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Carcinogenesis Advance Access originally published online on January 6, 2006
Carcinogenesis 2006 27(7):1377-1385; doi:10.1093/carcin/bgi330
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case–control study

Leah E. Mechanic 1, *, Robert C. Millikan 2, Jon Player 2, Allan René de Cotret 2, Scott Winkel 2, Kendra Worley 2, Kristin Heard 2, Kimberley Heard 2, Chiu-Kit Tse 2 and Temitope Keku 3

1 Laboratory of Human Carcinogenesis, NCI/NIH, 37 Convent Drive MSC 4255, Bldg 37 Rm 3060, Bethesda, MD 20892-4255, USA, 2 Department of Epidemiology, School of Public Health, and Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7435, USA and 3 Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7555, USA

* To whom correspondence should be addressed. Tel: +1 301 496 7278; Email: mechanil{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 References
 
Polymorphisms exist in several genes involved in nucleotide excision repair (NER), the principal pathway for removal of smoking-induced DNA damage. An epidemiologic study was conducted to determine whether these polymorphisms modify the association between smoking and breast cancer. DNA samples and exposure histories were analyzed as part of a large population-based case–control study of breast cancer in North Carolina. The study population included 2311 cases (894 African Americans, 1417 whites) and 2022 controls (788 African Americans, 1234 whites). Odds ratios (ORs) were calculated for breast cancer and smoking, and for breast cancer and nine non-synonymous coding polymorphisms in six NER genes (XPD codons 312 and 751, RAD23B codon 249, XPG codon 1104, XPC codon 939, XPF codons 415 and 662, and ERCC6 codons 1213 and 1230). Modification of ORs for smoking by single and combined NER genotypes was investigated. In this study population, smoking was more strongly associated with breast cancer in African American women compared with white women. Among African American women, the association of breast cancer and smoking was strongest among women with specific combinations of NER genotypes. Evidence for multiplicative interaction was found between combined NER genotypes and smoking dose (likelihood ratio test P = 0.06), duration (P = 0.09), time since cessation (P = 0.02), age at initiation (P = 0.04) and former smoking (P = 0.03). No interactions were observed in white women. Therefore, polymorphisms in NER genes may modify the relationship between breast cancer and smoking. These results are consistent with previous evidence of exposure-specific p53 mutations in breast tumors from current and former smokers, suggesting that smoking may play a role in breast cancer etiology.

Abbreviations: CBCS, Carolina Breast Cancer Study; CI, confidence interval; ETS, environmental tobacco smoke; LRT, likelihood ratio test; NER, nucleotide excision repair; nt, nucleotide; OR, odds ratio; rs, reference sequence number; SNP, single nucleotide polymorphism; TFIIH, transcription factor II H; XPC, Xeroderma Pigmentosum Group C


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary material
 References
 
Cigarette smoking is an established risk factor for lung, head and neck, and pancreatic cancer (1). However, the relationship between cigarette smoking and breast cancer is unclear. Cigarette smoke contains many known carcinogens, including the well-studied benzo[a]pyrene (1). Epidemiologic studies yielded positive, inverse or null associations for cigarette smoking and breast cancer risk (2–5). A recent literature review concluded cigarette smoking does not reduce the risk of breast cancer, and breast cancer risk may be increased by smoking of long duration, smoking before a first full-term pregnancy, and by exposure to passive smoking, also referred to as environmental tobacco smoke (ETS) (2). Molecular epidemiologic studies showed a higher frequency of smoking-related DNA adducts and p53 mutations in breast tumors from smokers compared with non-smokers (6–8).

Susceptibility to smoking-induced cancer may vary, and human populations show wide variability in the distribution of genotypes related to metabolism of carcinogens found in tobacco smoke (2). For example, individuals with variant CYP1A1, NAT1 and NAT2 alleles showed stronger associations for smoking and breast cancer (9–14). Nucleotide excision repair (NER) may be an important pathway modulating susceptibility to breast cancer, because it is the primary mechanism for the repair of bulky and helical distorting DNA adducts (15) generated by cigarette smoke (1,16,17). NER proteins also repair some forms of oxidative damage (18), abasic sites (19), and C–C mismatches (20). Therefore, reduced efficiency of NER could increase susceptibility to DNA damage caused by cigarette smoke, and thus increase risk of breast cancer associated with smoking.

