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Carcinogenesis Advance Access originally published online on October 19, 2006
Carcinogenesis 2007 28(3):698-703; doi:10.1093/carcin/bgl201
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genotypes, haplotypes and diplotypes of XPC and risk of bladder cancer

Yimin Zhu1,2, Maode Lai2, Hushan Yang1, Jie Lin1, Maosheng Huang1, H.Barton Grossman3, Colin P. Dinney3 and Xifeng Wu1,*

1 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA
2 Department of Epidemiology and Biostatistics, Zhejiang University School of Medicine Hangzhou 310006, China
3 Department of Urology, The University of Texas M. D. Anderson Cancer Center Houston, TX 77030, USA

*To whom correspondence should be addressed. Tel: +1 713 745 2485; Fax: +1 713 792 4657 Email: xwu{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 References
 
Xeroderma pigmentosum complementation group C (XPC) is responsible for DNA damage recognition in the initial steps of the nucleotide excision repair pathway. Genetic variations in the XPC gene may be associated with impaired protein function and increased risk for bladder cancer. To elucidate the roles of common polymorphisms of XPC in the etiology of bladder cancer, we conducted a hospital-based case–control study including 578 Caucasian incident bladder cancer patients and 578 age- and gender-matched Caucasian controls. We analyzed the associations of the genotypes, haplotypes and diplotypes of three XPC polymorphisms, Ala499Val (C->T), PAT (–/+) and Lys939Gln (A->C), with the risk of bladder cancer. No significant association was found for any individual polymorphism. However, the C-C and T-A (indicated as in the order of Ala499Val-PAT-Lys939Gln) haplotypes were associated with reduced bladder cancer risks, with odds ratios (ORs) of 0.51 [95% confidence interval (CI) = 0.34–0.78] and 0.79 (0.60–1.04), respectively. The protective effects were more evident in men, people younger than 59 years, and ever-smokers. We also found that four diplotypes were significantly associated with reduced bladder cancer risk, with ORs (and 95% CIs) of 0.53 (0.34–0.82) for C-A/T-A, 0.48 (0.27–0.84) for C-A/C-C, 0.18 (0.053–0.60) for C-C/C-C and 0.57 (0.36–0.90) for C+C/C+C. These results suggest that sequence variants in the XPC gene might modulate the risk of bladder cancer.

Abbreviations: CI, confidence intervals; DRC, DNA repair capacity; LD, linkage disequilibrium; NER, nucleotide excision repair; OR, odds ratio; PAT, poly (AT) insertion/deletion polymorphism; SNP, single nucleotide polymorphism; XPC, xeroderma pigmentosum complementation group C


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 References
 
Bladder cancer is the fourth most common cancer in men and the ninth most common in women in the United States, with more than 63 210 new cases diagnosed in 2005 (1,2). The known risk factors for bladder cancer include exposure to chemical carcinogens such as polycyclic aromatic hydrocarbons, aromatic amines and N-nitroso compounds from cigarette smoking, industrial pollution and certain occupations (3,4). These carcinogens and their intermediate activators can cause DNA damage, including bulky adducts, crosslinks and strand breaks. Four major pathways are responsible for repairing damaged DNA: base excision repair, nucleotide excision repair (NER), double strand break repair and mismatch repair (5,6). A failure to repair DNA lesions may cause mutations in oncogenes and tumor suppressor genes, leading to genomic instability and carcinogenesis; and interindividual differences in the ability to repair DNA damage are an important determinant of genetic susceptibility to cancer (7). Further, numerous epidemiological studies have suggested that suboptimal DNA repair capacity (DRC) plays an important role in the etiology of cigarette smoking-related cancers such as bladder cancer (8).

