Mutagenesis, Vol. 17, No. 6, 463-469,
November 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
ERCC2/XPD gene polymorphisms and cancer risk
1 EMI 00-06, INSERM -Universite d’Evry, 91034 Evry, France and 2 Laboratory of Genetic Instability and Cancer, UPR2169-CNRS, 94801 Villejuif, France
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Abstract |
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 Top Abstract IntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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DNA repair of bulky adducts is essential for a normal life, as demonstrated by the existence of rare but dramatic diseases, such as xeroderma pigmentosum (XP), associating DNA repair deficiency and a high cancer proneness. It is plausible that small variations in the efficacy of repair in the normal population may facilitate cancer development in exposed individuals. In order to check this hypothesis, associations between single nucleotide polymorphisms (SNPs) in key genes and some frequent human cancers have been researched. Among the repair proteins, the XPD protein is interesting because it is a major player in the nucleotide excision repair pathway and is also involved in transcription initiation and in the control of the cell cycle and apoptosis. Several SNPs have been described in the ERCC2/XPD gene, but three in particular have been studied: the C
A silent polymorphism (Arg156Arg) in exon 6, the GA polymorphism leading to Asp312Asn in exon 10 and the AC polymorphism leading to Lys751Gln in exon 23. We review here the epidemiological studies examining whether these polymorphisms are correlated with reduced DNA repair efficiency (analysed using different assays), their influence on the development of cutaneous carcinomas and smoking-related cancers and their possible interactions with environmental exposures. |
Introduction |
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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The nucleotide excision repair (NER) system is one of the basic mechanisms that cells employ in protection against genotoxic damage such as that induced by UV-irradiation or exposure to chemical carcinogens. NER system defects are causative in several human syndromes, including trichothiodystrophy (TTD), Cockayne’s syndrome (CS) and xeroderma pigmentosum (XP) (Hoeijmakers, 2001
; Stary and Sarasin, 2002). XP is a heritable human disease characterized by extreme sensitivity to UV radiation that leads to a high incidence of skin cancer in young affected individuals. XP was first linked to DNA repair based on the UV sensitivity of afflicted persons (Cleaver, 1968; Bootsma et al., 1995). Eight XP complementation groups were then identified based on the ability of the different cell types to complement UV sensitivity (Kraemer et al., 1994; Stary and Sarasin, 1996) and the gene products in the different complementation groups have now been identified (Wood, 1999; de Boer and Hoeijmakers, 2000;Friedberg et al., 2000).
The NER pathway repairs the damaged strand in a ‘cut and paste’ manner consisting mainly of five steps: recognition of the lesion carried out basically by the XPC-hHR23B complex; opening of the double helix at the lesion site by the concerted action of the two DNA helicases XPB and XPD; demarcation of the lesion necessitating the activity of the XPA and RPA proteins; dual incision of the damaged strand by the XPF and XPG endonucleases; synthesis of DNA in the gap left by the removal of a 24mer–32mer oligonucleotide by the replicative DNA polymerases and PCNA; ligation to the parental strand by DNA ligase I (Benhamou and Sarasin, 2000;Hoeijmakers, 2001).
The NER process is classically divided into global genomic repair (GGR) and transcription-coupled repair (TCR) (Hanawalt, 1994). Mainly, the mechanisms of these two pathways are similar except for recognition of the damage and, therefore, for initiation of the process. In TCR, lesions present on the transcribed strand constitute a block to RNA polymerase II that represents a signal initiating the repair process or inducing apoptosis (Queille et al., 2001). In contrast, during GGR the XPC protein recognizes helix deformation due to bulky adducts and initiates repair. In both processes, separation of the double helix is a major step necessitating the presence of the transcription factor TFIIH (Egly, 2001). The XPB and XPD proteins, two of the nine proteins constituting TFIIH, have helicase activities necessary for normal transcription initiation and NER (Schaeffer et al., 1993, 1994). Patients defective in one of these two activities are afflicted with XP, XP/CS, TTD or XP/TTD (Kraemer et al., 1994; Sarasin and Stary, 1997). Although these diseases are rare, there are several hundred XPD and TTD patients, but only two patients with both XPD and CS (XP/CS), and two patients with both TTD and XP symptoms have recently been described (Broughton et al., 2001). Half of these patients exhibit a high frequency of skin cancer and internal cancers, obviously linked to their DNA repair deficiency. Although these patients represent the extreme defect in NER, variations in the activity of the repair processes in the general population are highly plausible and probably implicated in the inherited susceptibility to cancers. Various techniques could be used to monitor NER efficacy, but determination of sequence variants in genes involved in the DNA repair pathways is still the easiest method for a large population.