The NER pathway includes several steps: (i) DNA damage recognition; (ii) assembly of repair factors; (iii) incision of damaged DNA; (iv) repair synthesis to fill gapped DNA; and (v) DNA ligation [as reviewed in (15)]. DNA damage is recognized by the Xeroderma Pigmentosum Group C (XPC)–RAD23B complex, followed by recruitment of the transcription factor IIH (TFIIH) complex of proteins. The TFIIH complex is composed of nine subunits, including XPD and XPB (21). TFIIH unwinds the DNA duplex around the damaged site. Next, XPG binds to the TFIIH complex and DNA, followed by recruitment of the XPF–ERCC1 complex. XPG and XPF–ERCC1 produce dual incisions 3' and 5' to the damaged site. After release of the damaged DNA strand, the gap is filled by repair synthesis and ligation. ERCC6 participates in NER of oxidative DNA damage by forming complexes with RNA polymerase 1, TFIIH and XPG (22).

Single nucleotide polymorphisms (SNPs) in NER genes have been discovered in human populations (23), and several epidemiologic studies have examined these SNPs as risk factors for cancer (24). Most studies examined the effects of single SNPs and few considered interactions with environmental factors (24). We hypothesized that genotypes for several NER genes could be combined to create ‘pathway genotypes’, as suggested by Mohrenweiser et al. (23), and that combined NER genotypes would modify the relationship between smoking and breast cancer risk. Based upon allele frequency, potential or known functional impact, and the results of previous epidemiologic studies, we selected common SNPs in six genes within the NER pathway (XPD, XPC, RAD23B, XPG, XPF and ERCC6) in order to test this hypothesis in the Carolina Breast Cancer Study (CBCS), a population-based study of African American and white women in North Carolina.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary material
 References
 
Study design
The Carolina Breast Cancer Study (CBCS) is a population-based, case–control study of invasive and in situ breast cancer conducted in 24 counties of central and eastern North Carolina (25). The CBCS enrolled invasive breast cancer cases and controls (Phase I, 1993–1996; Phase II, 1996–2001) and in situ cases and controls (1996–2001). Randomized recruitment was used to increase enrollment of African Americans and younger women, as previously described (13,25–27). Participants ranged in age from 21 to 74. Contact and cooperation rates for the CBCS, and characteristics of cases and controls, have been published previously (13,26–28). Response rates for blood draws and obtaining DNA were 89% for cases and 90% for controls. DNA samples were available for a total of 2045 cases (786 African Americans and 1277 whites) and 1818 controls (681 African Americans and 1137 whites). Odds ratios (ORs) for breast cancer risk factors did not differ significantly between persons who gave DNA and those who did not (data not shown).

Laboratory methods
DNA was extracted from peripheral blood lymphocytes by standard methods using an automated ABI-DNA extractor (Nuclei Acid Purification System, Applied Biosystems, Foster City, CA, USA) in the UNC SPORE Tissue Procurement Facility (28). Genotyping was conducted using the ABI 7700 Sequence Detection System, or Taqman assay (Applied Biosystems). The following loci were genotyped: XPD codon 312 (rs1799793), XPD codon 751 (rs13181), RAD23B codon 249 (rs1805329), XPG codon 1104 (rs17655), XPC codon 939 (rs2228001), XPF codon 415 (rs1800067), XPF codon 662 (rs2020955), ERCC6 codon 1213 (rs2228527) and ERCC6 codon 1230 (rs4253211). SNPs were chosen based upon several criteria: an essential role for the gene product in NER, minor allele frequency of 1% or greater in African Americans or whites, previous functional studies or computer simulations suggesting significant functional impact (29–36) and calculations that showed we had sufficient power to stratify on combinations of 6–8 polymorphisms when estimating ORs for smoking and breast cancer. Primer and probe sequences as well as annealing temperatures for each genotyping assay are listed in Supplementary Table I. Probes were labeled on the 5' end with either FAM or VIC (Applied Biosystems). Probes were labeled on the 3' end with the quencher dye 6-carboxy-N,N,N',N'-tetramethylrhodamine (TAMRA).

