N-acetyltransferase (NAT) enzymes, NAT1 and NAT2, are involved in the activation and detoxification of tobacco smoke constituents. Polymorphisms in these genes alter the ability of these enzymes to metabolize carcinogens, as certain allelic combinations result in a slow or rapid acetylation phenotype. Glutathione S-transferases (GSTs) also detoxify tobacco smoke constituents, and polymorphisms within the GSTM1 and GSTT1 genes can result in a complete lack of enzyme activity.Cigarette smoking is an established risk factor for bladder cancer. Epidemiological and biological data suggest that genetic polymorphisms in activating and detoxifying enzymes may play a role in determining an individual's susceptibility to bladder cancer in particular when in combination with specific environmental exposures such as cigarette smoking. GSTM1, GSTT1, NAT1, and NAT2 genes and the risk of bladder cancer in two nested case-control studies within the Nurses' Health Study  and the Health Professionals' Follow-up Study . We also evaluated whether cigarette smoking modified the associations of the genotypes and bladder cancer risk in men and women.We assessed the association between common polymorphisms identified in the NAT2 slow genotype and an increased risk in male never smokers with the GSTM1 null genotype.Overall, we observed no statistically significant associations between the polymorphisms and bladder cancer risk among men and women, although given our sample size, we had limited power to detect small to moderate effects. There was however the suggestion of an increased risk among female ever smokers with the NAT2 slow acetylation and the GSTM1 null genotypes.In summary, these prospective results are consistent with previous literature supporting associations between bladder cancer and the  N-acetyltransferase (NAT) enzymes, NAT1 and NAT2, are involved in the metabolism of these carcinogens via O- and N- acetylation [NAT1 alleles, NAT1*3, NAT1*4, NAT1*10, NAT*11 [NAT2 alleles, NAT2*5, NAT2*6, NAT2*7, have been identified in Caucasian populations [NAT2 rapid acetylator alleles are classified as rapid-acetylator phenotype; individuals homozygous for NAT2 slow acetylator alleles are classified as slow-acetylator phenotype, and heterozygous individuals  are classified as the intermediate phenotype [NAT2 acetylation genotype compromises its detoxification ability, and studies have consistently observed an association between the slow NAT2 genotype and increased bladder cancer risk [NAT1*10 allele has been associated with a rapid phenotype [NAT1 variant alleles and bladder cancer risk with inconsistent results [Cigarette smoking is the predominant risk factor for bladder cancer in males and females -5. Carcitylation . NAT2 antylation ,9. Four cer risk . The prehenotype ,10 howevhenotype . Several results -20. Fewe results ,18-20.S-transferase M1 (GSTM1) is involved in the detoxification of polycyclic aromatic hydrocarbons (PAHs) and benzo(a)pyrene found in tobacco smoke [S-transferase T1 (GSTT1) is involved in activation and detoxification reactions and catalyzes the conjugation of industrial chemicals, e.g. ethylene oxides, with glutathione [GSTM1 and GSTT1 genes are common and result in a complete loss of enzyme activity [GSTM1 and GSTT1 may modify the risk of bladder cancer associated with these carcinogens. The GSTM1 null polymorphism has been consistently associated with an increased risk of bladder cancer in pooled and meta-analyses [GSTT1 in bladder carcinogenesis are more limited and inconsistent [Glutathione S-transferases (GSTs) are involved in the metabolism of environmental carcinogens, reactive oxygen species, and chemotherapeutic agents by catalyzing reactions between glutathione and electrophilic compounds ,22. Glutco smoke ,24. Gluttathione . Homozygactivity ,27. Becaanalyses ,23,28. Snsistent ,24,29-35GSTT1, GSTM1, NAT1, and NAT2 genes may be important in determining an individual's susceptibility to bladder cancer. Recent studies have also suggested that although the risk associated with each variant may be small, in combination with other genetic and/or environmental factors, the effects of the polymorphisms may be increased. We examined the associations between polymorphisms within these key genes and bladder cancer risk in a nested case-control study of women participating in the Nurses' Health Study (NHS) and a nested case-control study of men participating in the Health Professionals' Follow-Up Study (HPFS). Furthermore, we assessed the potential for effect modification by cigarette smoking for the associations between the genotypes and bladder cancer risk.Since exposure to tobacco smoke carcinogens is a risk factor for bladder cancer, genetic modulation of carcinogen metabolism may explain some inter-individual bladder cancer susceptibility. Given their biological role, polymorphisms within the The NHS began in 1976 when 121,700 female United States registered nurses aged 30–55 years completed a self-administered questionnaire. Detailed information on individual characteristics and behaviors was obtained from the questionnaires at baseline and biennially thereafter. Between 1989 and 1990, blood samples were collected from 32,826 women; follow-up for this subcohort exceeds 96%. The methods used for blood collection have been previously detailed .NAT2 polymorphisms were included in unconditional logistic regression analyses to stabilize confidence intervals. A subset of the extra controls (n = 466) from the breast cancer nested case-control study [GSTM1 and GSTT1 polymorphisms and included in the unconditional logistic regression analyses. The study protocol was approved by the Committee on Use of Human Subjects of the Brigham and Women's Hospital, Boston, MA. Completion of the self-administered questionnaire and receipt of the blood sample were considered to imply informed consent.In our study, we included both incident and prevalent bladder cancer cases from the NHS blood cohort. Trained physicians who were blinded to exposure information reviewed hospital records and pathology reports. We were able to confirm approximately 95% of self-reported bladder cancer cases. Eligible incident cases consisted of women with confirmed bladder cancer that had been diagnosed anytime after blood collection (1989–90) and up to June 1, 2000, with no previously diagnosed cancer except for nonmelanoma skin cancer. Prevalent cases were defined as having confirmed bladder cancer diagnosed after questionnaire return in 1976 and before the date of blood collection, with no previously diagnosed cancer except for nonmelanoma skin cancer. Controls were randomly selected participants who had given a blood sample and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the case was diagnosed. Controls were matched to cases 3:1 according to year of birth, smoking status at blood draw (never versus ever), month of blood collection, and fasting status at blood draw . This case-control study consists of 78 bladder cancer cases , and 234 matched controls. In addition, 2646 women who were controls in either a nested case-control study of breast cancer (n = 1686) ,38, colool study  were genThe HPFS is an ongoing prospective study of the causes of chronic diseases in men. The cohort began in 1986 when 51,529 U.S. male health professionals aged 40 to 75 years responded to a mailed questionnaire . These mNAT2 polymorphisms were included in unconditional logistic regression analyses. Completion of the self-administered questionnaire and receipt of the blood sample were considered to imply informed consent.In our study, we included both incident and prevalent bladder cancer cases from the HPFS blood cohort. All cases in this analysis were confirmed through histopathologic reports reviewed by a study investigator. Eligible incident cases consisted of men with confirmed bladder cancer that had been diagnosed anytime after blood collection (1993–95) and up to June 1, 2000, with no previously diagnosed cancer except for nonmelanoma skin cancer. Prevalent cases were defined as having confirmed bladder cancer diagnosed after questionnaire return in 1986 and before the date of blood collection, with no previously diagnosed cancer except for nonmelanoma skin cancer. All controls were randomly selected participants who had given a blood sample and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the case was diagnosed. Controls were matched to cases 2:1 according to year of birth, smoking status at blood draw , fasting status , and month of sample collection. For cases accrued from 1998 to 2000, controls were matched to cases 3:1 with the previously described matching factors to increase our statistical power. This case-control study consists of 139 bladder cancer cases , and 293 matched controls. In addition, 1028 men who were controls in either a nested case-control study of colon cancer (n = 321) or colon polyps (n = 707), were free of cancer other than nonmelanoma skin cancer, and were also genotyped for the three Venous blood samples were separated into plasma, buffy coat, and red blood cells and stored in liquid nitrogen. Genomic DNA was extracted from 50 μL buffy coat diluted with 150 μL of PBS using the QIAGEN QIAmp  96-spin blood protocol according to the manufacturer's instructions. Genomic DNA concentrations were calculated in 96-well format using PicoGreen technology .NAT2 I114T (NAT2*5A), R197Q (NAT2*6A), and G286E (NAT2*7A) polymorphisms were genotyped by the 5' nuclease assay (Taqman) on the ABI PRISM 7900HT Sequence Detection System . A description of and methods for each NAT2 assay can be found at the National Cancer Institute SNP500Cancer website [NAT2*14 allele (G191A) [NAT2*5A, NAT2*6A, NAT2*7A)[NAT2*4 allele.Genotyping was performed at the DFCI/Harvard Cancer Center High Throughput Genotyping Core. The  website . We did  (G191A) . For conNAT1 alleles, NAT1*3 (C1095A), NAT1*4 (wildtype), NAT1*10 (C1095A and T1088A), NAT1*14 , and NAT1*11 (deletion of nine nucleotides from 1080 to 1088) [NAT1*4 allele is the most common allele in all populations studied, and the homozygous NAT1*4 genotype has been associated with normal NAT1 acetylation activity [NAT1*10 allele is considered the putative rapid allele in comparison with NAT1*3, NAT1*4, NAT1*11, and NAT1*14 [NAT1*10 genotype were classified as either homozygous or heterozygous rapid acetylators.We genotyped four common to 1088) ,44. The activity . The NATGSTT1 and GSTM1 deletions were determined by polymerase chain reaction (PCR) using a previously published protocol [Genotypes for the protocol . In bothAll genotyping was performed by laboratory personnel blinded to case-control status, and blinded quality control samples were inserted to validate genotyping identification procedures; concordance for blinded samples was 100%.2 test to assess whether the genotypes were in Hardy-Weinberg equilibrium and to determine P values for differences in genotype