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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 1828-1831, July 2005
© 2005 American Association for Cancer Research

Short Communication

Common Polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not Associated with Breast Cancer Risk

Bettina Kuschel1,4, Georgia Chenevix-Trench6, Amanda B. Spurdle6, Xiaoqing Chen6, John L. Hopper7, Graham G. Giles8, Margret McCredie9, Jenny Chang-Claude5, Catherine S. Gregory1, Nick E. Day3, Douglas F. Easton2, Bruce A.J. Ponder1, Alison M. Dunning1 and Paul D.P. Pharoah1

1 Department of Oncology and 2 Genetic Epidemiology Group, Cancer Research U.K.; 3 European Prospective Investigation of Cancer, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom; 4 Department of Obstetrics and Gynecology, Technical University Munich, Munich; 5 Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany; 6 Cancer and Cell Biology Division, Queensland Institute for Medical Research, Queensland; 7 Centre for Genetic Epidemiology, The University of Melbourne, Melbourne; 8 Cancer Epidemiology Centre, The Council of Victoria, Carlton, Australia; and 9 Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand

Request for reprints: Paul D.P. Pharoah, Cancer Research U.K., Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, United Kingdom. Phone: 44-1223-740166; Fax: 44-1223-411609. E-mail: paul.pharoah{at}srl.cam.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A substantial proportion of the familial risk of breast cancer may be due to genetic variants, each contributing a small effect. The protein encoded by ERCC2 is a key enzyme involved in nucleotide excision repair, in which gene defects could lead to cancer prone syndromes such as Xeroderma pigmentosum D. We have examined the association between single nucleotide polymorphisms in the ERCC2 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3,634 patients and of 3,340 controls. None of the three single nucleotide polymorphisms were significantly associated with the incidence of breast cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The known highly penetrant, rare cancer predisposition alleles, such as germ line mutations in the BRCA1 or BRCA2 tumor suppressor genes, are estimated to account for <5% of all breast cancer cases and <25% of the excess familial risk of breast cancer (1). It is likely that most of the unexplained heritable components of breast cancer susceptibility are due to multiple weakly penetrant alleles (2).

Polymorphisms in DNA repair genes are good candidates for such alleles. The nucleotide excision repair pathway is a mechanism to repair damage to DNA. ERCC2 is a key component of this pathway. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases (3). Defects in this gene could result in three different disorders, the cancer-prone syndrome Xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome (4). There are also data that show that coding polymorphic variants in ERCC2 variants have functional effects. The D312N variant, which occurs in a highly conserved helicase domain, has been shown to alter apoptosis (5), and K751Q has been shown to affect DNA repair capacity (6).

There have been several studies of polymorphisms in ERCC2 and risk of a variety of cancers including adult glioma, bladder cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head, and colorectal cancer (7). The results of these studies have been inconclusive, but Goode et al. concluded that small sample sizes might have contributed to false-positive or false-negative findings. Polymorphisms in ERCC2 have been studied in four breast cancer case-control studies. Forsti et al. reported no association for the K751Q polymorphism (8) and Tang et al. reported no association for either the K751Q or D312N polymorphisms (9). However, both these studies were small, with <400 cases and 400 controls, and had limited power to detect modest risks. More recently, Justenhoven et al. found a highly significant association between the D312N polymorphism and breast cancer risk; with DD homozygote individuals having a 2-fold increase in risk (10). No association with the K751Q polymorphism was reported. Another recent found no association between K751Q and breast cancer, but did not study the D312N polymorphism (11).

Based on these data, we have hypothesized that polymorphisms in ERCC2 play a role in the development of breast cancer. Therefore, we have analyzed the two known coding polymorphisms (D312N and K751Q) and an additional common single nucleotide polymorphism (SNP) in intron 4 in a large case-control study from an East Anglian, British population. Two other case-control studies from Australia and Germany were used for replication of the positive association we found with D312N in the initial study.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We initially identified three SNPs with validated allele frequencies from dbSNP (http://www.ncbi.nlm.nih.gov/SNP/). These were: rs1799783 in intron 4 (IVS4 a > g), rs1799793 in exon 10 (D312N), and rs1052559 in exon 23 (K751Q). These three SNPs were genotyped in the U.K. case-control series. A positive association was observed for D312N and so this polymorphism was also genotyped in the two additional case-control studies.

