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Carcinogenesis Advance Access originally published online on November 23, 2005
Carcinogenesis 2006 27(5):997-1007; doi:10.1093/carcin/bgi280
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

DNA repair polymorphisms and cancer risk in non-smokers in a cohort study

G. Matullo 1, *, A.M. Dunning 2, S. Guarrera 1, C. Baynes 2, S. Polidoro 1, S. Garte 3, H. Autrup 4, C. Malaveille 5, M. Peluso 6, L. Airoldi 7, F. Veglia 1, E. Gormally 5, G. Hoek 8, M. Krzyzanowski 9, K. Overvad 10, O. Raaschou-Nielsen 11, F. Clavel-Chapelon 12, J. Linseisen 13, H. Boeing 14, A. Trichopoulou 15, D. Palli 16, V. Krogh 17, R. Tumino 18, S. Panico 19, H.B. Bueno-De-Mesquita 20, P.H. Peeters 21, E. Lund 22, G. Pera 23, C. Martinez 24, M. Dorronsoro 25, A. Barricarte 26, M.J. Tormo 27, J.R. Quiros 28, N.E. Day 29, T.J. Key 30, R. Saracci 5, R. Kaaks 5, E. Riboli 5 and P. Vineis 31

1 ISI Foundation and Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy, 2 Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK, 3 Genetics Research Institute, Milan, Italy, 4 Department of Environmental and Occupational Medicine, University of Aarhus, Aarhus, Denmark, 5 International Agency for Research on Cancer, Lyon, France, 6 Cancer Risk Factor Branch, Molecular Biology Laboratory, CSPO-Scientific Institute of Tuscany, Florence, Italy, 7 Istituto Mario Negri, Milan, Italy, 8 Department of Environmental and Occupational Health, Utrecht University, Utrecht, Netherlands, 9 World Health Organization, European Centre for Environment and Health, Bonn, Germany, 10 Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus, Denmark, 11 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark, 12 INSERM U521, Institut Gustave Roussy, Villejuif, France, 13 Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany, 14 German Institute of Human Nutrition, Potsdam-Rehbücke, Germany, 15 Department of Hygiene and Epidemiology, Medical School, University of Athens, Greece, 16 Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany, Florence, Italy, 17 Department of Epidemiology, National Cancer Istitute, Milan, Italy, 18 Cancer Registry, Azienda Ospedaliera ‘Civile MP Arezzo’, Ragusa, Italy, 19 Dipartimento di Medicina Clinica e Sperimentale, Università Federico II, Naples, Italy, 20 Centre for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, Netherlands, 21 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Netherlands, 22 Institute of Community Medicine, University of Tromso, Norway, 23 Department of Epidemiology, Catalan Institute of Oncology Barcelona, Spain, 24 Andalusian School of Public Health, Granada, Spain, 25 Department of Public Health of Guipuzkoa, San Sebastian, Spain, 26 Public Health Institute, Navarra, Spain, 27 Consejería de Sanidad y Consumo, Murcia, Spain, 28 Dirección General de Salud Pública, Consejería de Salud y Servicios Sanitarios Asturias, Oviedo, Spain, 29 MRC Dunn Human Nutrition Unit, Cambridge, UK, 30 Cancer Research UK Epidemiology Unit, University of Oxford, UK, 31 Imperial College London, London UK and University of Torino, Italy

* To whom correspondence should be addressed at: Section of Epidemiology, I.S.I Foundation (Institute for Scientific Interchange), Viale Settimio Severo, 65, 10133 Torino, Italy; E-mail: matullo{at}isiosf.isi.it


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Environmental carcinogens contained in air pollution, such as polycyclic aromatic hydrocarbons, aromatic amines or N-nitroso compounds, predominantly form DNA adducts but can also generate interstrand cross-links and reactive oxygen species. If unrepaired, such lesions increase the risk of somatic mutations and cancer. Our study investigated the relationships between 22 polymorphisms (and their haplotypes) in 16 DNA repair genes belonging to different repair pathways in 1094 controls and 567 cancer cases (bladder cancer, 131; lung cancer, 134; oral–pharyngeal cancer, 41; laryngeal cancer, 47; leukaemia, 179; death from emphysema and chronic obstructive pulmonary disease, 84). The design was a case–control study nested within a prospective investigation. Among the many comparisons, few polymorphisms were associated with the diseases at the univariate analysis: XRCC1-399 Gln/Gln variant homozygotes [odds ratios (OR) = 2.20, 95% confidence intervals (CI) = 1.16–4.17] and XRCC3-241 Met/Met homozygotes (OR = 0.51, 95% CI = 0.27–0.96) and leukaemia. The recessive model in the stepwise multivariate analysis revealed a possible protective effect of XRCC1-399Gln/Gln in lung cancer (OR = 0.22, 95% CI = 0.05–0.98), and confirmed an opposite effect (OR = 2.47, 95% CI = 1.02–6.02) in the leukaemia group. Our results also suggest that the XPD/ERCC1-GAT haplotype may modulate leukaemia (OR = 1.28, 95% CI = 1.02–1.61), bladder cancer (OR = 1.38, 95% CI = 1.06–1.79) and possibly other cancer risks. Further investigations of the combined effects of polymorphisms within these DNA repair genes, smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process.