PCRs were performed in 15 µl reaction volumes. Reactions contained 0.7X Universal Master Mix (Applied Biosystems), 200 nM of each allele specific probe, 900 nM of each primer and 15 ng of genomic DNA. After reactions tubes were set up, amplification was performed using a Perkin-Elmer GenAmp 9700 thermocycler. Reaction tubes were placed into the thermocycler after the temperature reached 50°C. PCRs were carried out using the following conditions: 50°C for 2 min (AmpErase UNG Activation), 95°C for 10 min (AmpliTaq Gold Activation), and 40 cycles of 92°C for 15 s (denature) and 56, 60 or 62°C (Supplementary Table I) for 1 min (anneal/extend). Samples that failed to amplify were repeated. Those samples that failed to amplify on the second run were scored as missing. Missing genotypes for each loci were as follows: XPD codon 312 (18 cases, 10 controls), XPD codon 751 (11 cases, 6 controls), RAD23B codon 249 (15 cases, 6 controls), XPG codon 1104 (39 cases, 11 controls), XPC codon 939 (17 cases, 16 controls), XPF codon 415 (42 cases, 12 controls), XPF codon 662 (16 cases, 7 controls), ERCC6 codon 1213 (19 cases, 10 controls) and ERCC6 codon 1230 (12 cases, 9 controls). For XPF codon 662, genotyping was only performed on a sample of 250 white cases and 250 controls owing to the rarity of the variant allele among whites. A 10% random sample of genotypes was repeated for each locus, and results were 100% concordant to the initial analysis. For each genotyping assay, DNA samples from the Coriell tissue repository (Coriell Institute for Medical Research, Camden, NJ, USA) that had previously been sequenced at the National Cancer Institute (www.nci.snp500.gov) were used as positive controls.

Statistical methods
Departures from Hardy–Weinberg equilibrium were evaluated using {chi}2 tests. Tests for statistical significance were two-sided with an alpha level of 0.05. SAS Genetics (version 8.2; SAS Institute, Cary, NC, USA), based on the EM algorithm (37), was used to estimate XPD codon 312 + 751 and ERCC6 codon 1213 + 1230 haplotype frequencies and to compare haplotype frequencies in cases and controls. Lewontin's D' values were used to estimate the extent of linkage disequilibrium.

Unconditional logistic regression was used to calculate ORs for breast cancer and confidence intervals (CIs). 99% CIs were calculated for NER genotypes and breast cancer to account for the large number of separate comparisons. 95% CIs were calculated for smoking variables and breast cancer since the number of comparisons was smaller and the individual effects of smoking variables were not independent of each other. PROC GENMOD in SAS (version 8.2; SAS Institute) was used to incorporate offset terms derived from the sampling probabilities used for randomized recruitment of study participants (38). The offset term is the log of the sampling probability for a case divided by the sampling probability for a control. Offsets terms are calculated for strata defined by race (African American, white) and age (11 five-year categories). ORs for NER genotypes were similar across all phases of the study (invasive and in situ), thus results are presented combining all cases and controls for whom DNA samples were available.

In the smoking analyses, women who were not exposed to active or passive smoking were used as the common referent group. Ever active smokers were defined as women who smoked at least 100 cigarettes in their lifetime. Exposure to passive smoking was defined as living with a smoker after the age of 18 (ETS after 18). Women who smoked on the reference date (date of diagnosis for cases or date of selection for controls) were classified as current smokers, whereas those women who no longer smoked on the reference date were designated former smokers. Women were asked about the amount of cigarettes smoked (packs/day) and the duration of smoking (the total number of years the participant smoked regularly). Information regarding dose and duration of smoking was missing for three white cases. Information on duration was obtained by asking women to sum all the years they smoked, including times they stopped and started. Similarly, dose was obtained by asking for the usual number of packs of cigarettes smoked per day.

Multivariable logistic regression was used to adjust for potential confounding factors. Confounding was evaluated by determining whether adding a variable to a model resulted in a change in the beta coefficient of at least 10% for the exposure of interest. The following confounding variables were identified for the association of smoking and breast cancer: age at menarche, a composite term for age at first full-term pregnancy and parity, family history of breast cancer, and alcohol consumption. Stratified analyses were conducted as an additional test for confounding of smoking effects by alcohol consumption. Stratified analyses were used to investigate modification of ORs by menopausal status, as defined previously on the basis of menstrual history, surgery and/or radiation to the ovaries (13). ORs for smoking and breast cancer were unchanged after adjustment for menopausal status. Odds ratios for NER genotypes and breast cancer were unchanged after adjusting for smoking and the other covariates listed, and thus are presented adjusted for offsets (sampling probabilities) and age only. Participants with missing values for any of the variables in a regression model were omitted from the analysis.