Case-Control Samples
East Anglia (U.K.). Cases with invasive breast cancer were drawn from the Anglian Breast Cancer Study. This is an ongoing population-based study of breast cancer cases ascertained through the East Anglian Cancer Registry (12). All study participants completed an epidemiologic questionnaire and provided a blood sample for DNA extraction. Controls were randomly selected from the Norfolk component of the European Prospective Investigation of Cancer (13), a prospective study of diet and cancer being carried out in the same geographic region as the Anglian Breast Cancer Study. The median age of the cases was 51 years and that of the controls 62 years. Over 98% of cases and controls are white. The study is approved by the relevant research ethics committee.

Heidelberg, Germany. Cases were drawn from a population-based study of breast cancer diagnosed by age 50 years, conducted in two geographic areas in the State of Baden-Württemberg in southern Germany, and controls were matched to cases by age and area of residence (14). All study participants completed an epidemiologic questionnaire and provided a blood sample. The median age of the cases was 43 years and that of the controls 44 years. The present study was confined to the subset of cases and controls with at least one parent of German origin—98% of these had both parents of German origin.

Australia. Cases and controls were from a population-based case-control family study, the Australian Breast Cancer Family Study, conducted from 1992 to 2000 (15). Cases comprised women younger than 60 years and living in Sydney or Melbourne who were diagnosed with a first primary invasive breast cancer, and controls were a randomly selected population-based sample of unaffected women recruited using the electoral rolls, frequency-matched to the cases by age. Women were given a questionnaire to record known or potential risk factors for breast cancer and a detailed history of breast cancer among all first- and second-degree relatives of both cases and controls was recorded, and verified when possible. The median age of the cases was 50 years and that of the controls 50 years. Caucasian ethnicity was reported by 90% of cases and 84% of controls.

Genotyping
The genomic sequence of chromosome 19 was used for primer generation (RefSeq acc. no. L47234). We genotyped all patient and control samples for the ERCC2 polymorphisms using the ABI-PRISM-7700 sequence detection system (TaqMan, Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. TaqMan primers (Table 1) were designed using Primer Express Oligo Design Software v1.0 (Applied Biosystems). Fifteen-microliter assays were carried out on 20 ng (15 ng, Australian samples) genomic DNA according to the manufacturer's instructions. Primer and probe concentrations and annealing temperatures are also given in Table 1. Amplifications were carried out on MJ Tetrad thermal cyclers (GRI, Watertown, MA). Plates were read on the ABI PRISM 7700 Sequence detector in end-point mode using the Allelic Discrimination Sequence Detection software (Applied Biosystems). For the software to recognize the genotype, we included nontemplate controls and positive controls for each allele of the SNP (eight of each) in each 96-well plate.


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  		Table 1. Details of the TaqMan assays for each SNP

 
For the intronic SNP rs1799783, which was least likely to be functional, in order to save costs, only half the controls were genotyped with a view to genotyping the full set of controls only if there was some evidence of association in a preliminary analysis.

Statistical Analysis
For each SNP, deviation of genotype frequencies in controls from the Hardy-Weinberg equilibrium was assessed by {chi}2 test with 1 df. Genotype frequencies in cases and controls were compared by {chi}2 test for heterogeneity (2 df). Genotype-specific risks with the common homozygote as the baseline comparator were estimated as odds ratios (OR) by unconditional logistic regression. Haplotype frequencies were estimated from the unphased, multilocus genotype data using the program Haplo.Score, which also compares haplotype frequencies in cases and controls were compared using an appropriate permutation test (16).

For the analysis of the data for D312N, genotype frequencies in cases and controls were compared for each study separately using {chi}2 tests (2 df). The data were then pooled and genotype frequencies were compared in cases and controls using unconditional logistic regression with terms for genotype and study and an appropriate likelihood ratio test. Genotype-specific risks with the common homozygote as the baseline comparator were estimated as OR.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The genotype frequencies in the controls were consistent with Hardy-Weinberg equilibrium for all three SNPs (P = 0.67, 0.96, and 0.54 for IVS4 a > g, D312N, and K751Q, respectively). There was no difference in genotype frequencies between cases and controls for either IVS4 a > g (P = 0.96) or K751Q (P = 0.99), nor were any of the genotype-specific risks significantly different from unity (Table 2). In contrast, there was a significant association for the D312N polymorphism (P = 0.009) with an apparently recessive mode of action [NN versus DD OR, 1.4 (1.1-1.7); DN versus DD OR, 1.0 (0.88-1.1). There was no evidence for an association of D312N genotype with age in the controls (P = 0.29) and age-adjusted risks were virtually identical to the unadjusted risks (data not shown).