Abbreviations: AP, apurinic/apyrimidinic; BER, base excision repair; CA, chromosomal aberrations; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DHPLC, denaturing high performance liquid chromatography; DRC, defect repair capacity; DSB, double strand break; EPIC, European Prospective Investigation into Cancer and Nutrition; ETS, environmental tobacco smoke; FPRP, false positive report probability; IARC, International Agency for Research on Cancer; LD, linkage disequilibrium; MDMT, methylguanine-DNA methyltransferase; MMR, Mismatch repair; NER, nucleotide excision repair; OR, odds ratio; PE, primer extension technique; SNP, single nucleotide polymorphism; SSB, single strand break; UADC, upper aero-digestive cancer


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Environmental carcinogens contained in air pollution, such as polycyclic aromatic hydrocarbons, aromatic amines or N-nitroso compounds, predominantly form DNA adducts but also generate interstrand cross-links and reactive oxygen species [which induce base damage, abasic sites, and single and double strand breaks (SSBs and DSBs)]. Unrepaired damage can result in apoptosis or may lead to unregulated cell growth and cancer. If DNA damage is recognized by the cell's machinery, several responses may occur to prevent replication in the presence of genetic errors. At the cellular level, checkpoints can be activated to arrest the cell cycle, transcription can be upregulated to compensate for the damage or the cell can apoptose (1). Alternatively, the damage can be repaired at the DNA level enabling the cell to replicate as planned. Complex pathways involving numerous molecules have evolved to perform such repair. Because of the importance of maintaining genomic integrity in the general and specialized functions of cells as well as in the prevention of carcinogenesis, genes encoding for DNA repair molecules have been proposed as candidate cancer-susceptibility genes (2,3). At least four pathways of DNA repair operate on specific types of damaged DNA, and each pathway involves numerous molecules (4). The nucleotide excision repair (NER) pathway repairs bulky lesions such as pyrimidine dimers, other photo-products, larger chemical adducts and cross-links. The base excision repair (BER) operates on small lesions such as oxidized or reduced bases, fragmented or non-bulky adducts, or those produced by methylating agents. DSBs can be produced by replication errors and by exogenous agents such as ionizing radiation; they lead to chromosomal breakage and rearrangement—events that may result in apoptosis or tumorigenesis. At least two pathways for DSB repair exist: homologous recombination and non-homologous end-joining. Mismatch repair (MMR) is an additional category of DNA repair system that corrects replication errors (base–base or insertion–deletion mismatches) caused by the DNA polymerase errors. Finally, alkylated bases are also directly removed by the suicide enzyme methylguanine-DNA methyltransferase (MGMT).

Studies to date indicate that variation in DNA repair genes in each of the pathways may influence cancer susceptibility, including polymorphisms analysed in the present study (5,6; http://www.perseus.isi.it/huge); however, results are not consistent, and other potentially important polymorphisms in these and other genes have not been explored yet. Hundreds of polymorphisms in DNA repair genes have been identified; however, the impact on repair phenotype and cancer susceptibility remains uncertain for many of these genes (5–8). Among the polymorphisms analysed, few show an evidence of association with phenotype changes (8). Of these, XRCC1-Arg399Gln, has been analysed in a sister chromatid exchange assay, in three different studies and the results are difficult to interpret, but, positive associations were observed in cigarette smokers compared with non-smokers (9). However, the Gln399 homozygote genotype was significantly associated with increased levels of bulky-DNA adducts in leucocytes of non-smokers (10). Using healthy non-smokers, the Gln allele was found to be defective in the repair of X-ray- but not UV-light-induced chromosomal aberrations (CA) (11). The glycophorin A mutation assay indicated that the Gln allele influenced the production of the NN mutation but not the NO mutation (12). However, the observations were not confirmed in a second study with a much larger sample size (13). The XRCC3-241Met allele was also found to be significantly associated with increased bulky-DNA adducts in non-smokers (10). This is consistent with a study which indicated that the variant homozygote was deficient in the repair of X-ray- but not UV-light-induced chromosomal aberrations (11). However, in vitro experiments performed by Araujo et al. (14) have recently suggested that the increased cancer risk associated with the XRCC3-241Met allele may not be attributable to an intrinsic homology-directed repair. For the OGG1-Ser326Cys polymorphism, a study of the removal of 8-OH deoxyguanosine (8-OHdG) in lymphocyte DNA has been published (15). In this study, patients with the variant Cys allele had significantly higher 8-OHdG levels than those with the wild-type Ser allele. However, this association was not observed in the normal controls. Investigations on the repair of CA indicate that the Asn allele of XPD-Asp312Asn is proficient in the repair of X-ray-induced DNA damage (16), but defective in the repair of UV-light-induced damage (11). The observation was consistent with increased bulky-DNA adduct levels measured in leucocytes of non-smokers (10). For the XPD-Lys751Gln polymorphism, the use of the CA repair assay indicates that the variant Gln allele is defective in the repair of UV-light- but not X-ray-induced DNA damage (11). The XPD-751Gln variant leads to a conformational change of the protein thus altering its interaction with partner proteins within the TFIIH complex (17).