frequencies between cases and controls. The associations between the genotypes and bladder cancer risk were examined by using conditional and unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Unconditional logistic regression models assessing the main effect of the genotype on bladder cancer risk included the additional control groups to maximize the sample size, stabilize CIs, and to increase the power to detect meaningful associations. In addition to the matching factors, analyses were also adjusted for packyears of smoking (i.e. average reported number of cigarette packs smoked per day multiplied by the number of years of smoking). Inclusion of additional factors, e.g. geographic region, alcohol intake, cruciferous vegetable intake, did not substantially change the point estimates, and therefore these factors were not included in the final models. To test statistical interactions between the genotypes and cigarette smoking in unconditional models, we first used a likelihood-ratio test (LRT) to compare nested models that included terms for all combinations of the genotypes and cigarette smoking status to the models with indicator variables for the main effects only . To test the statistical interaction between the various genotypes, a similar approach was employed. All p-values are two-sided. We used the SAS Version 8.2 software . Because the allele frequencies of NAT1, NAT2, GSTM1, and GSTT1 differ by ethnicity [GSTM1 null genotype assuming a genotype prevalence of 50%; OR = 2.0 for the GSTT1 null genotype assuming a genotype prevalence of 15%; OR = 1.9 for the NAT2 slow acetylation genotype assuming a genotype prevalence of 62%; OR = 1.8 for the NAT1*10 carrier assuming a genotype prevalence of 35%. We had 80% power to detect the following ORs for the women: OR = 2.1 for the GSTM1 null genotype assuming a genotype prevalence of 50%; OR = 2.4 for the GSTT1 null genotype assuming a genotype prevalence of 15%; OR = 2.3 for the NAT2 slow acetylation genotype assuming a genotype prevalence of 62%; OR = 2.1 for the NAT1*10 carrier assuming a genotype prevalence of 35%.We used a χthnicity ,24,45,46Our study population included 78 bladder cancer cases and 234 matched controls from the NHS and 139 bladder cancer cases and 293 matched controls from the HPFS for a total of 217 bladder cancer cases and 526 matched controls. The risk factor profile for female bladder cancer cases and controls were similar with no statistically significant differences between cases and controls . Therefore, all incident and prevalent cases in each cohort were combined to form one case group for all statistical analyses. The genotype frequencies were in Hardy-Weinberg equilibrium for cases and controls. The allele frequencies among the controls for the GSTM1 null allele, GSTT1 null allele, NAT2 rapid genotype, and the NAT1 rapid genotype were similar to previously published reports in Caucasians [We compared the distributions of the ucasians ,38,46,47GSTM1 null genotype was similar among cases and controls , in contrast to the GSTT1 null genotype, which was more prevalent in cases than controls . After adjusting for the matching factors and packyears of smoking, we observed no association between the GSTM1 and GSTT1 polymorphisms and bladder cancer risk in women (Table GSTM1 and the GSTT1 null genotypes and bladder cancer risk (p for interaction > 0.30). Our results also do not support a gene-gene interaction between the GSTT1 and GSTM1 polymorphisms (p for interaction = 0.88).In the NHS, the prevalence of NAT2 slow acetylation genotype was similar among cases and controls   (p for interaction = 0.15). We observed no significant association between bladder cancer risk and individuals carrying the NAT1*10 allele (Table NAT1 genotypes and bladder cancer risk (p for interaction > 0.10).The frequency of the GSTM1 and GSTT1 genotype frequencies among cases and controls , and no statistically significant associations between the GSTM1 and GSTT1 polymorphisms and bladder cancer risk in males . Among never smokers, the GSTM1 null genotype was associated with a statistically significant increased risk ), and among ever smokers, the OR was 0.96 . The association between GSTT1 polymorphism and bladder cancer risk remained similar after stratification by smoking status (p for interaction = 0.69), and no significant gene-gene interactions with GSTM1 and GSTT1 were detected (p for interaction = 0.22).There were no significant differences in es Table . We did NAT2 slow acetylation genotype was similar among cases and controls  .The frequency of the e.g. from cigarette smoking. Overall, in our population-based case-control study, we observed no statistically significant associations between the GSTT1, GSTM1, NAT1, and NAT2 polymorphisms and bladder cancer risk.Evidence suggests that polymorphisms in activating and detoxifying enzymes may interact to effect the level of DNA damage sustained by a specific tissue and ultimately influence disease risk . TherefoNAT2 slow acetylation genotype and increased bladder cancer risk in female smokers. Our findings are biological plausible and are consistent with a recent study in Spain [NAT1 polymorphisms may also affect individual bladder cancer risk by interacting with cigarette smoking. Our findings do not support an association between the NAT1 polymorphisms, cigarette smoking, and bladder cancer; however we had little power to detect such an association. Additional studies that have assessed the relationship between NAT1*10 allele and bladder cancer risk have been inconsistent with some studies observing an increased risk [NAT1*10 allele.Aromatic amines within tobacco smoke are the most important class of bladder carcinogens . These cin Spain , which fsed risk ,20, a desed risk , or no ased risk ,16,18,19GSTM1 polymorphism and bladder cancer risk, which is in contrast with previous findings [GSTT1 polymorphism on bladder cancer susceptibility is less certain. Studies that have addressed the role of GSTT1 polymorphism and bladder cancer have been inconsistent. Of the published studies, some suggest an increased risk [GSTT1 null genotype, others no association [GSTT1 polymorphism and bladder cancer risk.We observed no significant associations with the findings ,23. The sed risk ,31,34,35ociation ,29,30, aociation . We obsei.e. cigarette smoking) prior to bladder cancer diagnosis. We were also able to formally assess and test gene-environment interactions. However, our study has a small sample size resulting in low power to detect minor to modest genotype-disease associations and gene-environment interactions, therefore such associations cannot be ruled out.The strengths of our study include the prospective design and the detailed collection of exposure information  declare that they have no competing interests.MM carried out the data analysis and wrote the manuscript. DM and ID conceived of the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Whether polymorphisms in these genes affect breast cancer risk or prognosis is still unclear. In this study, we focus on a rare non-synonymous polymorphism in cMyc (N11S) and a common polymorphism in p27 (V109G) and determine their role in risk and prognosis using data collected from the Ontario Breast Cancer Family Registry.Risk factor data was collected at baseline on a large group of women  and clinical data (including treatment and follow-up) were collected prospectively by periodic review of medical records for a subset of cases (N = 967) for nearly a decade. A centralized pathology review was conducted. Unconditional logistic regression was used to determine the association of polymorphisms with breast cancer risk and the Cox proportional hazards model was used to determine their association with survival.Our results suggest that while cMyc-N11S can be considered a putatively functional polymorphism located in the N-terminal domain, it is not associated with risk, tumor characteristics or survival. The p27-G109 allele was associated with a modest protective effect in adjusted analyses and higher T stage. We found no evidence to suggest that p27-V109G alone or in combination with cMyc-N11S was associated with survival. Age at onset and first-degree family history of breast or ovarian cancer did not significantly modify the association of these polymorphisms with breast cancer risk.Further work is recommended to understand the potential functional role of these specific non-synonymous amino acid changes and a larger, more comprehensive investigation of genetic variation in these genes  in combination with other relevant genes is needed as well as consideration for treatment effects when assessing their potential role in prognosis. Several studies have implicated cMyc and p27 in breast cancer ,2. cMyc Whether genetic variation in these two genes affects cancer risk or prognosis is not yet known. To our knowledge, only seven studies have examined polymorphisms in cMyc and p27 and all except one, which looked at haplotypes in p27, have focused on either cMyc-N11S or p27-V109G -9. cMyc-In this study, we explore whether these non-synonymous single nucleotide polymorphisms (nsSNPs) in cMyc (N11S) and p27 (V109G) are important risk and prognostic factors in breast cancer using a large, population-based cohort of incident breast cancer with systematically collected clinical data from the Ontario Familial Breast Cancer Registry (OFBCR).Our study sample consisted of incident histo-pathologically confirmed cases of primary breast cancer from the population-based OFBCR ,11. RecrTo conduct case-control studies, the OFBCR also collected unrelated, unaffected population controls (N = 710). They were recruited by calling randomly selected residential telephone numbers throughout the same geographical region. Eligible controls were women with no history of breast cancer and characteristics of the control population have been shown to be representative of the target population . ApproxiFor the prognostic study, those patients who provided a blood sample, had no prior malignancy  and consented to retrieval of medical records were followed prospectively for clinical outcomes. The study methodology has been reported elsewhere . In brieApproval for this study was obtained from the Research Ethics Board of Mount Sinai Hospital and the University of Toronto.We identified non-synonymous polymorphisms in cMyc and p27 that may be biologically relevant using the NCBI dbSNP database by considering whether they were deleterious changes using two bioinformatics tools: SIFT  and PolyPearson's chi-squared test or Fisher's exact test was used to determine the association between genotypes and patient/tumor characteristics. Variables were defined according to standard convention in order to facilitate comparison with other published studies. Age was dichotomized at 50 years of age to represent the approximate age of menopause for stratified analysis. An individual was