For each NER gene locus, stratified analyses were used to investigate modification of odds ratios for smoking and breast cancer. We used the term ‘any’ to refer to one or more copy of the specified allele within a genotype, e.g. ‘XPD 312 Any Asn’ refers to ‘XPD codon 312 Asn/Asp or Asn/Asn genotypes’. ERCC6 codon 1230, XPF codon 415 and XPF codon 662 were omitted from the combined analyses owing to low frequency in African American and/or white participants. Multiplicative interaction between each NER genotype and smoking was evaluated using a likelihood ratio test (LRT) to calculate P-values comparing models with main effects to models with main effects plus an interaction term. Tests for trend were conducted by calculating P-values for the beta coefficient in logistic regression models with smoking dose or duration coded as an ordinal variable.

We defined as ‘at risk’ the NER genotypes that showed positive associations between smoking and breast cancer in stratified analyses of each genotype alone. We combined ‘at risk’ NER genotypes, and calculated ORs for smoking and breast cancer stratifying on the number of ‘at risk’ genotypes: 0–1, 2–3, ≥4. LRTs were calculated testing for interaction between the number of ‘at risk’ NER genotypes coded as an ordinal variable (0–1, 2–3, ≥4) and smoking. LRTs were considered statistically significant at an alpha level of 0.20 to account for the low power of the test (39).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary material
 References
 
In African American participants, ORs were elevated for passive smoking (ETS after 18), former smoking, smoking for more than 20 years in duration, and among former smokers who quit smoking less than 10 years before the interview (Table I). With the exception of an elevated OR observed for time since cessation less than 10 years in former smokers, smoking was not associated with breast cancer among white participants. ORs for smoking and breast cancer did not differ among ever and never drinkers of alcohol (data not shown). Among African Americans, ORs for smoking and breast cancer were slightly stronger for premenopausal compared with postmenopausal women, but did not differ according to in situ versus invasive disease.


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  		Table I. ORs for smoking and breast cancer in African Americans and whites

 
In our study population, allele frequencies for XPD Asn312, XPD Gln751, XPG His1104, XPC Gln939, XPF Gln415 in white controls and XPD Gln751 and XPF Gln415 in African American controls were consistent with previous observations (30,35,36,40–60) (Table II). The frequencies of the other variant alleles were similar to the National Cancer Institute SNP500 database (http://snp500cancer.nci.nih.gov). Genotype frequencies in cases and controls did not differ from expected distributions based upon Hardy–Weinberg equilibrium (data not shown). ORs were close to the null for all loci, with the exception in African Americans of modest inverse associations for RAD23B Val-containing and XPF codon 415 Gln-containing genotypes and breast cancer, and borderline significant positive association for the XPF 415 Gln/Gln genotype and breast cancer in whites (Table II).


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  		Table II. Genotype frequencies and ORs for breast cancer for NER gene polymorphisms

 
Haplotypes frequencies for XPD did not differ significantly between cases and controls in African Americans (P = 0.35) or whites (P = 0.38). The Lewontin's estimate was consistent with strong linkage disequilibrium in African Americans (D' = 0.73) and whites (D' = 0.76) similar to previous reports (40,44,50,61). Haplotype frequencies for ERCC6 did not differ between cases and controls in African Americans (P = 0.42) or whites (P = 0.41). ORs for combined XPD 312 and 751 genotypes and breast cancer, as well as combined ERCC6 1213 and 1230 genotypes and breast cancer, were close to the null value in African Americans and whites (data not shown).

Modification of ORs for smoking and breast cancer by each NER genotype alone were assessed using stratified analyses. ORs for smoking and breast cancer were elevated for African American participants with the following NER genotypes: XPD 312 Asp/Asp, XPD 751 Lys/Lys, XPG 1104 Any His, XPC 939 Any Gln, RAD23B 249 Any Val and ERCC6 1213 Any Gly (Supplementary Tables II–XIII). Statistically significant LRTs (at alpha of 0.20) were observed for XPD 312 Asp/Asp genotype and smoking duration (P = 0.18), XPD 751 Lys/Lys genotype and smoking dose (P = 0.17), combined XPD 312 Asp/Asp and XPD 751 Lys/Lys genotypes and smoking dose (P = 0.11) and duration (P = 0.09), XPG Any His genotype and smoking dose (P = 0.08) and duration (P = 0.03), and ERCC6 1213 Any Gly genotype and smoking dose (P = 0.06). There were no differences in ORs for smoking according to XPF 415, XPF 662, or ERCC6 1230 genotypes in African Americans. ORs for smoking and breast cancer were slightly stronger among whites for XPD codons 312 Asp/Asp and 751 Lys/Lys, but did not differ according to the remaining NER genotypes (Supplementary Table III).