Qiao et al. (18) demonstrated that a post-UV defect repair capacity (DRC) for NER can be modulated by genetic polymorphisms of XPD in healthy subjects. The combination of XPD variant alleles, XPD-312Asn and XPD-751Gln, was associated with lower DRC of UV-induced DNA damage than homozygous wild-type alleles. However, these effects were not statistically significant, possibly due to the inherent high variation in the host cell reactivation assay. In addition, cigarette smoking may have some confounding effects on the DRC. The APEX-148 Glu variant allele has a small but non-significant effect on apurinic/apyrimidinic (AP) endonuclease and DNA binding activities (19). For the other polymorphisms analysed here, insufficient information has been published for any conclusion about their functional consequences to be drawn. Among the many biomarkers described, only two showed consistency with each other. Observations based on the chromosome aberration repair assay for three polymorphisms (XRCC1-Arg399Gln, XRCC3-Thr241Met and XPD-Lys751Gln) are consistent with those based on the presence of bulky-DNA adducts (10). In this study, smoking habit might interact with genetic differences in DNA repair activity. It becomes clear that investigation of cigarette smokers and cancer patients should be limited to addressing the repair capacities of these individuals and under their respective conditions, not the inherent activities of DNA repair genes. Even fewer molecular epidemiological studies have been published on cancer susceptibility conferred by specific DNA repair gene haplotypes (20–27) and none on the relationship between repair phenotypes and haplotypes, whose allelic combination may be more relevant in determining the possible functional change at the protein level than single low penetrant single nucleotide polymorphisms (SNPs).

In the present study, we analysed 22 biallelic polymorphisms in 16 DNA repair genes (Table I) involved in different repair pathways (BER, NER, DSB and direct repair) in the EPIC cohort, aiming at studying the relationship between some type of cancer (bladder, lung, oral, pharyngeal, laryngeal cancers and leukaemia) or deaths from respiratory diseases [chronic obstructive pulmonary disease (COPD), emphysema], environmental tobacco smoke (ETS) and genetic susceptibility.


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  		Table I. List of DNA repair genes and polymorphisms analysed

 

   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Subjects
EPIC (European Prospective Investigation into Cancer and Nutrition) is a multicentre European study, coordinated by the International Agency for Research on Cancer (IARC) (Lyon), in which >520 000 healthy volunteers were recruited in 10 European countries (France, Denmark, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden and UK) corresponding to 23 recruitment centres. The cohort includes subjects of both genders, mostly in the age range 35–74 years at recruitment. Recruitment took place between 1993 and 1998. Detailed dietary and lifestyle histories collected mainly through self-administered questionnaires, plus a 24 h dietary recall through person-to-person interview (in a 10% sample), anthropological measurements and a 30–40 ml blood sample are available. Signed informed consent forms were collected from all participants (except a subgroup of the Oxford cohort who gave consent on postal questionnaires).

The follow-up was based on population cancer registries in seven of the participating countries: Denmark, Italy, the Netherlands, Norway, Spain, Sweden and the UK. In France, Germany and Greece a combination of methods was used, including health insurance records, cancer and pathology registries, and active follow-up through study participants and their next-of-kin. Mortality data were also obtained from either the cancer registry or mortality registries at the regional or national level. All the information is centralized both at the national level and at IARC.

Gen-Air is a case–control study nested within the EPIC cohort, aiming at studying the relationship between some types of cancer and air pollution or ETS. Eleven centres (in France, Italy, Denmark, Sweden, the Netherlands, and Potsdam, Germany) collected data on exposure to ETS, investigating about place of exposure and exposure during childhood. In the present study we considered any exposure to ETS (someone regularly smokes at home and/or work). Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Individual pollutants (NO2, O3, PM10, SO2) and residence nearby heavy traffic roads were assessed. Cases were subjects with bladder, lung, oral, pharyngeal, or laryngeal cancers or leukaemia, all newly diagnosed after recruitment. Also deaths from respiratory diseases (COPD, emphysema) were identified and included. These diagnoses were chosen because they were suspected of being associated with air pollution or ETS exposure. Only non-smokers or ex-smokers since at least 10 years have been included in Gen-Air. We matched three controls per case for exposure assessment and the analysis of questionnaire data, and two controls per case for laboratory analyses. Matching criteria were gender, age (±5 years), smoking status (never or former smoker), country of recruitment and follow-up time. Matching was introduced to allow strict control of potentially confounding variables, considering that other risk factors may be stronger than ETS or air pollution. In addition, matching was needed for laboratory analyses, to avoid differential sample degradation between cases and controls. Mean follow-up was 89 months (minimum 51, maximum 123).