considered to have a family history of cancer if she had a first-degree female relative with breast or ovarian cancer at the time of diagnosis (or date of entry for controls) since first-degree family history has been shown to be valid and reproducible by self-report for breast cancer . Stage wdf. We report association results for a co-dominant model unless there were few variant homozygotes. The associations between SNPs and breast cancer risk were estimated as odds ratios (OR) and 95% confidence intervals (95% CI) by unconditional logistic regression adjusting for age (years) and ethnicity . We stratified by age and family history to compare risk estimates in each category. Tests for interaction by inclusion of the corresponding product terms in logistic models were non-significant (data not shown).Genotype frequencies among the controls were tested for Hardy-Weinberg equilibrium (HWE) using Pearson's chi-square test with 1 Contingency table analyses were used to examine the associations between selected tumor characteristics and genotypes among cases with complete clinical follow-up. The primary clinical outcomes were time to distant recurrence and death. Survival time was calculated from date of surgery to these endpoints, censoring at the date of last contact or date of non-breast primaries. The Cox proportional hazard model was used to evaluate the crude and covariate-adjusted associations of factors with survival. The final multivariable model included established prognostic factors regardless of level of significance or confounding. Family history and ethnicity were also included because of their potential association with genotype. Graphical evaluation by Schoenfeld's residual plot indicated that the proportional hazard assumption of the Cox model could not be rejected for any of the covariates. Stratified analyses by age or family history were not conducted due to limited sample size.To account for the sampling design in this study we also conducted a weighted analysis using the inverse of the sampling fractions as weights, and found no material differences. Therefore, we report results only from the unweighted analysis. Furthermore, our associations remain unchanged if limited to non-Ashkenazi or non-BRCA cases (data not shown).For analyses of combined cMyc and p27 alleles we report all possible combinations using the most common genotypes as the reference category in order to obtain stable risk estimates, and avoid testing all possible combinations.A priori power calculations using Quanto  showed tMissing data for given variables were reported in tables if >10% and all tests were two-sided. We did not adjust for multiple testing since this study focused on a few a priori defined hypotheses.The majority of breast cancer cases were White pre-menopausal women and slightly more than a third had a first-degree family history of breast or ovarian cancer Table . There wcMyc-N11S genotypes were not associated overall with breast cancer risk Table . The p27Table There was no association between any of the polymorphisms or their combined alleles and either distant-recurrence free survival or overall survival Table . Tests fThere has been great interest in understanding the role of cMyc and p27 amplification/expression in breast cancer risk and prognosis, but surprisingly little on the role of polymorphisms. Our study fills this gap by presenting findings on the role of two specific polymorphisms in these genes. Our data suggests that the p27-G109 allele may confer a protective effect against breast cancer. This observation needs to be confirmed by other breast cancer studies, since there is disagreement in the published literature about its potential role. A previous publication by our group showed no association with a smaller sample size , as did jab1 because it is located in the interaction surface [jab1 and thereby modify p27 degradation. However, since data from a homology-based bioinformatic tool suggests that this amino acid substitution is not deleterious [Previous studies have shown that reduced p27 expression correlates with poor clinical outcomes, invasiveness, poor prognosis, high tumor grade and progression in breast cancer [ surface . Since peterious , this isOur results do not confirm the recent findings by Wirtenberger et al. (2005) , who fouOur study also showed that the cMyc-N11S polymorphism was not related to any patient or tumor characteristic or prognosis. No other study has been published on this topic. In general, the role of cMyc in breast cancer prognosis is unclear. cMyc can direct cells to either proliferation, differentiation or apoptosis ,26. HoweWe believe this study represents an important contribution to the published literature. We investigated two polymorphisms that can be considered to be strongly biologically relevant in breast cancer. However, our study is limited in statistical power for the survival analysis as noted by the wider confidence intervals, and we cannot exclude the possibility of very small effects of these polymorphisms (OR<1.5). Nevertheless, this study still represents, to our knowledge, the largest study of cMyc-N11S in cancer risk and the only study examining prognostic effects in breast cancer. This is the largest investigation of the p27-V109G polymorphism in cancer risk and prognosis. It is also important to note that this study is investigating only two nsSNPs and indirectly any SNPs in strong linkage disequilibrium. Over-sampling cases that are likely to be genetically predisposed may be considered a limitation in terms of the generalizability of our results, but we have shown that genetic risk is not associated with survival in this cohort, and therefore cannot be a source of confounding . FurtherOur results do not support the hypothesis that these specific nsSNPs are strong factors influencing breast cancer risk or prognosis, although there is some suggested protective effect of the p27-G109 allele in risk. We have three recommendations for future studies: (i) a thorough functional analysis of the effect of these nsSNPs; (ii) focus on polymorphisms in coding or the promoter regions and the identification of those variants that correlate with intermediate phenotypes such as cMyc amplification and p27 over-expression, which are clinically relevant; and (iii) a comprehensive study of the association between genetic variation of these genes and breast cancer prognosis with consideration for the effect of treatment , which The author(s) declare that they have no competing interests.JCF participated in the defining the study objectives and design, performing the statistical analysis and writing the manuscript. JAK assisted in outlining the study objectives and design and manuscript writing. SC and SS assisted in the genotyping and manuscript writing with respect to the functional and bioinformatic aspects. LB assisted with the statistical analysis. UVO assisted in the genotyping of the p27 polymorphism. PJG assisted with study design of the prognostic study. JRM assisted with defining the study objectives and design and manuscript writing. ILA assisted with the study objectives and design and manuscript writing. HO assisted with the genotyping and manuscript writing. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA.The gene XRCC1 polymorphisms and breast cancer.Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer risk.We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers  than never smokers . An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes , and not in women who were lifelong non-smokers . No other factor examined modified the association between XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes.Our results support the hypothesis that genetic variation in  XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA BER that is essential in drawing different components of BER to the site of DNA damage and promoting efficiency of the BER pathway [Base excision repair (BER) corrects localized DNA damage such as oxidized or fragmented lesions and non-bulky adducts . Sources pathway ,5.XRCC1 gene contains 17 exons and is located on chromosome 19q13.2 [XRCC1  and Arg399Gln ) have been shown to alter DNA repair capacity in some phenotypic studies and have received considerable attention. The Trp194 variant has been associated with increased BER capacity, whereas the Gln399 variant has been associated with reduced repair capacity [XRCC1 expression has been examined extensively in relation to various age-related diseases, including cancer [The  19q13.2 . Althougcapacity -11. Becag cancer . DNA repXRCC1 polymorphisms Arg194Trp and Arg399Gln in relation to breast cancer risk, with inconsistent results [XRCC1 polymorphisms and breast cancer risk are stronger in women who smoke or who have higher exposure to various antioxidants [XRCC1 polymorphisms and breast cancer risk generally have been null [So far, 12 observational studies have examined  results ,14-24. Soxidants ,14,24,25oxidants ,19,21-23oxidants ,20,24,25oxidants ,20, one oxidants ,25, and XRCC1 polymorphisms aside from Arg194Trp and Arg399Gln [n = 250 cases) study population. Although the Arg280His polymorphism is non-synonymous, there is no functional data to support its potential role in repair capacity. A larger study  conducted by Han et al. [XRCC1 polymorphisms are all part of one haplotype block, but did not observe an association with haplotype blocks [XRCC1 that have been shown to have functional relevance in DNA repair capacity (Arg194Trp (rs1799782) and Arg399Gln (rs25487)) and postmenopausal breast cancer risk in a case-control study nested in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort.To our knowledge, only one previous study observed an association with any e blocks . On the Women in this analysis were drawn from the 97,786 female participants in the CPS-II Nutrition Cohort, which was established by the American Cancer Society in 1992 as a subgroup of the larger 1982 CPS-II baseline mortality cohort . Most pan = 21,965 women). After obtaining informed consent, we collected a maximum of 43 ml of non-fasting whole blood from each participant and samples were separated into aliquots of serum, plasma, red blood cells, and buffy coat. Samples then were frozen in liquid nitrogen vapor phase at about -130°C for long-term storage.From June 1998 to June 2001, blood samples were collected from a subgroup of 39,376 cohort members ; however, collection of DNA from buffy coat occurred in 1998 to 2001, in some cases after or only slightly before cancer diagnosis. For each case, we randomly selected one cancer-free (except non-melanoma skin cancer) female Nutrition Cohort control matched on single year of age (±6 months), race/ethnicity , date of blood collection (within 6 months), and selected from individuals who were cancer-free (except for non-melanoma skin cancer) at the beginning of the interval preceding the diagnosis of each case