The NER pathway is involved in the elimination of a wide variety of DNA lesions, mostly tobacco carcinogen-induced bulky adducts. The xeroderma pigmentosum complementation group C (XPC) protein becomes involved in the early damage recognition and initiation of NER by forming the XPC–HR23B complex (9). The XPC gene spans 33 kb on chromosome 3, contains 16 exons and 15 introns, and encodes a 940 amino acid protein (10–12). Sequence variants of the XPC gene may alter NER capacity and modulate cancer risk. Khan et al. (13) discovered an intronic biallelic poly (AT) insertion/deletion polymorphism (PAT) in intron 9 of XPC. Two non-synonymous single nucleotide polymorphisms (SNPs), Lys939Gln (an A->C transversion) in exon 15 and Ala499Val (a C->T transition) in exon 8, have also been identified (14,15). And although the variant alleles of the PAT polymorphism (16) and of Lys939Gln (14) have been associated with reduced DRC, the impact of Ala499Val on DRC has not been evaluated in previous studies.

The effects of all three of these XPC polymorphisms on cancer risk have been extensively studied, but with inconsistent results. In some studies, the three polymorphisms were found to significantly modify cancer risk (17–21), but other studies showed a lack of association between the polymorphisms and cancer risk (22–24). For example, studies on the PAT and the Lys939Gln polymorphisms have come to inconsistent conclusions about their association with bladder cancer risk (19,22). With a large sample size of 1150 bladder cancer patients and 1149 control subjects, Garcia-Closas et al. (25) reported that subjects carrying the heterozygous XPC Lys939Gln genotype were at a significantly higher risk of bladder cancer than were those who did not [odds ratio (OR) = 1.2, 95% confidence interval (CI) = 1.0–1.4].

The inconsistencies between these studies indicate that the associations of XPC polymorphisms and cancer risk may depend on the type of cancer and population. In addition, interactions between polymorphisms, environmental factors and host characteristics might also contribute to the discrepancies. If the interactions between genetic variants contribute to cancer risk, then the haplotype/diplotypes constructed by these polymorphisms may exert greater effects on tumorigenesis than individual SNPs (26,27). To test the hypothesis that XPC polymorphisms may contribute to bladder cancer carcinogenesis through gene–gene and gene–environment interactions, we performed a large hospital-based case-control study with 578 incident bladder cancer patients (case subjects) and 578 age- and gender-matched cancer-free control subjects.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 References
 
Study subjects
Study subjects were identified from an ongoing case–control study of bladder cancer that started recruiting participants in 1999. The procedures for subject recruitment and eligibility criteria have been previously described in detail (28). Briefly, after the study was approved by the institutional review boards of The University of Texas M. D. Anderson Cancer Center, Baylor College of Medicine, and Kelsey-Seybold Clinics, case subjects were recruited from The University of Texas M. D. Anderson Cancer Center and Baylor College of Medicine. Eligible case subjects had newly diagnosed and histologically confirmed urinary bladder cancer and had not received any previous chemotherapy or radiotherapy. No recruitment restrictions on age, gender, ethnicity, or cancer stage were applied. The majority of cases (90%) are transitional cell carcinoma (TCC). The control subjects were recruited in collaboration with the Kelsey-Seybold clinics, a private multi-specialty physician group that consists of more than 300 physicians in the Houston metropolitan area. The controls recruited were Kelsey-Seybold patients, the majority of whom visit for their annual health checkups. Controls were frequency-matched to case subjects by age (±5 years), sex and ethnicity and had no prior history of cancer (except non-melanoma skin cancer).

After both case and control subjects gave written informed consent to participate in the study, trained M. D. Anderson staff interviewed them to complete the study's risk factor questionnaire. Data were collected on demographic characteristics (e.g. age, sex and ethnicity), occupational history, tobacco use history and other lifestyle factors. Disease characteristics (e.g. invasiveness, histologic type and grade) were also recorded for the case subjects. Immediately after each interview, 40 ml of blood was drawn into a coded, heparinized tube and delivered to the laboratory for DNA isolation and molecular analysis. A total of 578 Caucasian bladder cancer patients and 578 age- and sex-matched Caucasian control patients were included in the study reported here.