Gen-Air has been approved by the Ethical Committee of the IARC and by the local Ethical Committees of the 23 centres.

We identified 4051 subjects (1074 cases and 2977 controls) who met the protocol criteria. Of these subjects, 2410 had blood samples (843 cases and 1564 controls). Blood samples of cases and controls for centres which have released an ethical approval was sent to laboratories for investigation. The Malmo center had decided not to allow the use of their blood samples, but it participated in the rest of the project.

The distribution of cases by cancer site or cause of death was as follows: bladder cancer 227, lung cancer 271, oral/pharyngeal cancer 73, laryngeal cancer 58, leukaemias 311, deaths from respiratory diseases 134.

DNA extraction and polymorphisms
DNA was extracted from 200–300 µl of buffy coat in the laboratory of M.P. according to a standard phenol–chloroform protocol (28), except for the Danish samples that were extracted and purified from lymphocytes using a salting out procedure. DNA was available for 1661 subjects, 567 cases and 1094 Controls; cases were distributed as follows: bladder cancer, 124; lung cancer, 116; oral/pharyngeal cancer, 43; laryngeal cancer, 39; leukaemias, 169; deaths from respiratory diseases (COPD), 77. DNA has been sent in dry ice to ISI Foundation, Torino (G.M.) and to Cambridge (A.M.D.) laboratories for the analysis of DNA repair gene polymorphisms. A list of the analysed DNA repair gene SNPs is reported in Table I with all the relevant information.

Genotyping of DNA repair polymorphisms
5' Nuclease Assay (TaqMan) was used to genotype all the polymorphisms reported in Table I except for OGG1-Ser326Cys. Cambridge laboratory used plain TaqMan probes, whereas Torino laboratories used fluorogenic MGB (minor groove binder) probes; allele specific probes were labelled in both laboratories with Fam and Vic fluorophors.

OGG1-Ser326Cys polymorphism has been genotyped by the primer extension technique (PE) on a denaturing high performance liquid chromatography (DHPLC) instrument (29) (Varian, Walnut Creek, CA) to avoid possible TaqMan mistyping due to the existence of other nucleotide substitution in codon 326. The primer extension technique, or single base extension, consists of a specific elongation of a primer by the dideoxynucleotide complementary to the base allelic substitution; the rate of appropriate dideoxynucleotide incorporation completely overwhelmed misincorporations, and heterozygotes were easily detectable after separation of the extended primers through a DHPLC column. Technical details on primers/probes and experimental conditions for TaqMan and PE/DHPLC analysis for genotyped SNPs are published on line as supplementary table.

DNA typing quality control
A methodological validation was performed at the ISI Foundation laboratory, including a comparison between PCR–RFLP, DHPLC and TaqMan assay (28). Moreover, at least 10% of the genotyping have been randomly repeated for each polymorphism. Concordance was in the range of 99–100% for all the comparisons; discordant genotypes were excluded from the analysis. Another extensive evaluation of genotyping methods has been performed in the Cambridge laboratory using 864 DNA samples of mixed quality on the BRCA2-Asn372His genotype by allele specific oligonucleotides (ASO) and by Taqman (28). If the two results did not agree, a forced RsaI digest was additionally used.