using risk-set sampling . The womDNA was extracted from buffy coat and genotyping assays were performed with TaqMan  as described previously . Genotyp2 test to assess whether XRCC1 genotype distributions were in Hardy-Weinberg equilibrium. Conditional logistic regression was used to examine the association between the XRCC1 polymorphisms and breast cancer in two models, one controlling for matching factors only and the other controlling for matching factors and other possible confounders.We used a χConditional logistic regression modeling was performed because controls were individually matched at the time of selection to each case patient. Potential confounders included in the multivariate models included education , age at menopause  and menarche , parity , age at first live birth , personal history of benign breast disease , family history of breast cancer in mother or sisters , alcohol intake , postmenopausal hormone replacement use , smoking status , body mass index , and physical activity  per week) . With the exception of age at menopause (8.5% missing), all covariates had less than 3.5% values unknown.XRCC1 polymorphisms and breast cancer risk, we constructed multiplicative interaction terms with cigarette smoking, fruit and vegetable intake, alcohol intake, physical activity, body mass index, folate intake, and multivitamin use. We also tested for potential interaction between the two polymorphisms of interest. Statistical interaction was assessed in multivariate models using the likelihood ratio test, and p < 0.05 was considered statistically significant [To test whether factors proposed to be associated with oxidative stress modified the association between nificant .XRCC1 polymorphisms and breast cancer. Because the Trp194 allele is uncommon , logistic regression models combined the Trp194 carriers (Trp/Trp and Arg/Trp genotypes combined) and compared them with non-carriers (Arg/Arg). After adjustment for various factors, breast cancer risk was 38% lower among Trp194 carriers than among non-carriers . Risk was 27% higher among women who were homozygous for the Gln399 variant than among women homozygous for the wild-type (Arg) allele, although this was not statistically significant , with a median age of 62 years (range 43 to 75) at enrollment in 1992. Table a priori that the association between XRCC1 polymorphisms and breast cancer risk might be stronger in women who had experienced greater exposure to DNA-damaging agents, such as tobacco smoke. Carriers of Trp194 were at lower risk of breast cancer than Trp194 non-carriers regardless of smoking status, although the inverse association was slightly attenuated among lifelong non-smokers . Among women who had ever smoked cigarettes, the OR was 2.76 when comparing the Gln/Gln399 genotype with the Arg/Arg399 genotype (95% CI 1.36 to 5.63), whereas no increased risk was associated with this polymorphism among lifelong non-smokers . The association between XRCC1 polymorphisms and breast cancer risk also did not differ by age at diagnosis or stage of disease (data not shown). Finally, when assessing the combined effects of both XRCC1 polymorphisms on breast cancer risk, women with 'low-risk' genotypes for both polymorphisms (Trp194 carriers and Gln399 non-carriers) had a 49% lower incidence of breast cancer than women with 'high-risk' genotypes for both polymorphisms .The association between XRCC1 may affect a woman's breast cancer risk, especially in women who have ever smoked cigarettes. Overall, women carrying the Trp194 allele had a 38% lower incidence of breast cancer than women who were Trp194 non-carriers. This association persisted regardless of smoking history. In contrast, the relationship between the Arg399Gln polymorphism and breast cancer risk seemed to be limited to women who had ever smoked. Among ever smokers, women with the Gln/Gln399 genotype had a 2.76-fold higher risk of breast cancer than women with the Arg/Arg399 genotype; however, we did not observe an increased risk among women who had never smoked.Results from this study support the hypothesis that genetic variation in XRCC1 polymorphisms and breast cancer risk that reported an inverse association between the Trp194 carriers and breast cancer risk in mostly Caucasian [Our findings are consistent with those from four previous studies of aucasian ,14 and oaucasian ,22 ethniaucasian ,17,23 oraucasian  associataucasian ,23, wheraucasian -22,24.XRCC1 Arg194Trp and Arg399Gln polymorphisms have been shown to affect XRCC1 protein-product expression and to alter BER capacity [XRCC1 have been associated with risk of many smoking-related cancers such as lung, bladder, and esophageal cancer [XRCC1 polymorphisms and breast cancer risk in subgroups of the population that may experience higher levels of DNA damage, such as smokers. Only two [XRCC1 variation by smoking reported evidence of effect modification by smoking status. Duell et al. [et al. [XRCC1 polymorphisms and breast cancer did not observe any meaningful differences by factors such as family history [capacity -11. Oxidl cancer . HoweverOnly two ,24 of foOnly two ,14,20,24 [et al. , had a p [et al. , or had  [et al. . However history ,23, ioni history ,20,24.XRCC1 polymorphisms and breast cancer risk among smokers in this study is interesting and adds support to the hypothesis, we cannot exclude chance as a possible explanation for the findings. For this reason, further replication of the findings is needed in larger study populations with higher smoking prevalence. Strengths of our study include the prospective collection of questionnaire data, which eliminates the potential for selection bias, and the extensive information collected from questionnaires on various factors that may be associated with oxidative DNA damage.The primary limitation of our study is the limited statistical power to examine whether factors such as the duration of smoking modify the association between breast cancer and the polymorphisms of interest. The statistical power is limited by both small sample size and low frequency of smokers in our cohort. Although the association observed between XRCC1 may be associated with postmenopausal breast cancer risk, especially among women who have ever smoked. Additional studies are needed to examine the association of these polymorphisms with breast cancer risk, focusing on subpopulations that may experience greater exposure to DNA-damaging agents.Our results suggest that non-synonymous coding polymorphisms in XRCC1 = X-ray cross-complementing group 1.BER = base excision repair; CI = confidence interval; CPS-II = Cancer Prevention Study II; OR = odds ratio; The authors declare that they have no competing interests.AVP was the principal investigator, developed the analytic plan, and drafted the manuscript. EEC participated in study design, conception of the study hypotheses, and critical review of the manuscript. ALP performed statistical analyses. HSF, MJT, and CR contributed to the analytic plan and were involved in critical review of the manuscript. All authors read and approved the final manuscript.


XRCC1  and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking.It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated by unconditional logistic regression analyses.XRCC1-399 Gln allele  or XPD-751 Gln/Gln genotype  compared to smoking women not carrying these genotypes. The risks were found to be confined to women smoking at least five pack-years; the respective ORs were 4.14 (95% CI 1.66–10.3) and 4.41 (95% CI 1.62–12.0). Moreover, a significant trend of increasing risk with increasing number of the putative at-risk genotypes (p for trend 0.042) was seen. Women with at least two at-risk genotypes had an OR of 1.54 (95% CI 1.00–2.41) compared to women with no at-risk genotypes. Even higher estimates were seen for ever actively smoking women with at least two at-risk genotypes.No statistically significant overall effect in the breast cancer risk was seen for any of the studied polymorphisms. However, a significant increase in breast cancer risk was seen among ever smoking women if they carried at least one XRCC1 and XPD polymorphisms in breast cancer susceptibility, but suggest that they may modify the risk especially among smoking women.Our results do not indicate a major role for  Breast cancer is the most common female cancer among western societies and its incidence increases constantly. Hormonal factors like early age at menarche, later age at menopause, later age at first full term pregnancy, and hormone replacement therapy are known to be the main risk factors for sporadic breast cancer ,2. Also,Unrepaired or misrepaired DNA damage can lead to gene mutations, chromosomal alterations, and genomic instability, known to have a role in cancer initiation. Accordingly, individuals with reduced DNA repair capacities might have an altered cancer risk -11. DuriXRCC1 (X-ray repair cross-complementing group 1) is known to participate in base excision repair (BER) of small lesions such as oxidized or reduced bases, fragmented or nonbulky adducts, and lesions caused by methylating agents . The XRCXRCC1 gene [XRCC1 Arg280His polymorphism lies in between the DNA polymerase β and PARP binding areas [280His variant allele has been suggested to confer increased mutagen sensitivity [Three gene polymorphisms resulting in non-conservative amino acid substitutions  have been identified in the CC1 gene . Two of CC1 gene . The XRCng areas . The 280sitivity  and breasitivity -22.XRCC1 Arg399Gln polymorphism is located in the area coding for a PARP binding site. PARP is a zinc-finger containing enzyme that detects DNA strand breaks [XRCC1-399 Gln variant allele have been shown to have higher levels of DNA adducts [399Gln variant allele and breast cancer risk has been seen in some studies [The d breaks . Carrier adducts  and to b adducts  and toba adducts -27. A po studies ,22,28,29 studies ,29-36.XPD (XP complementation group D) gene encodes a helicase involved in transcription and in the NER pathway by unwinding of double helix at the site of deleterious DNA lesions [XPD gene. Two of these SNPs lead to amino acid change, Asp312Asn in exon 10 and Lys751Gln in exon 23, and are in strong linkage disequilibrium with each other [XPD-751 Gln variant allele has been associated with increased DNA adduct levels [The nucleotide excision repair (NER) pathway repairs a wide variety of DNA damage, including cross-links, oxidative damage and bulky adducts (such as polycyclic aromatic hydrocarbon (PAH)-DNA adducts). The  lesions . Severalch other . The XPDt levels ,40 and st levels ,38, but t levels . It has t levels  and squat levels , and rect levels . Contrast levels ,40,45-47XRCC1 Arg280His, XRCC1 Arg399Gln, and XPD Lys751Gln polymorphisms in breast cancer susceptibility in our Finnish Caucasian study population. We especially aimed at examining the genotype effects in relation to smoking, which is known to cause