Since NER genes function along a common DNA repair pathway, a composite variable was created to examine the effect of combined NER genotypes and breast cancer as described in the Materials and methods section. ORs for combinations of ‘at risk’ NER genotypes and breast cancer were close to the null for 2–3 and ≥4 compared with the referent group of 0–1 ‘at risk’ genotypes (Table III). ORs were also close to the null when genotypes containing the less frequent allele were specified as the index group for each locus (data not shown). The interaction of smoking with the number of ‘at risk’ NER genotypes is presented in Tables IV and V. Compared with individuals with 0–1 ‘at risk’ genotypes, African American women with 2–3 ‘at risk’ genotypes showed stronger positive associations between smoking and breast cancer. The strongest positive associations were found among individuals with ≥4 ‘at risk’ genotypes (Table IV). LRTs were statistically significant for each smoking variable (smoking status, dose, duration, time since cessation and age at initiation), and trend tests were significant for dose and duration of smoking among women with ≥4 ‘at risk’ genotypes. ORs were unchanged when menopausal status was included in models. Modification of ORs for smoking and breast cancer were not observed among white women (Table V). In general, the modifying effects of combined NER genotypes in African American women did not appear to be driven by any single locus or subgroup of loci, since the ORs for smoking were of a similar range for each NER ‘at risk’ genotype alone (Supplementary Tables II–XIII).


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  		Table III. ORs for breast cancer and combinations of NER genotypes in African Americans and whites

 

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  		Table IV. ORs for smoking and breast cancer according to combinations of NER genotypes in African Americans

 

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  		Table V. ORs for smoking and breast cancer according to combinations of NER genotypes in whites

 
Since ORs for smoking were imprecise in the 0–1 ‘at risk’ genotype group, we conducted additional analyses collapsing the 0–1 and 2–3 ‘at risk’ genotype categories into a single category, comparing participants with 0–3 and ≥4 ‘at risk’ genotypes. In African American women, LRTs for the interaction of 0–3 and ≥4 ‘at risk’ genotypes and smoking were significant for smoking status (P = 0.08), dose (P = 0.06), duration (P = 0.06), time since smoking cessation (P = 0.10) and age of smoking initiation (P = 0.03). LRTs for genotypes and smoking in white women were not significant (P ≥ 0.4 for all tests).

African American women often have an earlier age at onset of breast cancer compared with white women (62). Therefore, interactions between ‘at-risk’ NER genotypes and smoking were examined separately in pre- and postmenopausal African American women. ORs for smoking were elevated in pre- and postmenopausal African American women with ≥4 ‘at risk’ genotypes, although ORs were imprecise. For example, the OR for smoking duration >20 years among premenopausal African American women with ≥4 ‘at risk’ genotypes was 3.7 (95% CI 1.2–11.6) and the corresponding OR in postmenopausal African American women was 3.0 (95% CI 1.1–8.9). Trend tests for smoking duration yielded similar results: P = 0.02 for premenopausal and P = 0.03 for postmenopausal African American women with ≥4 ‘at risk’ genotypes.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary material
 References
 
Previous epidemiologic studies investigating the association of cigarette smoking and breast cancer showed inverse, null or positive associations [for review (2)]. The inconsistent results may be due in part to failure to address genetic susceptibility. Recent evidence suggests that a variety genetic polymorphisms modify the relationship between cigarette smoking and breast cancer (2,9–11). Null or inconsistent findings may also have results from inadequately quantifying smoking exposure by classifying smoking as never, former or current smoking. Such classification may miss associations requiring long induction period, or long smoking duration, which may be associated with increased breast cancer risk (2). The association of smoking and breast cancer may be further attenuated by the inclusion of passive smokers, or individuals exposed to ETS, in the non-smoking referent group (63). Unlike studies examining active smoking, studies of ETS and breast cancer have more consistently reported an increase in the risk of breast cancer in individuals with exposure to ETS (4,64,65) and it was argued that sidestream smoke could contain higher doses of some carcinogens than mainstream smoke [for review (65)]. Finally, some investigators have suggested that the association between cigarette smoking and breast cancer could be due to confounding by alcohol intake (5). We addressed these issues by investigating the role of NER genotypes in modifying the association of exposure to active smoking (characterized by dose, duration, time since cessation and age at initiation) and ETS. As was reported previously for the CBCS, former smokers and women who smoked for long duration had an increased odds of breast cancer (13), and the association was stronger for African American compared with white women (66).

