNA repair capacity and consequently may be associated with altered cancer risk [10].

The xeroderma pigmentosum group D (XPD) gene encoding for NER protein is located on chromosome 19q 13.3. It comprises 23 exons and spans about 54,000 base pairs [11], [12]. The XPD gene, also known as excision repair cross-complementing rodent repair deficiency Group 2 (ERCC2), is important in environmentally induced cancer [13]. XPD is an enzyme in the NER pathway that removes certain DNA cross-links, UV photo-lesions, and bulky chemical adducts [14]. Mutations in the XPD gene can completely prevent DNA opening and dual incision, steps that lead to the repair of DNA adducts [15].

Two common non-synonymous single-nucleotide polymorphisms (SNP) in the coding region of the XPD gene have been identified: a G→A substitution causing exon 10 codon 312 Asp to be exchanged for Asn (Asp312Asn, D312N, G23592A, rs1799793) and an A→C substitution causing exon 23 codon 751 Lys to be substituted for Gln (Lys751Gln, L751Q, A35931C, rs13181) [16], [17]. These two polymorphisms are associated with lower DNA repair capacity and a higher level of DNA adducts [17], [18].

Several epidemiologic studies have examined associations between SNPs in DNA repair genes, mostly non-synonymous SNPs in XPD gene with potential functional significance and risk of PCa [19]–[26]. However, results have been inconsistent across these studies due in part to different study populations, case ascertainment, or due to small sample sizes of each study and thus the potential for false-positive findings as well as limited power to detect modest associations. The objective of our study was to examine associations between two XPD polymorphisms and risk of PCa in larger samples by meta-analysis.

Materials and Methods

Results

Studies characteristics

A total of 29 articles were achieved by literature search from the Pubmed and Embase, using different combinations of key terms. As shown in Figure 1, nine eligible studies were retrieved for detailed evaluation. We excluded 20 studies: 12 were reduplicate, one article type was review, 3 papers were about other cancer types (ovarian cancer, colorectal adenoma and non-melanoma skin cancer), two were not relate to case-control studies and last article was about SNP-SNP interactions not for single SNP polymorphism. Finally, we identified 8 articles (9 case-control studies, 3165 cases and 3539 controls) for Gln751Lys polymorphism and 6 articles (7 case-control studies, 2555 cases and 3182 controls) for Asn312Asp polymorphism to evaluate the association with risk for PCa, respectively (Table S1). The distribution of genotypes among controls was consistent with HWE in all studies except two [16], [19]. To our regret, in all of included studies, the diet and a family history of PCa were not established. With the exception of two studies (Gao et al and Lavender et al), the age between cases and controls was matched. Control population including all consisted of study participants with a normal digital rectal examination (DRE) and serum prostatic specific antigen (PSA) values of <4 ng/ml, as well as old matched men, not cancer family history and not previous cancer history. Rybicki et al. [16] reported a case-control study that 90% were Caucasians, 9% were African-Americans, and only 1% were Asians or Hispanics, we selected the primarily Caucasians in our meta. For the Gln751Lys polymorphism, three studies had been conducted on Caucasians, four on Asians, two studies on Africans. Two studies were HB; the others were PB. For the Asn312Asp polymorphism, there had 3 studies about Caucasians, 2 about Africans and 2 about Asians; three studied came from HB and 4 from PB. Two studies [25], [26] refered to Gleason scoring system and clinical tumor stage (Table 1). The genotyping methods included PCR-FLIP (polymerase chain reaction and restrictive fragment length polymorphism), ABI SNPlex (Applied Biosystems SNPlex™ Genotyping system), ARM-PCR (amplification refractory mutation-specific polymerase chain reaction) and MALDI-TOF-MS (matrix-assisted laser desorption ionization time of flight mass spectrometry).

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Figure 1. Flow chart of selection studies in our meta-analysis.

https://doi.org/10.1371/journal.pone.0044756.g001

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Table 1. The number of different genotypes of two polymorphisms of XPD gene in PCa cases and the relationship in clinical characteristics.

https://doi.org/10.1371/journal.pone.0044756.t001

Discussion

The identification of SNPs that affect gene function or expression and contribute to PCa susceptibility is important to help predict individual and population risk and understand the pathogenesis of PCa. Rybicki et al. first found XPD two common polymorphisms to be associated with the risk of PCa in a Caucasian population in 2004 [16]. After that, several investigators duplicated his work in different populations. However, the results remained confusing, even within the same population. Meta-analysis is a means of increasing the effective sample size under investigation through the pooling of data from individual association studies, thus enhancing the statistical power of the analysis for the estimation of genetic effects [32]. The two XPD polymorphisms have been associated with the risk of head and neck cancer [33], esophageal cancer [34], lung cancer [35] and breast cancer [36]. However, the relationship between these two polymorphisms and PCa susceptibility is undetermined. In our present study, we analyzed the associations between XPD two SNPs (Asn312Asp/Gln751Lys) and PCa risk by using meta method to get a powerful conclusion. The potential role of XPD two polymorphisms as determinant of PCa risk was investigated in a sample of 6752 subjects (3165 cases and 3539 controls for Gln751Lys and 2555 cases and 3182 controls for Asn312Asp) from nine published case-control studies.