DNA damage repaired by DNA repair enzymes of the BER and NER pathways. The role of alcohol was also evaluated in this context.In this study, we evaluated the role of Breast cancer cases had been referred by a physician to the Kuopio University Hospital (Finland) during the recruiting period from 1990 to 1995 because of a suspect breast sign or symptom. Women were asked to participate in the study and were interviewed by a trained study nurse before any diagnostic procedures. The study was approved by the Joint Committee of the University of Kuopio and Kuopio University Hospital. Participation was based on written consent.A total of 516 out of 1,919 women were eventually diagnosed with histologically confirmed breast cancer. The details of the study population and recruitment have been described earlier . The conHealthy population controls living in the same area as the cases were a randomly selected group of subjects drawn from the Finnish National Population register. They were initially contacted by a letter explaining the study protocol, and subsequently called up and invited to the hospital to be interviewed. In all, 514 controls were interviewed in parallel with the cases, all of whom agreed to participate in a genetic study. The cooperation rate for the controls was 72%.Blood samples were collected at the time of the interview. Lymphocyte DNA was available for 483 breast cancer patients and 488 controls. Six subjects among controls were excluded, four because of earlier breast cancer diagnosis and two because of non-Finnish origin. The final case group included 483 cases  and 482 controls , all of Finnish Caucasian origin.Detailed data on smoking habits included the amount of cigarettes with or without filter/day, years of smoking, time since quitting smoking, and time (in years) of passive smoking at home and/or at work.XRCC1 Arg280His genotype determination, a 282 base pair (bp) fragment was amplified using the primers described earlier [RsaI, the 280Arg wild-type allele was revealed by two 141 bp fragments, while an intact 282 bp fragment indicated the presence of the 280His variant allele.Lymphocyte DNA (100 ng) extracted by standard methods was used as a template in PCR-based restriction fragment length polymorphism (RFLP) assays. For the  earlier . After dXRCC1 Arg399Gln genotype analysis, a 615 bp fragment amplified using the primers described in [MspI restriction enzyme; the XRCC1-399 Arg wild-type allele was revealed by the presence of 221 bp and 374 bp fragments while the 399Gln variant allele remained intact (615 bp).In the ribed in  was digeXPD Lys751Gln genotypes were determined by amplifying a 324 bp fragment with the primers described in [PstI; the amplicon from the 751Lys wild-type allele was cut into 220 bp and 104 bp fragments while the amplicon from the 751Gln variant allele was cut into 157 bp, 104 bp and 63 bp fragments.The ribed in . The resXRCC1 Arg280His genotype could not be determined for three cases and three controls, the Arg399Gln genotype for four cases and four controls, and the XPD Lys751Gln genotype for two cases and two controls.The genotype analyses were performed unaware of the case-control status. Two positive controls with known genotype and two negative controls were used within each PCR amplification batch, and two independent researchers interpreted the gel images to ensure the validity of genotyping for each polymorphism. The PCR for samples with divergent results was repeated and an additional 10% of all samples were reanalysed for each polymorphism for quality control. No discrepancies were found in the replicate tests. The Association between genotypes and risk of breast cancer were evaluated by unconditional logistic regression to calculate multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using SPSS version 11.5 . Calendar age, age at menarche, age at first full term pregnancy, number of children, history of benign breast diseases, first degree  family history of breast cancer, waist-to-hip ratio and use of alcohol and smoking were used as adjusting variables in all analyses. Subjects with missing values in any of the adjusting variables were excluded from the analysis. When the adjusted ORs differed significantly from the unadjusted ORs, both are shown.Women who had smoked daily for longer than three months were considered as smokers. Never smokers were categorized as those who had never been exposed to either passive or active smoking, and as those exposed to passive smoking only. Ever smokers were further categorized according to the approximate median smoking years (15 years), daily consumption (10 cigarettes) and pack-years of smoking (5 pack-years) in the control population. Pack-years of cigarettes were calculated as the number of packs (20 cigarettes/pack) smoked per day multiplied by years of smoking.XRCC1-280 Arg/Arg and XRCC1-399 Arg/Arg genotypes were used as reference categories for all separate analyses. As the frequency of the XRCC1-280 His variant allele was low, the ORs were calculated for the combined XRCC1-280 His allele containing genotypes in all analyses. Similarly, in the stratified analyses, the XRCC1-399 Gln allele containing genotypes were combined to increase statistical power. In contrast, a recessive model was used for the XPD Lys751Gln polymorphism based on the observed genotype distributions and some earlier publications [XPD-751 Lys/Gln genotype was combined with the wild-type Lys/Lys genotype to serve as a reference category. Possible gene environment interactions were assessed using stratified analyses and interaction terms. Variables of interest were smoking and use of alcohol. Tests for interactions were assessed by the likelihood ratio test to compare goodness of fit of the model with the interaction term, to the reduced model including the main effect variable (genotype) and the main adjusting variables. All reported p-values are two-sided. No attempt was made to adjust for multiple comparisons.Based on the prior knowledge of the functional significance or epidemiological evidence, the ications ,51. Therp = 0.10), or in smoking years .Characteristics of the study population are shown in Table XRCC1-280 His, XRCC1-399 Gln, and XPD-751 Gln variant alleles in controls were 0.08, 0.27, and 0.43, respectively. All the genotype distributions in the control population conformed to Hardy-Weinberg equilibrium . No statistically significant differences were seen in the frequency of these genotypes between cases and controls  compared to those with the Arg/Arg genotype. No increase in risk was seen for lower stage (I or II) breast cancer . A similar tendency of increased risk for advanced stage cancer was seen for subjects with the XRCC1-280 Arg/His or His/His genotype  compared to subjects with the Arg/Arg genotype. Similarly, women with the XRCC1-399 Gln/Gln genotype presented with a significantly increased risk for grade II and grade III tumours  when compared to those with the Arg/Arg genotype, while no increase was seen for grade I tumours . Moreover, women who carried the XRCC1-399 Gln/Gln genotype and were diagnosed with early stage (I or II) breast cancer had tumours of higher grade (II or III) marginally  more often than those with the Arg/Arg genotype, 86.1% (31/36) versus 72.5 % (137/189), respectively.When subjects were studied by the stage of the disease at the time of diagnosis, a significant increase for advanced stage (III or IV) breast cancer was seen for women with the XRCC1-399 genotypes and breast cancer risk was studied according to smoking habits, increased breast cancer risk with dose-response was seen among women who had ever smoked actively and carried either one  or two  XRCC1-399 Gln variant alleles compared to those carrying the Arg/Arg genotype (p for interaction between smoking habits and XRCC1-399 genotype 0.025) .When the association between XRCC1-399 Gln allele , or the XPD-751 Gln/Gln genotype  compared to similarly smoking women without these genotypes  or by smoking years . The ORs were 5.32 (95% CI 1.97–14.4) for women smoking ≥10 cigarettes/day and carrying at least one XRCC1-399 Gln allele, and 4.03 (95% CI 1.40–11.6) for women who had smoked ≥15 years and carried at least one XRCC1-399 Gln allele, compared to women with similar smoking habits but with the XRCC1-399 Arg/Arg genotype. For the carriers of the XPD-751 Gln/Gln genotype, a similar increase in the risk of breast cancer was seen for women smoking ≥10 cigarettes/day  while no statistically significant increase was seen by smoking years , compared to women smoking the same amount, but not carrying the homozygous variant XPD-751 Gln/Gln genotype.When ever smoking women were further stratified by pack-years smoked , the increase in risk was seen to be confined to those who had smoked over five pack-years and carried at least one XPD-751 Gln/Gln genotype were at 3.18-fold (95% CI 1.34–7.57) increased risk of breast cancer compared to similarly drinking women carrying the other genotypes (p for interaction 0.026). No interaction was found between XRCC1-280 or XRCC1-399 genotypes and current use of alcohol (data not shown).When stratified by current use of alcohol, women who reported using alcohol weekly to daily and carried the XRCC1-280, XRCC1-399, and XPD-751 genotypes was studied, a statistically significant increase in the risk of breast cancer was seen for subjects carrying two at-risk genotypes of these genes  compared to subjects with the wild-type genotypes for all three polymorphic sites . A trend of increasing risk with increasing number of at-risk genotypes was seen (p for trend 0.042). However, this estimate did not reach statistical significance , possibly due to the low number of subjects with all the three at-risk genotypes (four cases and one control). When the combined effects were studied among ever active smokers, women who carried any two at-risk genotypes were at remarkably increased risk of breast cancer; the adjusted OR was 10.7 (95% CI 3.62–31.6) compared to those without these genotypes . When the combined effect was calculated for the number of at risk alleles , a similar increase in the risk was seen; subjects with three at-risk alleles had an OR of 1.72  among all women, and OR 4.62  among ever actively smoking women compared to women with no at-risk alleles. Only four cases and one control carried simultaneously four at-risk alleles, and none more than four (of the six).When the joint effect of the XRCC1 Arg280His, XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in relation to breast cancer risk in a Finnish study population. As the products of these genes act in BER and NER pathways, and as some evidence exists on the association of these polymorphisms with smoking-related cancers [XPD-751 Gln/Gln genotype and breast cancer risk in smoking women [In this study, we examined the role of  cancers ,42,43,52ng women .Arg280His and Arg399Gln in the coding region of the