The stronger ORs for smoking and breast cancer in African American women are not attributable to higher reported levels of active smoking. The proportion of controls who were former smokers and who smoked more than 20 years were higher in white controls (31 and 24%, respectively) compared with African American controls (21 and 17%) (Table I). However, African American controls had higher exposure to ETS than white controls (38% of African Americans versus 31% of whites). Previously, it was shown in the CBCS dataset that community level socioeconomic characteristics, such as low education, high unemployment and high crime, were related to smoking behavior (67). Thus, African American women who actively smoked in our study could have been exposed to higher levels of ETS in addition to their own active smoking. Higher ORs in African American women would thus reflect the combined effects of active smoking and greater ETS exposure compared with white women. Another possible explanation relates to the theory that smoking has opposing effects on breast cancer risk: the carcinogenic effects of DNA-damaging agents such as benzo[a]pyrene and other aromatic hydrocarbons versus the anti-estrogenic effect of nicotine [for a review see (2)]. Cumulative exposure to reproductive hormones is driven by multiple factors, including age of menarche, parity, lactation and possibly by polymorphic alleles in hormone metabolism genes (68,69). Some studies suggest that many of these factors differ in frequency in African American and white women (26,66,70,71). It is possible that higher lifetime exposure to estrogen could negate the anti-estrogenic effects of nicotine in African American women, leading to stronger carcinogenic effects for smoking compared with white women. Finally, the stronger ORs for smoking in African Americans could be due to residual confounding. Although ORs for smoking were unchanged after adjustment for income, education, lactation, BMI, use of birth control pills and hormone replacement therapy, misclassification of one or more of these variables could contribute to the observed associations. The effects of smoking did not appear to be confounded by alcohol intake, as ORs for smoking were elevated among non-drinkers.

Since NER is the predominant pathway for repair of smoking-induced DNA damage, we investigated the role of polymorphisms in NER genes as modifiers of the association between smoking and breast cancer risk. Associations were not observed between NER gene polymorphisms and breast cancer, ignoring smoking history. There are no known previous reports investigating the association between polymorphisms RAD23B codon 249, XPF codon 662, ERCC6 codons 1213 and 1230 with cancer, or specifically breast cancer. Results from most previous studies of the NER polymorphisms including XPF Arg415Gln (60), XPD Asp312Asn and XPD Lys751Gln (36,40–42,44,47,50,51,53,58,61,72–78), XPC Lys939Gln (73), and XPG Asp1104His (31,35,36,58) often differed and were close to the null [for a review see (24)], consistent with the lack of main effects for NER gene polymorphisms in our study.

In order to examine the effects of combined NER genotypes, we identified ‘at risk’ genotypes based on examination of the joint effects of each individual genotype and smoking. The rationale for combining genotypes is based on the fact that the protein products of NER genes cooperate in a highly coordinated DNA damage repair process (23). ORs for smoking and breast cancer were strongest among women with four or more ‘at risk’ genotypes in NER genes. These results suggest that polymorphisms in NER genes modify the relationship of smoking and breast cancer. Consistent with these results, a higher frequency of p53 mutations and G:C to T:A transversions in p53 was observed in breast tumors from smokers compared with never smokers in the CBCS (6). Cigarette smoking results in the formation of bulky DNA adducts, which are primarily targets of NER (15). If unrepaired, bulky DNA adducts generated by cigarette smoking are predicted to result in G:C to T:A mutations in p53, the type of mutations most strongly related to smoking exposure (79). Previous studies examined interactions between the XPG codon 1104 polymorphism and smoking in lung cancer (31), or XPD codon 312 and codon 751 polymorphisms and smoking in lung (42,44,77,80) and breast cancer (61,74). Odds of lung cancer was elevated in light smokers with XPG1104 Any His genotypes (31) or with XPD Any Asp genotypes (44), or heavy smokers with XPD 312 Asp/Asp and XPD 751 Lys/Lys genotypes (77,80), consistent with the interaction suggested in our study. No previous studies of breast cancer or other cancer sites examined combinations of NER genotypes as susceptibility factors for smoking.