Genotyping
Genomic DNA was isolated from peripheral blood lymphocytes. Genotyping was performed blind to case and control status. The Lys939Gln and Ala499Val polymorphisms were detected using TaqMan real-time polymerase chain reaction (PCR). The primer and probe sequences were obtained from the National Cancer Institute's SNP500Cancer database. The probes were labeled with fluorescent FAM or VIC dyes on the 5' end and a non-fluorescent minor groove binder quencher on the 3' end (Applied Biosystems, Foster City, CA, USA). Typical amplification mixes (5 µl) contained 5 ng of sample DNA, 1x TaqMan buffer A, 200 µm of deoxynucleotide triphosphates, 5 mmol MgCl2, 0.65 units of AmpliTaq Gold, 900 nmol l–1 each primer and 200 nmol l–1 each probe. The thermal cycling conditions consisted of 1 cycle for 10 min at 95°C, 40 cycles for 15 s at 95°C and 1 min at 60°C. SDS version 2.1 software (Applied Biosystems) was used to analyze endpoint fluorescence. Water controls, internal controls and previously genotyped samples were included in each plate to ensure the accuracy of the genotyping.

Genotyping for the XPC PAT polymorphism was done according to a previous protocol with minor modifications (13). Briefly, two primers, 5'-TAG CAC CCA GCA GTC AAA G-3' (forward) and 5'-TGT GAA TGT GCT TAA TGC TG-3' (reverse), were used to amplify the XPC PAT+/– polymorphism site. Each PCR was performed with a total volume of 15 µl, which contained 100 ng of DNA, 50 ng of forward and reverse primers, 1.5 µl of 2 mM dNTP, 2.5 mM MgCl2 and 1.5 U of Taq DNA polymerase. Amplification conditions consisted of an initial denaturing step at 94°C for 5 min, 35 cycles of denaturation at 94°C for 30 s, annealing at 57°C for 30 s, extension at 72°C for 30 s and a final elongation at 72°C for 5 min. Fifteen microliters of PCR products was electrophoresed on a 1.5% agarose gel. A 266 bp fragment indicated the absence of the insertion–deletion polymorphism (PAT–), and a 344 bp fragment indicated its presence (PAT+).

Statistical analyses
The Pearson {chi}2 test was used to test for differences in the distribution of case and control subjects' sex, smoking status and XPC genotypes. Student's t-test was used to assess the significance of differences between the case and control subjects' continuous variables, such as age and pack-years smoked. The Hardy–Weinberg equilibrium for the XPC genotypes was tested by a goodness-of-fit {chi}2 test. ORs and 95% CIs were calculated as an estimate of relative risk. Unconditional multivariate logistic regression was used to control for age, sex and smoking status, whenever appropriate. D', a linkage disequilibrium (LD) index, and haplotype and diplotype frequencies were analyzed using the HelixTree Genetics Analysis Software (version 4.1.0, Golden Helix, Bozeman, MT). Only haplotypes with frequencies >5% in controls were analyzed in this study. Age was categorized into three groups as follows: <59 years, 59–68 years and ≥69 years, based on the tertile values in controls. Smoking status was classified as ‘never-smoker’ and ‘ever-smoker’, which included both current and former smokers. The definition of smoking status was described in a previous study (29). All the statistical analyses were performed using Stata software (Stata Corp., College Station, TX, USA). All the statistical tests were two-sided. Values of P < 0.05 were considered statistically significant. To account for the use of multiple comparisons, the Bonferroni correction was used to adjust P-values while setting the family wise significance level at 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 References
 
Characteristics of the study subjects and of the disease in case subjects are shown in Table I. The majority of study subjects (77.7%) were men. The mean age [±1 standard deviation (SD), n = 578] was 63.7 ± 10.8 years in cases and 63.1 ± 10.5 years in controls (P = 0.328). The percentage of ever-smokers was significantly higher in the cases than in the controls (74.4% versus 54.5%, P < 0.001). Cases also smoked more pack-years than the controls (42.4 versus 28.9 pack-years, P < 0.001). Among the cases, 315 (54.5%) had superficial bladder cancer and 250 (43.3%) had invasive disease. According to the WHO 1973 classification of bladder tumors (30), the majority of tumors (68.7%) is type of papillary, and grade III tumors represented 68.9% of the tumors (Table I). Carcinoma in situ (CIS) was present in 27.9% of tumors (Table I). Most of these CIS are associated with invasive carcinoma.