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The XPD protein |
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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TFIIH can be found as a nine subunit complex, a core TFIIH involved in transcription, or in a cdk-activating kinase (CAK) complex involved in the phosphorylation of numerous substrates such as RNA polymerase II, transcription activators and nuclear hormone receptors such as RAR and ER (Coin et al., 1998
; Keriel et al., 2002) (Figure 1). The XPD protein is found in these three different complexes (Coin et al., 1999). Mutations in the XPD gene can diminish the activity of these complexes giving rise to repair defects, transcription defects, abnormal responses to apoptosis and, probably, hormonal dysfunctions. All these deficiencies provoke syndromes associated with mental retardation, skeletal abnormalities, immature sexual development and, for most XPD patients, a high cancer proneness. A direct relationship can be established for XP patients (but not for TTD patients) between low DNA repair and a high frequency of skin cancers (Kraemer et al., 1994; Coin et al., 1999). The XPD protein is a 5'3' helicase with a molecular weight of 86.9 kDa and comprising 761 amino acids (Figure 2). The XPD helicase activity is only required for NER and is not absolutely necessary for basal transcription, in contrast to XPB protein. In transcription, XPD seems rather to have a structural role (Figure 1).
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The XPD gene and its SNPs |
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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The genomic DNA of the XPD gene comprises 23 exons and spans ~54.3 kb at 19q13.3. The cDNA has a size of 2400 nt. Almost 100 mutations have been mapped in this gene (Itin et al., 2001
). Most of them are point mutations, indicating that the presence of a full-length XPD protein is necessary for life. Two-thirds of these mutations are located at the C-terminal end of the protein, which is the domain of interaction with p44, a constituent of the TFIIH complex, which is the activator of XPD helicase activity (Coin et al., 1998). Apart from point mutations that cause disease and are found in the homozygous state in patients or in only one XPD allele of asymptomatic parents, variations in the XPD sequence are found among the general population. These variations are called single nucleotide polymorphisms (SNPs), with a frequency highly variable between 1% and >50%.
Seventeen SNPs in the XPD gene have recently been detected in screening 12 individuals, of which six were found in exons and 11 in introns (Shen et al., 1998). The six coding region polymorphisms include a CA at codon 156, a CG at codon 199, a CT at codon 201, a GA at codon 312, a CT at codon 711 and an AC at codon 751 (Figure 2
). Of these polymorphisms, those in codons 156 and 711 are silent and the frequency of these variant alleles has been estimated to be ~25%. The four remaining polymorphisms result in amino acid changes: isoleucine to methionine in codon 199, histidine to tyrosine in codon 201, aspartic acid to asparagine in codon 312 and lysine to glutamine in codon 751. Whereas the codon 199 and 201 polymorphisms are rare (allele frequency ~4%), the codon 312 and 751 polymorphisms are common (allele frequencies ~42 and ~29%, respectively) (Shen et al., 1998).
Most of the epidemiological studies on cancer reported to date have focused on SNPs in codons 156, 312 and 751, because of their high frequencies. The functional significance of these XPD variants has not yet been elucidated, but some of the variants may be associated with a reduced repair capacity and increased cancer susceptibility.
The 312 variant has the acidic moiety of the aspartic acid removed and the 751 variant completely changes the electronic configuration of the amino acid. This is a major change, located in the important domain of interaction between XPD protein and its helicase activator, p44 protein, inside the TFIIH complex (Coin et al., 1998). In theory, the consequence of the SNP at amino acid 751 should be the most important in terms of XPD activity.
SNPs are usually discovered by sequencing the gene of interest in populations of known ethnic origin. Once the SNP map is established, SNP determination can be carried out on groups of patients with cancer and controls by specific assays, such as localized PCR followed by DNA sequencing or restriction enzyme analysis, mass spectrometry, transfer of fluorescent probes and so on. All these techniques should be specific, easy to perform and automate and cheap.