XRCC1 gene were recently predicted to be 'possibly damaging' to XRCC1 function based on the conservation of the sequences in mammalian orthologues [XRCC1-399 Gln allele was somewhat higher among the present cases compared to controls, leading to a tendency of increased breast cancer risk. A similar effect has been reported in studies among Korean [The two polymorphisms hologues . In agreg Korean , Indian g Korean , and Afrg Korean  women. Ng Korean , in agreg Korean -33. Moreg Korean , French g Korean , Canadiag Korean , Turkishg Korean  and Danig Korean  women.XRCC1 Arg399Gln polymorphisms, the Arg280His polymorphism did not significantly modify breast cancer risk in the present study. Similarly, no association was seen for Indian women [XRCC1-280 Arg/His genotype [280His allele is low (0.08) among Caucasians, including Finns. Consequently, even though having almost twice the size of the French study, the power of our study to detect an OR of 1.5 at a 0.05 significance level was only 67% for the XRCC1-280 His allele containing genotypes. As the XRCC1-194 Trp variant allele is even less frequent among Finns (approximately 0.03) [In contrast to the an women  or for Uan women . On the genotype . One realy 0.03)  comparedly 0.03) , we deciXPD Lys751Gln polymorphism has been suggested to be the most important functional polymorphism in the gene due to major change in the electronic configuration of the respective amino acid in an important interaction domain of the protein [XPD Lys751Gln genotypes. This was in agreement with the other five studies on the XPD Lys751Gln polymorphism and breast cancer risk including one in Finnish [XPD-751 Gln allele and breast cancer risk was seen in a recent study among American women [XPD Asp312Asn polymorphism was recently shown to be associated with breast cancer risk in a German population [XPD Asp312Asn polymorphism as it has been shown to be strictly linked with the Lys751Gln polymorphism [The  protein . However Finnish , one in  Finnish , one in  Finnish , and two Finnish ,40. In can women . Moreovepulation . We decimorphism .XRCC1-399 Gln allele posed an elevated risk for more advanced stage breast cancer. A similar tendency of increased risk for more advanced stage breast cancer was also seen for the Arg280His polymorphism. It can be hypothesized that defective DNA repair leads to more aggressive and, therefore, more advanced tumours at the time of diagnosis. This was also supported by the association of the XRCC1-399 Gln allele with higher grade tumours. However, as earlier studies on breast cancer have not evaluated the genotype effects by the stage of the disease or tumour grade, these findings remain to be confirmed in future studies.When the present study subjects were stratified by stage of disease, the XRCC1 Arg399Gln (p = 0.025) or XPD Lys751Gln (p = 0.011) genotypes. Subjects with the variant Gln/Gln genotypes were at increased risk of developing breast cancer if they had ever smoked. Furthermore, a gene-dosage effect was seen for the XRCC1 Arg399Gln genotype; the increased risk was higher for subjects carrying two XRCC1-399 Gln alleles. In contrast, the effect of the XPD-751 Gln allele seemed to be recessive. When ever smokers were further stratified by the amount of smoking, the risk estimates remained statistically significant among those who reported having smoked more than five pack-years.Smoking alone did not significantly affect breast cancer risk in the present study. This is in agreement with the majority of epidemiological studies on smoking and breast cancer risk, as well as with a recent report of the Collaborative Group on Hormonal Factors in Breast cancer, which concluded that cigarette smoking has little or no effect on the risk of developing breast cancer . There aXRCC1 Arg399Gln and/or XPD Lys751Gln genotypes, smoking, and breast cancer risk are biologically plausible. Cigarette smoke is a rich source of chemical carcinogens and ROS [XRCC1-399 Gln/Gln genotype has been found to be related to increased sister chromatid exchange frequencies among smokers [399Gln allele who have smoked ≥10 cigarettes/day [XRCC1-399 Gln allele containing genotypes compared to cells homozygous for the Arg allele [XRCC1-399 Gln allele is associated with increased risk of smoking-dependent cancers. In agreement with this, a higher risk of lung cancer has been reported for the carriers of the XRCC1 Gln/Gln genotype [XRCC1-399 Gln allele was significantly associated with detectable PAH-adducts only in never smokers [XRCC1-399 polymorphism and smoking, but in contrast to our study, the highest risk was seen for subjects who were homozygous for the XRCC1-399 Arg allele [XRCC1-399 genotypes [The associations found between the  smokers . Similarttes/day , and higg allele . It can genotype , althouggenotype ,55. Brea smokers . They spg allele . Unfortuenotypes ,30,31,36XPD-751 Gln allele has been associated with increased DNA adduct levels in never smokers [XPD-751 Gln/Gln genotype and increased lung cancer risk [XPD-751 Gln/Gln genotype [In addition to ROS, tobacco smoke includes chemical carcinogens, such as polycyclic aromatic hydrocarbons, aromatic amines and tobacco-specific nitrosamines, that can produce bulky DNA adducts, which are repaired through the NER pathway. There is evidence that tobacco smoke constituents can reach breast tissue , and hig smokers  and in t smokers , as well smokers ,38. A recer risk . This wacer risk . In accogenotype . SimilarXPD-751 Gln/Gln genotype and used alcohol weekly or daily. No earlier studies on the XPD genotype and breast cancer have reported an association with the use of alcohol. However, a 2.59-fold (95% CI 1.25–5.34) risk was seen for squamous cell carcinoma of head and neck among current drinkers carrying the XPD-751 Gln/Gln genotype compared to those drinking the same amount but with the other genotypes [Alcohol is a known risk factor for breast cancer; increased estrogen and androgen levels have been observed in alcohol consuming women . Alcoholenotypes .XRCC1-399 and XPD-751 genotypes while the XRCC1-280 genotype was a minor contributor, possibly partly due to the very low frequency of the XRCC1-280His variant alleles. When the combined effect was studied according to the number of at-risk alleles, subjects with any three variant alleles were found to be at increased risk. There was no subject who simultaneously carried more than four at-risk alleles in these three polymorphic sites.When the gene-gene interactions were studied, clear combined effects were seen, especially among ever smoking women; smoking women with any two at-risk genotypes were at remarkably increased risk of breast cancer  compared to smoking women without these genotypes. These effects were mainly due to It should be noted that even if our study involved a reasonable number of study subjects, the numbers in some subgroup analyses were small, and the statistical power to detect significant point-estimates is, therefore, low. Furthermore, due to multiple comparisons performed in the study, the possibility of chance findings should be borne in mind. However, in addition to the plausibility of the findings, the dose-response seen by the number of at-risk alleles or genotypes and amounts smoked support the causality of the findings.In case-control studies, the possibility of selection and recall bias should be considered. However, the detailed data about smoking habits and other life style factors were collected prior to diagnosis, and the exposure to passive smoking, quite often disregarded, was taken into account. It is also unlikely that selection would be related to an individual's genotype. As the statistical analyses were performed within exposure groups and not between them, the possibility of biased estimates is further reduced.RAI, ASE-1 and ERCC1, in the same chromosomal region 19q13.2-3 define a high-risk haplotype that poses women under 55 years to a significantly increased breast cancer risk [XRCC1 or XPD genotypes but the effects were not studied by smoking habits. In our study, no difference in the risk estimates was seen by age.Even though the present findings are biologically plausible, the possibility of the association with another gene polymorphism in the same region should be considered. Accordingly, it was recently reported that three markers, cer risk . In thatXRCC1 Arg194Trp polymorphism, association has been seen with increased mutagen sensitivity [OGG1, encoding an enzyme important in the BER pathway, as well as numerous other genes encoding for possibly important repair enzymes in the NER pathway, namely XPA, XPC, XPF and XPG.Finally, it should be noted that not all the known polymorphisms in the BER and NER pathways were analysed in this study. For the sitivity , risk ofsitivity , and it XRCC1 and XPD genotypes and breast cancer risk in Finnish smoking women, especially when enzymes in both DNA repair pathways were defective. This finding is of particular interest as smoking, being the main preventable risk factor for cancer, is constantly increasing among female adolescents in many countries, including Finland. However, it should be borne in mind that the two studied DNA repair genes account for only a small part of the known genetic variations in these pathways and, therefore, most probably do not explain the whole picture, but should be considered in the context of other possible genes. These results, together with our earlier results concerning polymorphisms in estrogen metabolizing enzymes [We found a statistically significant association between the  enzymes , supportBER = base excision repair; bp = base pair; CI = confidence interval; NER, nucleotide excision repair; OR = odds ratio; PARP = poly(ADP-ribose)polymerase; PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism; ROS = reactive oxygen species.The authors declare that they have no competing interests.KM was responsible for supervising the laboratory work, for performing statistical analyses, and for manuscript preparation. VK participated in the design and coordination of the study, helped to draft the manuscript and acts as the principal clinician in the study group. PS, PS and LH carried out the genotyping analyses and drafted the manuscript. ME participated in the design and coordination of the study and was clinical coordinator of collection of study patient material. VMK performed histopathological analyses of all cases, and helped to draft the manuscript. MU has been involved in the planning of the study, collection of clinical data, in particular with respect to the genetic part of the study, and he has commented on the manuscript in the writing phase. AH participated in the design and coordination of the molecular epidemiology part of the study, was responsible for acquisition of funding for the molecular epidemiology part, and was involved in the preparation of the manuscript. All authors read and approved the final manuscript.