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  		Table I Characteristics of bladder cancer patients and controls

 
The three polymorphisms were in Hardy–Weinberg equilibrium in both the case and control groups (Table II). The minor allele frequencies of PAT, Lys939Gln and Ala499Val in cases were 0.38, 0.39 and 0.23, respectively, which were not significantly different from the frequencies found in controls of 0.39, 0.40 and 0.24, respectively (all values of P > 0.05). None of the SNPs were associated with bladder cancer risk in individual-SNP analyses (Table II). The PAT polymorphism was in LD with the Lys939Gln and Ala499Val (D' = 0.968, 0.833, respectively, both values of P < 0.001). Lys939Gln was also in LD with Ala499Val (D' = 0.863, P < 0.001).


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  		Table II XPC polymorphisms and bladder cancer risk

 
Haplotypes based on the three XPC polymorphisms are shown in Table III. The five common haplotypes (C-A, T-A, C-C, C+C and T+C) in the control group accounted for 95.5% of all haplotypes. The most common haplotype, occurring in 49.1% and 45.5% of the case and control groups, respectively, was C-A, in which all the alleles are wild-type.


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  		Table III Association between XPC haplotypes and bladder cancer risk

 
Using C-A, the most common haplotype, as the reference group, the haplotype C-C was associated with a significantly reduced risk of bladder cancer (OR = 0.51, 95% CI = 0.34–0.78). The result remained significant after the Bonferroni adjustment for multiple comparisons was applied (Table III). Haplotype T–A showed a borderline significant protective effect with an OR of 0.79 (95% CI = 0.60–1.04) (Table III).

In stratified analyses, the protective effect of the C-C haplotype was more evident in younger subjects, men and ever-smokers, with ORs of 0.49 (95% CI = 0.24–0.99), 0.48 (95% CI = 0.30–0.77) and 0.51 (95% CI = 0.31–0.81), respectively (Table IV). The effects in men and ever-smokers remained significant after the Bonferroni adjustment for multiple comparisons was applied (Table IV). For the T-A haplotype, borderline significant associations were observed in younger people (<59 years old) and ever-smokers, with ORs of 0.64 (95% CI = 0.40–1.03) and 0.75 (95% CI = 0.54–1.06), respectively. However, none of the interactions between genotype and stratified variables were statistically significant (results not shown).


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  		Table IV Odds ratios for associations of XPC haplotypes and bladder cancer risk stratified by selected variables (with 95% confidence intervals)

 
Ten XPC diplotypes with frequencies >2% in controls are shown in Table V. The five most common diplotypes, C-A/C-A, C-A/T-A, C-A/C+C, C-A/T+C and C+C/C+C, accounted for 77.4% of all the diplotypes in the controls. Using the C-A/C-A diplotype as a reference group, we calculated the bladder cancer risk for the 10 most common diplotypes and adjusted for age, sex and smoking status. Results showed that diplotypes C-A/T-A, C-A/C-C, C-C/C-C and C+C/C+C were significantly associated with reduced bladder cancer risk, with ORs of 0.53 (95% CI = 0.34–0.82), 0.48 (95% CI = 0.27–0.84), 0.18 (95% CI = 0.053–0.60) and 0.57 (95% CI = 0.36–0.90), respectively. For diplotypes C-A/T-A and C-C/C-C, the results remained significant after the Bonferroni adjustment for multiple comparisons was applied (Table V). Borderline significant associations were observed for two diplotypes, C-A/T-C and C-A/C+A (Table V).


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  		Table V Associations of XPC diplotypes and bladder cancer risk stratified by selected variables

 

   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
References
 
In this large case–control study, we found no associations between bladder cancer risk and the presence of XPC polymorphisms Ala499Val, PAT and Lys939Gln in individual-SNP analyses. However, certain haplotypes and diplotypes derived from the three polymorphisms had significant protective effects against bladder cancer, suggesting that the combined effects of several SNPs may be detected by haplotype-based analyses.