There are several limitations to our study. Since the response rate among controls was ~55%, there is potential for selection bias if controls that participated differed significantly in their exposure to cigarette smoking than those who refused to participate. It has been suggested that individuals who smoke are less likely than non-smokers to participate as controls in epidemiologic studies (3). However, smoking prevalence in CBCS controls was similar to previous telephone surveys conducted in North Carolina women (13). It is possible that cases were more likely to recall or report smoking than controls, or were more likely to report ETS after 18 years of age, but reporting is unlikely to be differential by NER genotype. We lacked comprehensive assessment of exposure to ETS. Asking women about whether they have lived with a smoker ignores duration of exposure, leisure time and occupational exposure (81).

The functional significance of NER gene polymorphisms is unknown or poorly characterized at present. Functional assays suggest that the XPD codon 312 and 751 genotypes impact DNA repair, but these studies are not consistent regarding which alleles would be predicted to increase cancer risk [for review, see (29)]. The XPC codon 939 Gln variant was reported to have no functional significance in vitro, but to exhibit linkage disequilibrium with a polyAT insertion and intronic polymorphism that causes reduced XPC expression and DNA repair activity of XPC (32,33,46) and was associated with reduced repair of radiation-induced DNA damage (57). The polymorphisms chosen for the present study represent non-conservative amino acid substitutions within conserved regions of the encoded proteins (30). Conserved regions often mediate protein–protein interactions and regulate enzymatic activity (34,82). Based upon the degree of conservation across species and the change in polarity, charge and protein structure caused by the substituted amino acid, the XPD codon 312, XPD codon 751 (30), XPG codon 1104, and XPC codon 939 (H. Mohrenweiser, personal communication) and ERCC6 codon 1213 (34) polymorphisms are predicted to have significant functional impact. Power calculations for detecting interactions lead us to focus on a limited number of polymorphisms. We chose nine SNPs that were most likely to reduce efficiency of the NER pathway. It is important to note that there are many other non-synonymous SNPs in NER genes that may modulate the NER pathway, including promoter polymorphisms and complex haplotypes, which were not investigated by this study. The growing list of polymorphisms in NER genes and functional assays for NER (83) provide important reagents for future investigations.

After stratification by race and NER genotypes, the number of participants in many categories was small, resulting in wide confidence intervals for some ORs. Thus, the observed interactions between smoking and NER polymorphisms in African American (but not white) women may be due to chance. The effects of these NER gene polymorphisms and smoking need to be evaluated in other study populations, particularly among African Americans.

Our results suggest that polymorphisms in NER genes may modify the relationship between cigarette smoking and breast cancer. Evidence for an association of smoking with breast cancer and modification of ORs for smoking and breast cancer was observed in African American but not white women. These differences could result from different levels of exposure to cigarette smoke (in particular ETS) or from differences in other susceptibility factors. Since relatively few epidemiologic studies have included African American women, and our study is the first to address multiple polymorphisms in NER genes, these results require further evaluation. If confirmed, evidence for interaction between NER genotypes and smoking is consistent with a causal but complex relationship between cigarette smoking and breast cancer. Furthermore, the ‘pathway genotype’ model employed in this paper for examining ‘gene–gene–environment’ interactions may be applicable to other cancer sites.


   Supplementary material
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
References
 
Supplementary material can be found at http://www.carcin.oxfordjournals.org/


   Acknowledgments
 
L.M., R.M., J.P., A.R., S.W. and T.K. participated in interpretation of results and writing the manuscript; C-KT conducted the statistical analyses; J.P., A.R., S.W., K.H. and K.H. conducted the laboratory analyses. The authors thank Allison Eaton, Kendra Worley, Sara Duckworth, Beri Massa, Rachel Holston and Patti Williams (UNC High Throughput Genotyping Core Laboratory) and Daynise Skeen (UNC SPORE Tissue Procurement Facility) for technical assistance and Mia Gaudet for helpful comments on the manuscript. The study was supported by specialized program of Research Excellence (SPORE) In Breast Cancer (NIH/NCI P50-CA58223), Lineberger Comprehensive Cancer Center Core Grant (NIS/NCI P30-CA16086), Center for Environmental Health and Susceptibility (NIEHS P30-ES10126), and Superfund Basic Research Program (NIEHS P42-ES05948).

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 References
 

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Received October 8, 2005; revised November 12, 2005; accepted December 20, 2005.


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