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  		Table 2. Genotype frequencies for IVS4 a > g, K751Q, and D312N by study

 
The haplotype analysis was based on 1,701 controls and 1,634 cases where genotype data were available for at least two of the three polymorphisms. The estimated haplotype frequencies in cases and controls are shown in Table 3. Of the eight possible haplotypes, five were common in the U.K. population. There was no significant difference in haplotype frequencies between cases and controls ({chi}2 = 7.60, 5 df; P = 0.18).


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  		Table 3. Haplotype frequencies in controls and cases

 
The finding for D312N in the U.K. data was not confirmed in either of the Australian or Heidelberg studies (P = 0.31 and P = 0.80). In the pooled data analysis, there was no association between genotype frequency and breast cancer (P = 0.28). Nor were the genotype risks significantly different from unity [DN versus DD OR, 0.99 (0.89-1.1); and NN versus DD OR, 1.1 (0.96-1.3)]. These risks were similar after adjustment for age (data not shown). There was no evidence of heterogeneity between studies for the heterozygote risk (P = 0.85), but there was some evidence of heterogeneity between studies for the for the rare homozygote risk (P = 0.02). However, some heterogeneity might be expected where a replication study is carried out after an initial positive association.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Polymorphic variants in ERCC2 are good candidates for breast cancer susceptibility because of its key role in the nucleotide excision repair pathway. We have estimated the breast cancer risks associated with three polymorphisms in ERCC2 using a case-control study design using samples from the Anglian Breast Cancer Study. A positive association was observed for D312N and so this polymorphism was also genotyped in the two additional case-control studies. In the combined data, we found no statistically significant differences between cases and controls.

There are several reasons for the nonreplication of the initial significant result for D312N. The first of these is that the result for the U.K. data may have been a false-positive. Hidden population stratification is one explanation for a spurious positive association in the U.K. study. This occurs when allele frequencies differ between population subgroups and cases and controls are drawn differentially from those subgroups. However, it seems unlikely that population stratification is relevant here because the cases and controls were drawn from the same ethnic groups (>95% white). Furthermore, we have looked for an association between unlinked markers in the U.K. study controls and found no evidence for population stratification (17). A more likely explanation for a false-positive is that the initial finding was a type I statistical error. There are a very large number of candidate breast cancer susceptibility polymorphisms. Consequently, the prior probability that any one is real is very low. So, even when the type I error rate ({alpha}) is set at 0.01, most significant results will turn out to be type I errors. An initial type I error would also explain why there was some evidence for heterogeneity between studies, as the results of the replication studies would be expected to be different from the initial finding if it were due to chance.

An alternative to an initial false-positive is nonreplication because of a lack of adequate statistical power, resulting in false-negatives (type II error) in the replication studies. However, the combined Australian and Heidelberg data had >85% power at a significance of 0.05 to detect a recessive allele with a minor allele frequency of 0.35 that confers a risk of 1.4. Power decreases to 66% if the allele confers a recessive risk of 1.3. Alternatively, failure to confirm associations may be the result of heterogeneity in risk between populations. This might occur if there were population differences in linkage disequilibrium, or population differences in allele frequencies of interacting genes or interacting lifestyle and environmental factors. Given that all three populations are of western European origin, this seems to be unlikely.

Overall, our negative results are broadly in line with previously published data. Only one other study has found a positive association, as we did in our initial study, for the D312N polymorphism (10). However, the effect of the N allele was in the opposite direction in the two which provides further support for the type I error as an explanation for positive findings.