Little is know for sure about the underlying mechanism for this association. The XPD gene has been mapped in chromosome 19q13.3. It spans over 20 kb, contains 23 exons and encodes the 761-amino acid protein. The XPD protein, on one hand, possesses both single-strand DNA-dependant ATPase and 5′-3′ DNA helicase activities, which is essential for NER pathway and transcription; on the other hand, is absolutely necessary for efficient DNA repair capacity, which is essential for the maintenance of genetic stability and associated with cancer susceptibility when incompetent [13], [37]. Two common SNPs in XPD gene are in linkage disequilibrium, and their mutant phenotypes have shown to be associated with lower DNA repair capacity [18], which means these SNPs may contribute to carcinogenesis and can be as risk factors for cancer development. Many epidemiological studies have investigated the association between two XPD polymorphisms and PCa, but the results were inconclusive. Bau et al. [19] reported a 1.81-fold increased PCa risk in individuals who carry at least 1 mutant allele for the Asn312Asp or Gln751Lys polymorphism. Similarly, Rybicki et al. [16] also reported a modest increase in PCa risk (OR 1.16 and 1.14) in individuals if they are carriers of the rarer variant genotype (312Asn/Asn or 751Gln/Gln, respectively). Lavender et al. [24] found that individuals possessing at least one XPD 312 Asn allele had a 1.3- to 8.6-fold higher PCa risk when compared to those with the 312 Asp/Asp genotype, however, there were no significant differences in the allele frequencies between cases and controls for Gln751Lys polymorphism. Our study showed similar observation with Lavender et al. [24] and Mandal et al. [26].

In present study, no significant association was found under any genetic model in the overall analysis. However, in the stratified analysis by ethnicity, significant increased associations were detected between XPD Asn312Asp not Gln751Lys polymorphism and PCa among Asian and African populations. There must be some factors that would contribute to this discrepancy. First, multiple genes and environmental factors may lead to PCa formation. Second, ethnicity may be related to PCa incidence. For example, PCa is the most common non-cutaneous malignancy and the second leading cause of cancer mortality in Western men. In contrast to the trends of western countries, incidence and mortality rates are rising in several Asian and central/eastern-European countries, such as Japan, China and Poland, suggesting an increasingly westernized lifestyle in these regions [38], [39]. Finally, time lag bias and publication bias may also play a role in this meta-analysis.

We all know that the Gleason score grading system has withstood the test of time as a predictor of PCa outcome. Additionally, the tumor stage of PCa is central to management because it contributes both to predicting prognosis and planning treatment. In the current study, the frequency of PCa cases carried 312Asn/Asn genotype in early stage cases was more higher than in advanced stage cases, in addition, Asn/Asn genotype was associated with increased PCa risk, thus, we predicted 312Asn/Asn genotype could poorly help us to detect PCa and evaluate its prognosis. No association was detected between clinical characteristics of PCa and Gln751Lys SNP.

Although, we have put considerable efforts and resources into testing possible association between XPD polymorphisms and PCa risk, there are still some limitations inherited from the published studies. First, although we collected all the eligible studies, the sample size of the included studies was not large enough, which could increase the likehood of type I and type II errors. Therefore, there was a lack of statistical power to better evaluate the association between XPD polymorphisms and PCa risk, especially in subgroup analysis by ethnicity. Second, gene-gene and gene-environment interactions were not analyzed. It is possible that specific environmental and lifestyle factors may alter those associations between gene polymorphisms and PCa. Therefore, it is necessary to evaluate the roles of some special environment factors and lifestyles such as diet, alcohol consumption and smoking status and cancer family history. Third, two studies refered to Gleason score for Gln751Lys and also two studies about tumor stage about Asn312Asp, the number of which was small, further studies should increase these relations to enlarge the subsequent meta-analysis. Fourth, we classified the tumor stage into ‘early stage’ [localized stage or none bone metastasis (−)] and ‘advanced stage’ [regional/distant stage or bone metastasis (+)], however, the criteria of patient's selection in these two studies were not quite concordant. In spite of these, our meta-analysis also had three advantages. First, substantial number of cases and controls were pooled from different studies, which significantly increased statistical power of the analysis. Second, the quality of case–control studies included in the current meta-analysis was satisfactory based on our selection criteria. Third, the control groups were all healthy people.

In conclusion, present analysis suggested that XPD Asn312Asp not Gln751Lys polymorphism may contribute to genetic susceptibility for increased PCa risk in Africans and Asians. Furthermore, XPD Asn312Asp polymorphism was associated with PCa prognosis and/or outcome. Large population studies are needed to be performed to clarify possible roles of XPD polymorphisms in the etiology and clinical characteristics of PCa.

Supporting Information