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XPD polymorphisms and repair capacity |
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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Few studies have examined the relationship between XPD variants and DNA repair capacity measured using the biological tests available in the literature. In a small study of 31 women at risk for breast cancer (Lunn et al., 2000
), the Lys/Lys codon 751 XPD genotype was found to be associated with a reduced repair of X-ray-induced DNA damage. Individuals homozygous for the wild-type Lys allele had higher levels of chromatid aberrations than those with one or two Gln alleles. The Asp312Asn polymorphism did not appear to affect DNA repair proficiency in this study. Moller et al. (2000), using the Comet assay in resting lymphocytes from 40 psoriasis patients with or without basal cell carcinomas (BCC), reported that the Lys751 allele was associated with a high level of UVC-induced formation of strand breaks. A similar result was found with the A allele at codon 156, although this SNP does not modify the amino acid. This Comet assay measures the initial rate of nucleotide excision repair incisions at lesions but is not proof of an efficient and error-free repair activity.
In contrast, two other studies, with larger sample sizes and healthy individuals, suggested that DNA repair capacity, measured by the host cell reactivation (HCR) assay using BPDE-treated plasmids in 360 controls (Spitz et al., 2001) or UV-irradiated plasmids in 102 healthy individuals (Qiao et al., 2002), was reduced in subjects carrying two variant alleles (Asn312 or Gln751) compared with those homozygous for the respective wild-type alleles. When both genotypes were combined, the best repair activity was found in cells from individuals homozygous wild-type at both loci and the lowest repair capacity in those carrying at least two variant alleles (Spitz et al., 2001).
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XPD polymorphisms and cancer risk |
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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Similar to the studies regarding the relationship between XPD variants and repair capacity, few epidemiological studies have investigated the association between XPD polymorphisms and cancer. Characteristics of case–control studies on smoking-related cancers and skin cancers, the types of cancer most frequently investigated, are summarized in Table I
. To enable a comparison between the various reports, we calculated the crude odds ratios (ORs) and their 95% confidence intervals (95% CIs) associated with XPD variant alleles for several individual studies, using the homozygous wild-type genotype at the different loci as the reference category.
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To our knowledge, seven recent case–control studies have investigated the effect of XPD polymorphisms on smoking-related cancers. Contradictory results have been observed for the Asp312Asn polymorphism in relation to lung cancer (Table II
). The Asn allele was shown to have a protective effect when compared with the Asp/Asp genotype in a study of 96 lung cancer cases (Butkiewicz et al., 2001), whereas it was associated with higher lung cancer risk in the very large study by Zhou et al. (2002). The genotype distribution in cases and controls was not different in two other studies (Spitz et al., 2001; Hou et al., 2002). Regarding the Lys751Gln polymorphism, the homozygous variant genotype was associated with a higher risk of head and neck cancer (Sturgis et al., 2000); in contrast, no overall association was found in all the studies on lung cancer (Table II). The joint effect of these two XPD polymorphisms was investigated in one study, which revealed a higher risk of lung cancer for individuals carrying two or more variant alleles (Spitz et al., 2001). Because XPD polymorphisms are presumed to affect smoking-related cancers by repairing DNA damage caused by tobacco carcinogens, the potential modifying effect of XPD genotype on the relationship between these cancers and tobacco smoking is of particular interest. Differences in association for XPD polymorphisms by level of smoking were investigated in some studies, however, the statistical power to detect them was generally limited and contradictory results were reported. Stratified analyses revealed a significant protective effect of the XPD Asn312 allele against lung cancer in smokers but not in never-smokers in one study (Butkiewicz et al., 2001), whereas it was associated with an increased risk among never-smokers only in another study (Hou et al., 2002). In the large study by Zhou et al. (2002)), gene–smoking interaction analyses revealed that the lung cancer risks associated with the Asn/Asn genotype decreased significantly as levels of tobacco exposure increased, the highest risk being observed among never-smokers. A similar risk elevation was also observed for the XPD Gln751 allele among never-smokers in two studies (Hou et al., 2002; Zhou et al., 2002), but not in the others (Sturgis et al., 2000; David-Beabes et al., 2001; Spitz et al., 2001; Park et al., 2002).