Statistical analysis
We computed odds ratios (OR) and 95% confidence intervals (CI) in conditional logistic regression models for matched groups. All association analyses, at the level of individual SNPs, were performed assuming recessive or co-dominant model of inheritance of traits associated with alleles. In the ‘recessive’ model, disease risks were compared between subjects who were homozygous for the rare allele and all others. In the ‘co-dominant’ model, disease risks were related to the number of copies of an allele (0–2) carried by the individuals. A dominant model has not been tested due to the general biological implausibility of this hypothesis, avoiding, at the same time, unnecessary multiple comparisons. If the single allelic dose was sufficient to show the same phenotype in heterozygotes and variant homozygotes, we should expect a strong effect of the SNP in terms of changes in activity/expression of the gene, which is generally not observed with phenotypic assays, being characteristic of more severe mutations rather than low penetrant SNPs. We tested the association between polymorphisms and a number of other variables, including dietary variables, BMI, physical exercise and educational level, but none was identified as a potential confounder. The stepwise method was employed to select the set of polymorphisms independently associated with the outcomes. In this procedure the significance level to keep a variable in the model was set to 0.1. We further performed the analysis of each polymorphism stratified by gender, passive smoking (ETS) and previous smoking (former smokers) habits. We tested for interaction under a multiplicative model between gender, smoking (ETS and former smokers) and each genotype by including an interaction term in the logistic regression models. D' linkage disequilibrium (LD) values were calculated in the control population using the maximum likelihood method (Arlequin ver. 2.000) and haplotype frequencies were estimated in cases and controls. Crude ORs and 95% CI were computed from contingency tables on derived absolute frequencies in cases and controls to identify possible unfavourable (at risk)/favourable (protective) haplotypes; each haplotype was compared with the sum of the remaining in order to increase the statistical power and due to the difficulty to define strong a priori reference haplotypes. We also used a Bayesian approach proposed by Wacholder et al. (30,31) to estimate the false positive report probability (FPRP) of positive results; this method requires the estimation (from previous biochemical or molecular information and/or results from meta-analyses) of the prior probabilities that the specific SNPs are associated with the disease under study. We gave a high prior probability (of 0.25) when (i) the biological plausibility was high and (ii) the existing epidemiological evidence of association with cancer was fair; a prior probability of 0.1 was given when the prior epidemiological evidence was poor but biological plausibility was high, and a prior probability of 0.01 when both were poor. The available epidemiological evidence did not allow higher prior probabilities. On this basis, we decided to consider a prior probability of 0.25 for XRCC1 codon 399 and for XRCC3 codon 241, 0.1 for XPD codon 751 and OGG1 codon 326, and ≤0.01 for all the other genes/polymorphisms, with the estimated statistical power to detect an OR of 1.5 or of 2.0 (or 0.67 and 0.5, respectively, if observed ORs were <1) and {alpha} level equal to the observed P-value. Given the many comparisons, we preferred to be conservative using a cut point of 0.2 for FPRP, even though we cannot exclude higher thresholds. All the analyses were performed by the SAS package for personal computers (SAS, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
We analysed 22 DNA repair SNPs (Table I) in 567 cancer patients (bladder cancer, 124; lung cancer, 116; oral/pharyngeal cancer, 43; laryngeal cancer, 39; leukaemias, 169; and COPD, 77) and in 1094 controls in the framework of the case–control Gen-Air project nested within the EPIC study. Oral/pharyngeal cancers and laryngeal cancers were pooled and defined as upper aero-digestive cancer (UADC). All polymorphisms studied were in Hardy–Weinberg equilibrium in controls except for XRCC1-Pro206Pro (P = 0.038) and LIG4 codon 3 (P << 0.0001); whereas, the XRCC1-Pro206Pro deviation can be disregarded, the second could strongly affect haplotype reconstruction, thus LIG4 results must be interpreted with caution. A genotyping error seems unlikely as 10% of samples have been re-genotyped with 99% of concordance. Genotype frequencies and ORs (95% CI) related to the variant alleles are shown in Table II for controls and cases (stratified by tumour type and COPD).


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  		Table II. Case–control distribution of genotypes for the different DNA repair gene polymorphisms

 
The variant allele frequencies in 1094 controls were as follows: APEX-148Glu = 0.48; OGG1-326Cys = 0.21; PCNA-3'-UTR C = 0.11; XRCC1-194Trp = 0.07; XRCC1-206Pro = 0.45; XRCC1-399Gln = 0.34; ERCC1-118Asn = 0.40; ERCC2/XPD-312Asn = 0.39; ERCC2/XPD-751Gln = 0.41; MGMT-84Phe = 0.14; BRCA1-871Leu = 0.33; BRCA2-372His = 0.28; LIG4-3Val = 0.08; LIG4-9Ile = 0.16; NBS1-185Gln = 0.31; RAD51-5'UTRG->C C = 0.07; RAD51-5'UTRG->T T = 0.42; RAD52-3'UTR T = 0.42; XRCC2-188His = 0.08; XRCC3-IVS6 -14 G = 0.29; XRCC3-241Met = 0.40; TP53-72Pro = 0.24. All the gene frequencies were in agreement with previous studies in Caucasian populations (http://perseus.isi.it/huge; http://www.ncbi.nlm.nih.gov/SNP/).

Few polymorphisms are individually associated with the diseases that we considered when analysed by either univariate (Table II) or multivariate analyses; results observed at univariate analyses were not further considered if significance was limited only to the heterozygotes, unless significances were confirmed by the multivariate analyses. Among the many comparisons (Table II), the following significant associations were found Table II: XRCC1-399 Gln/Gln variant homozygotes (OR = 2.20, 95% CI = 1.16–4.17) and XRCC3-241 Met/Met homozygotes (OR = 0.51, 95% CI = 0.27–0.96) in leukaemia, whereas for XRCC1-206 Pro/Pro (G/G) variant homozygotes the association was borderline (OR = 0.57, 95% CI = 0.32–1.01).