We had initially selected SNPs for genotyping based on polymorphic variation that was known at the start of the study. However, knowledge of polymorphic variation across the human genome is expanding rapidly, and data from the National Institute of Environmental Health Sciences resequencing project has recently become available for ERCC2 (http://egp.gs.washington.edu/). These data have provided the opportunity for us to estimate how well we have excluded the possibility that any common variant in the gene is associated with breast cancer. In the multiethnic, NIH Polymorphism Discovery Resource (NIHPDR), 90 individual screening subset samples were used for the National Institute of Environmental Health Sciences project, but this panel includes 28 samples from the African-American population. No ethnic group identifiers are available for the individuals, so we have identified the 28 samples most likely to be African-American in this population by comparing the genotypes for the NIHPDR90 samples with the genotypes for the same SNPs from the National Heart, Lung, and Blood Institute Variation Discovery Resource project African-American panel (http://pga.gs.washington.edu/finished_genes.html). In the remaining 62 NIHPDR90 samples, 41 polymorphisms were identified with a minor allele frequency of ≥0.05. We used the TAGSNPS program (18) to estimate how efficiently we had "tagged" all the common SNPs in the gene using the three SNPs genotyped in the U.K. set. Twenty-five (75%) of the SNPs were tagged with Rs2 > 0.7 and a further 9 SNPS were tagged with 0.7 > Rs2 > 0.4. Rs2 is the squared correlation coefficients between multilocus haplotypes and individual SNPs and is analogous to the bivariate correlation coefficient between a pair of SNPs, r2. If a true risk variable is measured with error (squared correlation r2), it can be shown that for sample size n, the effective sample size is n x r2. Thus, using the U.K. data, we have 90% power to detect a codominant allele of frequency 0.35 that confers a risk of 1.3 and 70% power to detect a codominant allele with a frequency of 0.05 that confers a relative risk of 1.5, given that they are tagged with Rs2 = 0.4. Thus, we had reasonably good power to exclude 34 of 41 known SNPs in the gene as modest risk susceptibility alleles. The remaining SNPs were poorly tagged: these SNPs were all in introns and none were efficiently marked by any other SNPs, so all six would need to be typed to exclude them as risk alleles.

In conclusion, we have found no evidence that the three analyzed ERCC2 polymorphisms confer an increased risk of breast cancer. Furthermore, it is unlikely that other SNPs in this gene confer a significant risk of breast cancer.


   Acknowledgments
 
This work was funded by the Cancer Research UK [CR-UK]. BAJP is a CR-UK Gibb Fellow, PP is a CR-UK Senior Clinical Research Fellow and DFE is a CR-UK Principal Research Fellow. BK was funded by the "Deutsche Krebshilfe". The authors thank the EPIC management team (Sheila Bingham, Kay-Tee Khaw and Nick Wareham) and as the ABC study team.

We thank Gillian Dite, Melissa Southey, Andrea Tesoriero, Sarah Steinborner, and Deon Venter for supply of data and DNA for this project. The ABCFS has been funded by the National Health and Medical Research Council, the Victorian Health Promotion Foundation, the New South Wales Cancer Council, and the National Institute of Health, as part of the Cancer Family Registry for Breast Cancer Study (CA 69638). ABS is funded by an NHMRC Career Development Award, and GC-T and JLH are NHMRC Senior and Senior Principle Research Fellows, respectively. The epidemiologic study in Germany was funded by the Deutsche Krebshilfe (Project number 70492).


   Footnotes
 
Grant support: This work was funded by Cancer Research UK. B.A.J. Ponder is a Cancer Research UK Gibb Fellow, P. Pharoah is a Cancer Research UK Senior Clinical Research Fellow, and D.F. Easton is a Cancer Research UK Principal Research Fellow. B. Kuschel was funded by the "Deutsche Krebshilfe." The Australian Breast Cancer Family Study has been funded by the National Health and Medical Research Council, the Victorian Health Promotion Foundation, the New South Wales Cancer Council, and the NIH, as part of the Cancer Family Registry for Breast Cancer Study (CA 69638). A.B. Spurdle is funded by an NHMRC Career Development Award, and G. Chenevix-Trench and J.L. Hopper are NHMRC Senior and Senior Principle Research Fellows, respectively. The epidemiologic study in Germany was funded by the Deutsche Krebshilfe (project no. 70492).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 5/04; revised 4/11/05; accepted 4/ 5/05.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Easton DF. How many more breast cancer predisposition genes are there. Breast Cancer Res 1999;1:14–7.[CrossRef][Medline]
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