Late presentation of patients at advanced stages when little or no benefit can be derived from any form of therapy is the hallmark of breast cancer in Nigerian women. Recent global cancer statistics indicate rising global incidence of breast cancer and the increase is occurring at a faster rate in populations of the developing countries that hitherto enjoyed low incidence of the disease. Worried by this prevailing situation and with recent data suggesting that health behavior may be influenced by level of awareness about breast cancer, a cross-sectional study was designed to assess the knowledge, attitude and practices of community-dwelling women in Nigeria towards breast cancer.One thousand community-dwelling women from a semi-urban neighborhood in Nigeria were recruited for the study in January and February 2000 using interviewer-administered questionnaires designed to elicit sociodemographic information and knowledge, attitude and practices of these women towards breast cancer. Data analysis was carried out using Statistical Analysis Software (SAS) version 8.2.2 = 80.66, p < 0.0001) and those employed in professional jobs  were significantly more knowledgeable about breast cancer. Participants with higher level of education were 3.6 times more likely to practice BSE .Study participants had poor knowledge of breast cancer. Mean knowledge score was 42.3% and only 214 participants (21.4%) knew that breast cancer presents commonly as a painless breast lump. Practice of breast self examination (BSE) was low; only 432 participants (43.2%) admitted to carrying out the procedure in the past year. Only 91 study participants (9.1%) had clinical breast examination (CBE) in the past year. Women with higher level of education (XThe results of this study suggest that community-dwelling women in Nigeria have poor knowledge of breast cancer and minority practice BSE and CBE. In addition, education appears to be the major determinant of level of knowledge and health behavior among the study participants. We recommend the establishment and sustenance of institutional framework and policy guidelines that will enhance adequate and urgent dissemination of information about breast cancer to all women in Nigeria. Breast cancer is the most common cancer and the second principal cause of cancer deaths in women worldwide as well as in Nigeria ,2. The iAlthough there is strong evidence suggesting that older women in the developed countries are more likely to delay their presentation with breast cancer, , there iBreast cancer presents most commonly as a painless breast lump and a smaller proportion with non-lump symptoms. For women to present early to hospital they need to be "breast aware"; they must be able to recognize symptoms of breast cancer through routine practice of practicable screening. At the present time, routine mammography cannot be recommended in developing countries due to financial constraints and the lack of accurate data on the burden of breast cancer in these countries. Few studies have examined the knowledge, attitude and practice of women towards breast cancer in Nigeria ,18,19. TThe study was designed to assess knowledge, attitude and practice towards breast cancer among 1000 community-dwelling women recruited from Egor local government area, a semi-urban community with a population of 229,681 comprising 115,550 males and 114,131 females in Edo State of Nigeria (1991 Population Census of Nigeria). Participants were recruited from randomly selected households using the 1991 National Population Census database listing of households in the local government area. For participants that declined participation, other households were randomly selected until the sample size of 1000 participants was achieved. University of Benin Research and Ethics Committee approved the study protocol and written informed consent was obtained from study participants prior to recruitment. Participants were recruited in their homes in January and February 2000.Data collection was accomplished using interviewer-administered questionnaires designed to obtain relevant socio-demographic characteristics, knowledge, attitude and practice towards breast cancer. The questionnaire was developed by the authors based on information in the literature on risk-factors, common symptoms and signs of breast cancer, common methods of early detection, and current treatment modalities for the disease. The questionnaire was reviewed by a senior oncologist in our institution, who is not among the authors. The questionnaire was pre-tested on a convenient sample of 25 women drawn from the local community from whom study participants were recruited. As a result of this pretest, some of the items on the questionnaire were discarded mostly due to ambiguity of these questions. Some other questions were revised to ensure that vocabulary was within the comprehension of study participants while at the same time retaining the message of the question. Twenty core questions on knowledge of study participants on risk factors, common symptoms, methods of early detection, and treatment methods of breast cancer were retained out of the initial 31 items on the questionnaire. Except for the section of socio-demographic characteristics, most of the questions were designed to elicit "yes", "no" or "don't know" answers.Participants were recruited by trained nurses, who had two days training session prior to commencement of study. Each respondent was identified by a study identification number. Socio-demographic information relating to age, educational status, religion, occupation, and marital status were collected in the first section of the questionnaire. In the second part, respondents were asked specific questions to elicit their knowledge of the common symptoms and signs of breast cancer, etiological factors, diagnostic procedures, and treatment options available for the disease. The third section examined participant's action and attitude towards breast cancer. Respondents were asked questions related to their practice of breast self examination (BSE), clinical breast examination (CBE) and mammography screening. Participants were also asked about specific actions they will take in the event of being diagnosed with breast cancer and acceptance of mastectomy as a treatment procedure.Data analysis was carried using the Statistical Analysis Software (SAS) Version 8.2. Each respondent was scored based on the number of correct answers on 20 questions related to knowledge of common symptoms and signs of breast cancer, causal factors and available treatment options and percentage scores were computed. Pearson chi-square test was used to assess relationship between percentage scores and sociodemographic variables. We examined the practice of breast self examination (BSE) to determine factors that might influence this behavior. Variables considered for this analysis included education, age, marital status, and religion. Unconditional logistic regression models were used to assess the relationship of these variables with practice of BSE. Dummy variables were created for nominal categorical variables prior to the logistic regression. Univariate unconditional logistic regression models were first used to assess the relationship of these variables with practice of BSE; those with p > 0.25 were then dropped. Next, variables with p ≤ 0.25 were selectively added to the model, starting with the variable with the lowest p-value. Variables with p ≤ 0.10 were retained while those with p > 0.10 were dropped from the model. At the next stage variables with p > 0.05 were selectively removed from the model, one at time, beginning with the variable with the highest p-value. The model was then re-assessed, followed by dropping of the variable with the next highest p-value until all the variables with p > 0.05 were eliminated from the final multivariate model model. In addition, relationship between these variables and acceptance of mastectomy was similarly examined using unconditional logistic regression.One thousand community-dwelling women out of a total of 1052 potential participants that were contacted for the study were recruited from a semi-urban local government area in Nigeria.The sociodemographic characteristics of study participants are shown in Table Twenty questions with "yes", "no", or "don't know" responses were designed to elicit participant's knowledge in three key areas, including risk factors for breast cancer and common symptoms, methods of early detection and diagnosis, and their attitudes and practices including practice of breast self examination (BSE), clinical breast examination (CBE) and mammography screening. Table Study participants had good knowledge of the burden of breast cancer in women. A large proportion of participants (673 [67.3%]) agreed that breast cancer is a major problem in women and 726 participants (72.6%) correctly identified breast cancer as the most common cancer in women. Knowledge of study participants about risk factors for breast cancer was low. For example, in response to the question on the inheritability of breast cancer, only 244 (26.2%) were aware that breast cancer could be inherited in some families. There were many erroneous impressions about the etiology of breast cancer. A large proportion of participants (400 [40.0%]) believed that evil spirits causes breast cancer and 259 (25.9%) indicated that breast cancer results from an infection.Participant's knowledge about symptoms of breast cancer was rather poor. Only 214 participants (21.4%) knew that breast cancer presents commonly as a painless breast lump. Fewer participants were able to respond correctly to questions on non-lump symptoms of breast cancer such as pain in the breast, nipple discharge, and ulceration of the nipple. In terms of methods of diagnosis, only 432 participants (43.2%) were able to correctly identify breast self-examination (BSE) as a method for detection of breast cancer. A very small proportion of study participants indicated mammography as enhancing in early detection of breast cancer. Four hundred and fourteen participants (41.4%) correctly noted that breast cancer is curable when detected early.There was an indication of positive medical help-seeking behavior as majority of participants indicated visiting the doctor as the best approach to breast cancer care. Only 82 (8.2%) indicated visiting alternative health practitioners for breast cancer care. In terms of practice, only 349 participants (34.9%) practice BSE; the source of information about BSE was from the doctors' offices in 91 participants (21.1%), leaflets in 117 (27.1%), televisions in 134 (31.0%), churches/religious organizations in 35 (8.1%), feminist organizations in 29 participants (6.7%) and Nigerian Cancer Society programs in 26 participants (6.0%). Only 91 participants (9.1%) had clinical breast examination (CBE) in the past year. The main reasons advanced for not having clinical breast examination (CBE) include not having a breast problem in majority of the participants  and being unaware of the need for CBE in 293 participants (32.2%) as shown in Table 2 = 80.66, p < 0.0001). Participants engaged in self-employed small businesses such as trading and hair dressing and secretarial jobs had significantly poorer scores compared with those employed in professional jobs such as sales, teaching, and nursing . Although age was not significantly related to scores, we found that older women appear to have higher scores compared with younger women. Forty percent of women aged 50 years and above compared with 35.5% of those aged 40–49 years and 28.4% of those below the age of 40 years scored 50.0% and above . Religion was not significantly related to scores as shown in Table We computed percentage score of participants' knowledge of breast cancer in order to examine the determinants of breast cancer knowledge. The mean score of the participants was rather low (42.3% ± 12.3). Only 229 participants (22.9%) scored 50.0% and above. Performance was found to be significantly related to level of education and occupation as shown in Table Eight hundred and sixty-six participants had information on education and practice of BSE. A smaller proportion (31.8% [209]) of study participants with high school education and below practiced BSE compared with 62.3% (132) of those with education above high school. Higher level of education was significantly associated with practice of BSE .Next, we assessed the association of knowledge score with practice of BSE. There were 791 study participants with complete information on knowledge scores and practice of BSE. One hundred and eighty (30.9%) participants with knowledge scores below 50.0% practiced BSE compared with 131 participants (58.0%) of those with knowledge scores of 50.0% and above. Unconditional logistic regression showed a significant association between knowledge scores and practice of BSE. Participants with higher knowledge scores were about 3 times more likely to practice BSE compared with those with scores below 50.0% . In the final unconditional logistic regression models, only education  and knowledge scores  remained in the model. There was no significant association between age, religion and marital status and practice of BSE as shown in Table The relationship between acceptance of mastectomy and sociodemographic variables and knowledge score were also assessed using unconditional logistic regression. Eight hundred and sixty-six participants had complete information on education and acceptance of mastectomy as a treatment of modality. Fifty-one percent (340) of study participants with high school education and below indicated accepting mastectomy compared to 65.8% (133) of those with education above high school. Participants with higher level of education were 1.3 times more likely to accept this treatment procedure compared with those with high school education and below . As shown in Table The results of this study suggest that community-dwelling women in Nigeria have rather poor knowledge of breast cancer. This may partly explain the late presentation seen in over 70% of women with the disease -5. A meaThe low level of knowledge found in this study is in keeping with reports of other investigators ,18,19. Iet al, [These results in Nigerian women sharply contrast with reports from the Western world. In a study of women's knowledge and belief about breast cancer among British women, Grunfeld et al,  noted thet al, [Our results indicate that education and employment in professional jobs significantly influenced knowledge of breast cancer. Women with education greater than High School and those employed in professional jobs such as nursing, teaching and sales had significantly higher knowledge scores compared with those employed in small businesses. Other demographic variables including age, marital status and religion were not significantly related to knowledge score. These results are in agreement with the findings of others but at variance with the report of others. Among a cross section of British women, Grunfeld et al,  found thet al, , and Auset al,  have demet al, . Furtheret al, .et al, [Participants in our study had the right attitude towards breast cancer as majority indicated visiting the doctor for breast complaints. The use of screening methods was very low among our study subjects; only 34.9% practice BSE and only 9.1% had had CBE in the past year and none ever had a mammogram. Odusanya and Tayo  reportedet al,  found thet al, .Higher level of education and higher knowledge score were significant determinants of BSE practice in our study; age and other demographic variables were not significantly related to BSE practice. Similar to our findings, other investigators have reported that demographic characteristics such as higher levels of education and income, marital status, younger age, social support, knowledge and preventive attitudes, a history of breast diseases, a family history of breast cancer, having a regular physician, ethnic background and residence area are significant determinants of adherence to BSE practice ,15,28.The guidelines for breast cancer screening recommended by a consortium of American medical organizations including the American Cancer Society, stipulates that: between the ages of 40 and 49 years, women should undergo a CBE and mammography every year or two; women older than 50 years should have an annual CBE as well as a mammogram . MammogrThe value of BSE is less established. While the findings of a clinical trial suggested that BSE results in no difference in risk of mortality from breast cancer, a review of case-control studies found that BSE might reduce this risk. Despite inconclusive evidence, it is thought that BSE makes women more "breast aware", which in turn may lead to earlier diagnosis of breast cancer . The ratRoutine breast cancer screening is currently not being practiced in Nigeria. Even then, applying the recommended mammography screening guidelines in Nigeria will catch only a proportion of breast cancer cases as about 57% of breast cancer cases in Nigeria occur in women below the age of 50 years . In addiAs previously indicated, the interviewer-administered questionnaire developed by the authors was the only instrument employed for recruitment of study participants. Although, this may limit comparability of our findings with that of other investigators, it is important to note that efforts were made to ensure some measure of validity by pre-testing the questionnaire on a convenient sample before commencement of the study.The results of this study have demonstrated the extremely low level of breast awareness among community-dwelling women in Nigeria. Until circumstances are ripe for routine mammography screening, emphasis should be on encouraging women to practice BSE and CBE. Health education programs should be targeted at women through various media including leaflets, television, and radio. In addition, health education should be channeled through women friendly agencies/organizations such as hospital antenatal and postnatal clinics, religious organizations, and Feminist organizations. Use of leaflets, although effective to some extent in literate societies, may be of limited value in the Nigerian population. Even in highly literate societies, there is evidence suggesting that leaflets produce only limited and short-lived changes in knowledge . FurtherThe author(s) declare that they have no competing interests.MO, CB, UO, FO participated in conceptualization, design of the study and preparation of manuscript;MO, CB, UO, FO participated in data analysis and preparation of the manuscript.All the authors read and approved the final manuscript.