Stepwise multivariate analysis
Multivariate analyses were perfomed with stepwise selection of variables, using both a co-dominant and a recessive model. The first model did not reveal any significant association for lung and bladder cancers, but confirmed the protective effect for the XRCC1-206Pro (G) allele (OR = 0.65, 95% CI = 0.44–0.94) in the leukaemia group. A significant decreased risk emerged for the APEX-148Glu allele (OR = 0.59, 95% CI = 0.35–0.99) in UADC. The recessive model in the stepwise multivariate analysis revealed a protective effect of the XRCC1-399Gln/Gln in lung cancer (OR = 0.22, 95% CI = 0.05–0.98), and confirmed the opposite effect (OR = 2.47, 95% CI = 1.02–6.02) in the leukaemia group.

ETS, former smoking and gender
Table III shows the distribution of ETS, former smoking and gender in the current population. As we previously published (32), in the nested case–control study exposure to ETS was associated with increased risks (odds ratio 1.70, 1.02 to 2.82, for respiratory diseases; 1.76, 0.96 to 3.23, for lung cancer alone). Odds ratios were consistently higher in former smokers than in those who had never smoked. Except for leukaemia, all the other cancers are strongly related to smoking, and gender is a risk factor for most of the cancers, justifying a selection of these variables for the interaction analysis.


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  		Table III. Cases and controls stratified by country, gender, smoking status and ETS

 
After stratification by ETS, no significant association has been found for individual polymorphisms both in the exposed and non-exposed group, neither for each single kind of tumour or COPD, nor for the overall tumours. Among former smokers, an increased risk of lung cancer has been found for XPD-751Gln (C) carriers (CC versus AA, OR = 2.53, 95% CI = 1.00–6.44 and CA versus AA, OR = 2.84, 95% CI = 1.27–6.37, respectively; P = 0.007 for interaction), and also a possible increased risk of UADC for XRCC3-241Met/Met carriers (OR = 10.11, 95% CI = 1.02–99.93), although the CI is very wide due to subgrouping. In addition, the previously described associations with leukaemia seems to be limited to the never-smoker group: an increased risk for XRCC1-399Gln/Gln variant homozygotes (OR = 2.57, 95% CI = 1.19–5.52) and a decreased risk for XRCC3-241Met/Met homozygotes (OR = 0.33, 95% CI = 0.14–0.77; P = 0.007 for interaction).

A differential risk associated with gender seems also to be apparent, with an increased leukaemia risk among males for BRCA1-871Leu/Leu carriers (OR = 4.17, 95% CI = 1.25–13.92; P = 0.018 for interaction) and for ERCC1-118Asn/Asn (OR = 3.35, 95% CI = 1.23–9.13; P = 0.03 for interaction) among upper aero-digestive cancers. On the other hand, a protective effect on bladder cancer has been observed for XPD-751Gln/Gln female carriers (OR = 0.21, 95% CI = 0.05–0.86) and an increased risk for females heterozygotes for MGMT-84Leu/Phe (OR = 3.08, 95% CI = 1.18–8.02) and for NBS1-185Glu/Gln (OR = 2.88, 95% CI = 1.15–7.26).

No significant results have been observed for any of the polymorphisms in relation to air pollution expressed as either residence nearby heavy traffic roads or individual pollutants.

Haplotype analysis
We reconstructed maximum likelihood haplotypes for RAD51, XRCC1, XPD/ERCC1, XRCC3 and LIG4 genes (Table IV), and estimated haplotype frequencies and ORs (95% CI) for cases and controls. D' LD measures for the control population showed that the XRCC1 and XPD/ERCC1 genes are on two different LD blocks, although they are physically very close; thus, we reconstructed haplotypes separately. A significantly increased risk associated with the XPD/ERCC1-GAT haplotype was observed in bladder cancers (OR = 1.38, 95% CI = 1.06–1.79) and leukaemias (OR = 1.28, 95% CI = 1.02–1.61), even though a non-significant higher risk was evident for lung and UADC (Table IV). We found a slightly elevated odds ratio associated with the XRCC3-AC haplotype for leukaemias (OR = 1.28, 95% CI = 1.02–1.62). A reduced risk was observed for the XRCC1-TAG haplotype (OR = 0.69, 95% CI = 0.50–0.97) in the UADC. None of the associations with haplotypes were statistically significant in lung cancer and COPD.