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Results of four case–control studies on ERCC2/XPD polymorphisms and skin cancer are summarized in Table III
. The risk estimates could not be calculated for the two studies on cutaneous melanoma as numbers of cases and controls by genotype were not reported (Winsey et al., 2000; Tomescu et al., 2001). The two remaining studies (Dybdahl et al., 1999; Vogel et al., 2001), based on very small sample sizes, suggested that individuals with the A allele of the silent Arg156Arg polymorphism were at increased risk of basal cell carcinoma. No overall association was found with the Asp312Asn polymorphism (Vogel et al., 2001). Contradictory results have been observed for the Lys751Gln polymorphism. A protective effect of the Gln allele against BCC was suggested when compared with the Lys/Lys genotype in one study (Dybdahl et al., 1999), whereas it was associated with higher risk, although not significantly, in the other study (Vogel et al., 2001).
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Conclusions |
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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The XPD protein is a major player in the NER pathway and is essential for life, probably through its role in the transcription process. This is demonstrated by the lethality of xpd knockout mice and the few numbers of XPD-mutated patients. It is plausible that variations in NER efficiency are found among the general population and that individuals with a low repair capacity could be more sensitive to DNA damage and therefore more prone to cancer. Among the numerous repair genes that are known, XPD particularly has been analyzed in epidemiological studies on skin and smoking-related cancers. The results are somewhat disappointing, since no obvious relationships between cancer risk and XPD SNPs have been found. Only one study associated the homozygous variant genotype Lys751Lys with a higher risk of head and neck cancer (Sturgis et al., 2000
). Another study, investigating the joint effect of multiple XPD polymorphisms, revealed a higher risk of lung cancer for individuals carrying two or more variant alleles (Spitz et al., 2001). Appreciable variability in study results can arise from differences in study design. The reviewed investigations differed greatly in terms of study size, selection of controls, matching criteria, control for known confounding factors and statistical methods. The lack of cohesiveness in the results could be due in part to methodological deficiencies in some studies. Up to now, the techniques used are not sensitive enough nor easy to extend to a large population. Therefore, data currently available on XPD polymorphisms and cancer should be interpreted with caution and well-designed studies, with adequate statistical power, are warranted to clarify this issue in the future. Additional studies are also needed to clarify the functional significance of XPD variants.
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Notes |
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3 To whom correspondence should be addressed at: EMI 00-06, INSERM – Universite d’Evry, Tour Evry 2, 523 Place des Terrasses de l’Agora, 91034 Evry Cedex, France. Tel: +33 1 60 87 38 36; Fax: +33 1 60 87 38 48; Email: benhamou{at}evry.inserm.fr
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TopAbstractIntroductionThe XPD proteinThe XPD gene and...XPD polymorphisms and repair...XPD polymorphisms and cancer...ConclusionsReferences |
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Received on July 1, 2002; revised on August 7, 2002; accepted on August 7, 2002.
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T. Paz-Elizur, D. E. Brenner, and Z. Livneh Interrogating DNA Repair in Cancer Risk Assessment Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1585 - 1587. [Full Text] [PDF]
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M. B. Schabath, G. L. Delclos, H. B. Grossman, Y. Wang, S. P. Lerner, R. M. Chamberlain, M. R. Spitz, and X. Wu Polymorphisms in XPD Exons 10 and 23 and Bladder Cancer Risk Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 878 - 884. [Abstract] [Full Text] [PDF]
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S. Sadetzki, P. Flint-Richter, S. Starinsky, I. Novikov, Y. Lerman, B. Goldman, and E. Friedman Genotyping of Patients with Sporadic and Radiation-Associated Meningiomas Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 969 - 976. [Abstract] [Full Text] [PDF]
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L. E. Mechanic, A. J. Marrogi, J. A. Welsh, E. D. Bowman, M. A. Khan, L. Enewold, Y.-L. Zheng, S. Chanock, P. G. Shields, and C. C. Harris Polymorphisms in XPD and TP53 and mutation in human lung cancer Carcinogenesis, March 1, 2005; 26(3): 597 - 604. [Abstract] [Full Text] [PDF]
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C. Justenhoven, U. Hamann, B. Pesch, V. Harth, S. Rabstein, C. Baisch, C. Vollmert, T. Illig, Y.-D. Ko, T. Bruning, et al. ERCC2 Genotypes and a Corresponding Haplotype Are Linked with Breast Cancer Risk in a German Population Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2059 - 2064. [Abstract] [Full Text] [PDF]
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