Male and female age standardised mortality and incidence rates of colorectal cancer have increased over the most recent 30 years in New Zealand. Among men and women aged 40 to 74, age standardised mortality and incidence rates increased 18 to 105%. However, age standardised mortality and incidence rates among younger men and women have declined from 14 to 69%. Analysis of trends in age specific mortality and incidence rates indicates that the occurrence of colorectal cancer has been declining equally for men and women in successive cohorts born about 1943 to 1953 in New Zealand. This decline in the frequency of colorectal cancer among recent generations was apparent for both the right and left sides of the colon and the rectum. Age-specific trends in coronary heart disease and breast cancer differed from those apparent for colorectal cancer, suggesting that the factors producing the reduction in colorectal cancer risk may affect these diseases among different age groups or may not be of major aetiological importance in these diseases. These trends provide empirical evidence that the occurrence of colorectal cancer can be reduced by at least 50% with a substantial component of the risk being determined before the age of 30. Further study is needed to establish whether changes in risk factors at older ages contribute to the prevention of the disease.


XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively.Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1 Arg194Trp, Arg280His, Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption.We used a case-control study design  to test the association between five polymorphisms in these DNA repair genes . The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas . Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas , while no association was found with risk of carcinomas.The XRCC1 Arg280His polymorphism and a reduced risk associated with the XRCC1 Arg399Gln polymorphism. Interestingly, individuals with the XPD Lys751Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas.Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the  In Western populations the vast majorities of colorectal cancers (CRC) arise from benign adenomatous polyps  and evolve through the adenoma-carcinoma sequence, a multistep process of genetic alterations ,2. The lXRCC1, XRCC3 and XPD genes.The risk of sporadic CRC is associated with lifestyle factors like cigarette smoking and alcohol consumption which may be modulated by several genetic factors of low penetrance ,4. CigarXRCC1 gene codes for a protein involved in the repair of single-strand breaks (SSB) and in base excision repair (BER) of damaged bases caused by endogenous and exogenous oxidants. Three polymorphisms occurring at conserved sequences in the XRCC1 gene were reported by Shen et al. . Hof. HofXPD XPD Lys751Gln polymorphism may predispose slightly to development of colorectal adenomas or that the polymorphism may be of importance for arresting the adenoma-carcinoma sequence in the low-risk phase and facilitate regression of adenomas. Large prospective studies would be required to clarify this issue. XPD polymorphisms have been analyzed particularly in epidemiological studies on skin and smoking-related cancers and no obvious relationship has been found for these types of cancers. Mort et al. [et al. [XPD Lys751Gln polymorphism and colorectal cancer. To our knowledge no studies have been published on the association between XPD polymorphisms and colorectal adenomas.Our results indicate that the t et al.  and Yeh  [et al.  have repXRCC1 194Trp allele and colorectal adenoma or carcinoma risk. This is not in agreement with the results reported by Abdel-Rahman et al. [et al. [We found no significant association between the n et al. , but con [et al. .XRCC1 399Gln allele was associated with a slightly decreased risk of colorectal adenomas and carcinomas, although statistically significant only for the high-risk adenomas, . This protective role of the XRCC1 399Gln allele is in contrast to previous reports [OGG1 Ser326Cys [XRCC1 codon 399 and OGG1 codon 326 variant alleles in combination, but it showed no significant association with colorectal adenoma or cancer risk  (further data not shown).In our study, the  reports ,13 on ther326Cys . We haveXRCC1 280His allele and risk of colorectal adenomas and carcinomas, but again, this increased risk was only significant for the adenomas . As far as we know, the KAM study is the first reporting an association between the XRCC1 Arg280His polymorphism and colorectal adenoma and carcinoma risk. There are few reports on this polymorphism. In 1999, Lunn et al. [XRCC1 genotypes and different levels of aflatoxin B1-DNA adducts (51 controls and 69 cases), but no significant effects were observed for the XRCC1 280His allele. Recently, Hong et al. [et al. [XRCC1 Arg280His variant protein has an ineffective or reduced ability to localize a damaged site in the chromosome, thereby reducing the cellular BER/SSB repair efficiency. The variant 280His allele may allow un-repaired SSBs to accumulate, thereby accelerating genomic instability which consequently increases the risk of carcinogenesis. This is supported by our findings of an association between a variant 280His allele and high-risk adenomas. We found that the two polymorphisms XRCC1 Arg280His and XRCC1 Arg399Gln were linked such that the variant allele of XRCC1 codon 280 co-segregated with the wild type allele of XRCC1 codon 399 (p = 0.045). When the XRCC1 Arg280His and XRCC1 Arg399Gln polymorphisms were combined, the effects of the polymorphisms appeared independently of each other. The variant carriers of XRCC1 codon 399 were not statistically significantly, but consistently, at decreased risk of cancer, whereas XRCC1 codon 280 heterozygotes were at increased risk of cancer.In this study we identified an association between the n et al.  examinedg et al.  reported [et al.  have repXRCC3 Thr241Met polymorphism and colorectal adenomas or carcinomas in our study. This XRCC3 codon 241 polymorphism has previously shown a significant association with colorectal cancer risk [XRCC3 polymorphism and colorectal adenoma risk [No significant association was found between the cer risk   (further data not shown). We have also tested the interaction between each of the five DNA repair polymorphisms and cigarette smoking, but they showed no significant association with colorectal adenoma or carcinoma (further data not shown). These results are in agreement with other published studies [We have tested the combination of the  studies ,47. To tXRCC1, XRCC3 and XPD polymorphisms may be related to variation in carcinogenic exposure and ethnic origin of the studied populations. Too small sample size and/or the inadequate controlling for certain confounders such as age, gender, alcohol consumption and cigarette smoking may contribute to differing results. It is possible that some of the candidate genes only contribute to colorectal cancer development in combination with certain dietary and /or lifestyle factors. Interaction between various gene products may increase cancer risk. A combination of polymorphisms in these genes may have additive or synergistic effects. For polymorphisms not showing an obvious association with colorectal adenoma or cancer when studied separately, an association with colorectal adenoma or cancer is still possible in combination with other polymorphisms. We have tested the combination of the three polymorphisms in the XRCC1 gene but none of the estimated haplotypes showed a significant association with colorectal adenoma or carcinoma risk.The divergence in results from different studies on The design of this study is relatively strong because the controls were recruited from the same cohort as the adenoma and carcinoma cases. The CRC cases and controls have not been matched by age which may affect the results in a study. However, our controls have been screened and found polyp free and the risk of any of them having colon cancer at the time of inclusion is not very likely. The definition of polyp-free controls was based on a negative flexible sigmoidoscopy screening examination. It has been estimated that the risk of erroneously classifying individuals with proximal advanced neoplasia as neoplasia-free is less than 3 % at flexible sigmoidoscopy ,49. TherXRCC1 Arg280His polymorphism and a reduced risk for persons with XRCC1 Arg399Gln. The increased risk of having low-risk adenomas in contrast to advanced neoplasia for individuals with XPD Lys751Gln polymorphism may suggest a role in regression of adenomas and should be explored in prospective studies of in situ adenomas.In conclusion, our results suggest an increased risk for advanced colorectal neoplasia in individuals with The author(s) declare that they have no competing interests.XRCC1 and XRCC3 genes and prepared the first draft of the paper. She did the data analysis. MS prepared samples for analysis. She also contributed to the manuscript and with advice on data analysis. PCH contributed with statistical advice. SA and IMBL contributed with the pathology of the cancer cases. EJ participated in the collection of blood samples and questionnaires from the cancer cases. ILH participated in collection and quality control of the questionnaires. UBV contributed with genotyping of the XPD gene and together with CFS, MS and EHK interpreted the results. EHK brought the idea of the KAM study and organized it. She was also responsible for the revisions of the manuscript. All authors discussed the results, contributed to interpretation of the results and the final manuscript.CFS established the methods in the lab and performed the genotyping analysis of the The pre-publication history for this paper can be accessed here:


We present the findings of a pilot study to assess the perception of risk in 155 women with a family history of breast cancer by questionnaire. Only 11% of women were able to identify the correct population risk and more than half were unable to assess their own lifetime risk within 50% of the clinicians' estimate. Although it is probable that women are helped by genetic counselling and if at substantial risk, annual mammography, the psychological impact of assigning true risk and the value of mammography need to be evaluated.