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  		Table IV. Case–control distribution of estimated haplotypes for the different DNA repair gene polymorphisms

 
False positive report probability
On the basis of biological evidence and results from meta-analyses (see Introduction and Statistical methods), we considered a prior probability of 0.25 for XRCC1 codon 399 and for XRCC3 codon 241, 0.1 for XPD codon 751 and OGG1 codon 326, and ≤0.01 for all the other genes/polymorphisms. Table V shows the FPRPs for the statistically significant associations we observed from univariate and multivariate analyses, and from the haplotype analysis. None of the single SNP associations seems to be a truly positive association with disease at the prior probability levels defined above (Table V), with a statistical power to detect an OR of 1.5 or 0.67 and using a stringent FPRP cut point of 0.2, even though the XRCC1-206 polymorphism was associated at a prior probability level of 0.25 with leukaemia. However, considering an FPRP cut point of 0.5 most of the associations were likely to be true associations (Table V). Moreover, we identified three possible interesting haplotypes with FPRP ≤ 0.2 (Table V): an increased risk for XPD-ERCC1-GAT both in bladder cancer (prior probability = 0.1) and leukaemia (prior probability = 0.25), and an increased risk for XRCC3-AC in leukaemia (prior probability = 0.1); a decreased risk was observed for XRCC1-TAG in UADC but only with OR = 0.5 and a prior probability = 0.5.


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  		Table V. False positive report probability

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Most of the analysed DNA repair polymorphisms did not show any significant difference in the genotype distribution between cases and controls. However, several potential associations emerged from our data. Some associations were not stable in both univariate and multivariate analyses, but this was expected when considering different models of inheritance. Moreover, with the accumulation of evidence on DNA repair gene polymorphism data, some SNPs seem to have opposite risk trends in different cancer sites. This is the case of the XRCC1-399Gln/Gln which, with a recessive model in a stepwise multivariate analysis, revealed a strong protective effect on lung cancer risk, but had the opposite effect on risk of leukaemia (31,33,34). These results could simply indicate a chance association although a possible explanation could be the tissue specific balance between apoptotic signal and repair effects in the different tissues. Less efficient repair variants of specific repair pathways can result in a protective signal (accumulation of damage, cell-cycle block and apoptosis) in some tissues (e.g. lung) whereas in others (e.g. blood cells) they are risk factors (unrepaired or abortive attempt to repair damage and subsequent mutation). For many of the analysed polymorphisms there is insufficient functional information to formulate strong a priori hypotheses, but association studies suggested different risks for some cancer sites (http://perseus.isi.it/huge).

The XRCC1-Pro206Pro polymorphism was associated with a significantly reduced risk of leukaemia for carriers of the G variant allele, but this SNP does not lead to an amino acid substitution. For this reason, this polymorphism is unlikely to be the direct cause of a functional change (35). However, the relatively high frequency (0.38) of the minor allele gives the opportunity for linkage disequilibrium studies. As far as we know, this variant has been tested only in breast cancer (21), but no significant association was detected. The contrasting results reported for the well-studied XRCC1-Arg194Trp and XRCC1-Arg399Gln polymorphisms in different cancer sites (5,6; http://perseus.isi.it/huge) suggest that other polymorphisms and, in particular, a combination of SNPs in the XRCC1 gene could be more important than single SNPs. The decreased lung cancer risk that we observed for XRCC1-399 Gln/Gln homozygotes seems to be in agreement with the opposite ORs in smokers and non-smokers reported by Zhou et al. (36) and David-Beabes et al. (37)

We found also an association between the XRCC3-241Met variant allele and a reduced risk of leukaemia. No results has been previously reported for leukaemia although an increased risk has been shown by our group (38) and by Stern et al. (39) in bladder cancer, and by Winsey et al. (40) in melanoma. However, a putative protective effect has been described by Shen et al. (41) in bladder cancer and no association has been reported for cancers of the lung (42–44), skin (45–47), acute myeloblastic leukaemia (48), breast cancer (21,47), and gastric carcinoma (49). More extensive investigations on the combined and haplotype effects of SNPs in the XRCC3 gene are required to better clarify its possible involvement in cancer aetiology.

We also found that the APEX-148Glu variant allele was significantly associated with a reduced risk of UADC but there are no previous cancer association studies with this polymorphism. However, given the essential role played by this protein in BER and other pathways (4) we believe that it is important to investigate APEX polymorphisms in the future.

Notwithstanding the above results, after applying a method for the estimation of the number of false positive results, no polymorphism can be considered a true association, although with the power to detect an OR of 1.5 and a prior probability of 0.5 (as suggested by Wacholder et al. 2004, for smaller initial studies) most of the associations would not be considered likely false positive findings. However, it is also true that for some polymorphisms we could have been too much conservative in the estimation of false positive rate, in particular for those polymorphisms that are in linkage disequilibrium with other possible functional variants (e.g. XRCC1-206 polymorphism, Table V).

From a genetic perspective, in most multifactorial diseases, single polymorphisms in single genes are unlikely to alter the expression or function of specific proteins to the extent of producing a pathological phenotype. It is more likely that the combined effect of different SNPs in a gene produce a change in expression or protein function. Therefore, to look at the combination of putative functional SNPs, we further estimated haplotype frequencies for RAD51, XRCC1, XPD/ERCC1, XRCC3 and LIG4 genes; even though XRCC1 and XPD/ERCC1 are in the same chromosomal location (19q32.2) we did not find any significant LD between these two loci, as it has been described previously (20,23,25).

The most interesting result is the significantly increased risk of both bladder cancer and leukaemias associated with the XPD/ERCC1-GAT haplotype; a non-significant increased risk was also evident for the other cancers. These genes are included in the 19q13.2–13.3 chromosomal location that comprises two other genes (RAI and ASEI). This region seems to be the candidate for susceptibility to basal cell carcinoma (20,23) and post-menopausal breast cancer before the age of 55 years (25); in particular, the most significant results refer to the association with the polymorphisms in the RAI gene. Previous studies have found markers in XPD located near RAI to be associated with the development of melanoma, glioma and lung cancer (5,22,50,51). Thus it is possible that this limited region is important for other cancers as well. However, further studies are required to clarify whether the same haplotype could have different roles in different cancers as seems to be suggested by the accumulating data on single SNPs. In fact, we observed an increased risk of leukaemia for the XRCC3-AC haplotype, in agreement with Jacobsen et al. (52), who showed that this haplotype was associated with the risk of lung cancer.

The observed discrepancies among studies could be due not only to cancer and/or population-specific differences, but also to the sample sizes and multiple subgroup analyses; additional work to select tagging SNPs in DNA repair genes in different populations is required in order to better define possible high-risk haplotypes in relation to different ethnic/population-specific distributions. We have undertaken a better characterization of our control population in terms of allele and haplotype distributions among countries and centres. Although the vast majority of our samples are Caucasians, no specific information on ethnic origins has been collected. However, current studies on linkage disequilibrium variation in Europe stress the need to test for both ethnic and population-specific differences.

Few studies have been published on XRCC1 haplotypes and cancer (21,24,26,53) but unfortunately the results are not directly comparable due to the genotyping of different numbers of SNPs and of different polymorphisms. In particular, we analysed the XRCC1-Pro206Pro polymorphism, previously investigated only by Han et al. (21). Lee et al. (24) showed a protective effect on gastric cancer of the XRCC1 haplotype ‘A’ (194Trp/280Arg/399Arg) corresponding to our T (A)G haplotype; they also found an increased risk for the haplotype ‘D’ corresponding to our C (G)G/C (A)G haplotypes.

Along similar lines, Han et al. (21) described the protective effect on breast cancer of the XRCC1 haplotype defined by the XRCC1-194Trp variant, but the results were significant only when considering the single polymorphism. No significant association has been shown by Hao et al. (26) between oesophageal squamous cell carcinoma and XRCC1 haplotypes, except for the XRCC1-77T->C polymorphism. Likewise, no association was found by Yin et al. (53) of XRCC1 haplotypes with basal cell carcinoma.

Although on the basis of published data, no precise prior probability can be defined for haplotypes, we identified three possible interesting haplotypes (FPRP ≤ 0.2): increased risk for XPD-ERCC1-GAT both in bladder cancer and leukaemia, and increased risk for XRCC3-AC in leukaemia; a decreased risk was also observed for XRCC1-TAG in UADC but only with OR = 0.5 and a prior probability = 0.5.

Due to the limited contribution that single DNA repair SNPs seem to confer to the risk of UADC—at least in non-smokers—future studies should be designed to consider more SNPs of a specific gene trying to define possibly population-specific tagging SNPs, in order to confirm gene involvement in the (total or partial) absence of functional evidence. Our results suggest that a particular haplotype spanning the XPD-ERCC1 region may modulate leukaemia and bladder cancer risk and possibly also other cancers. Further investigations of the combined effects of polymorphisms within these DNA repair genes, smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process. Larger collaborative studies are required to investigate the above cancers in a non-smoker population.


   Acknowledgments
 
This paper was made possible by a grant from the European Community (5th Framework Programme) to PV (GENAIR investigation, grant QLK4-CT-1999-00927) and a grant from the Compagnia di San Paolo to the ISI Foundation. All authors are independent from funders. Also, the work described in the paper was carried out with the financial support of Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health; Spanish Regional Governments of Andalucia, Asturia, Basque Country, Murcia and Navarra; ISCIII, Red de Centros RCESP, C03/09, Spain; Cancer Research UK; Medical Research Council, UK; Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; Wellcome Trust, UK; Greek Ministry of Health; Greek Ministry of Education; Italian Association for Research on Cancer (AIRC); Dutch Ministry of Public Health, Welfare and Sports;World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skåne, Sweden; Norwegian Cancer Society; Research Council of Norway; Role of the sponsors: The sponsors did not have any input into study design, study conduct, data collection, analysis or interpretation, nor did they influence the preparation, review or approval of the manuscript.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received July 29, 2005; revised November 7, 2005; accepted November 15, 2005.


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