Previous studies on the role of XPC genetic polymorphisms have generated contradictory results (19,22,31). The lack of associations found in our study is a finding consistent with the results of a previous study of XPC polymorphisms PAT, IVS11-6 and A939C in bladder cancer (22), but our results contradict the findings of another study, in which a significantly elevated risk of bladder cancer was observed with a variant allele of Lys939Gln (19). Studies based on individual-SNP analyses frequently generate contradictory results, and often, later analyses are unable to replicate findings that suggest positive associations exist (28). The limitations and pitfalls of individual-SNP studies have been discussed in depth (28) and include inadequate statistical power, small sample size and lack of evaluation of the effects of multiple related genes in the same pathways. In the current study, we calculated minimum detectable ORs for each SNP on the basis of the minor allele frequencies in control subjects, significance level (P = 0.05), sample size and the ratio of case to control subjects. For XPC PAT, Lys939Gln and Ala499Val, our tests had an 80% power to detect an OR of 1.41, 1.42 and 1.18, respectively. Therefore, the power in our study was sufficient to detect increased ORs for complex diseases (such as cancer), and the lack of association cannot be attributed to inadequate statistical power.

In this study, analyses based on haplotypes showed that compared to the most abundant C–A haplotype, the T–A haplotype, which contains one variant T allele, conferred a significantly decreased risk of bladder cancer. Weiss et al. (32) observed a decreased risk of endometrial cancer (OR = 0.64, 95% CI = 0.42–0.99) in subjects with at least one variant T allele of XPC Ala499Val and one wild-type A allele of Lys939Gln. In addition, the variant PAT+ allele and the variant C allele of the Lys939Gln were found to be associated with suboptimal DRC in previous genotype-phenotype correlation studies (16,33). According to our recent Comet assay data (unpublished data), the variant T allele of the Ala499Val was correlated with efficient DRC. Hence, the T-A haplotype, which includes all favorable alleles, may determine a favorable DRC status and subsequently confer a decreased risk of bladder cancer.

In addition to our results showing that the T-A haplotype had a protective effect, our results also demonstrated that the C-C haplotype, which contains two adverse alleles, the C allele of the Ala499Val and the C allele of the Lys939Gln, was also protective. According to the ‘greater apoptosis’ hypothesis (23,34,35), adverse alleles with less efficient DRCs may have a greater protective effect by increasing the chance apoptosis triggered by low-level mutagenic challenges. In fact, several studies have found that apoptosis is one of the most common responses of bladder urothelial cells to mutagenic challenge (36–38).

Our results further support the conclusion that the reduced risk of cancer associated with the presence of these variant alleles may be explained by the interaction among the three XPC polymorphisms. It has been consistently observed that gene–gene interactions might modulate the effects of specific alleles on cancer risk in the context of different combinations of genetic components, even though each allele's subtle, individual influence might not be detected (26,39,40). For example, in our study, the protective effect of the Lys939Gln C allele was evident only when accompanying the PAT– allele, and the effect of the Ala499Val T allele was evident only in the presence of the PAT– and Lys939Gln A allele.

In stratified analyses, the protective effects of the C–C and T–A haplotypes were more evident in ever-smokers. This suggests that these haplotypes may exert their protective effects by modulating responses to carcinogenic exposures. Similar effects of DNA repair polymorphisms on cancer risk in smokers have been documented elsewhere (26,29,41), suggesting a possible interaction between genes and smoking habits. The ‘greater apoptosis’ hypothesis described above also provides an explanation for the observed increased protective effects seen in smokers, because the apoptosis is triggered by exposure to a carcinogen. For XPC-PAT, Lys939Gln and Ala499Val, given the exposed proportions of smoking and adverse genotype distribution in controls, the specified significance level (P = 0.05) and the sample size, our study's power to detect a significant interaction OR of 2.0 was 70.3, 71.0 and 54.7%, respectively. Therefore, our study was sufficiently powered to detect modestly increased interaction ORs, although power is attenuated when the minor allele frequency is low.

We also observed that the protective effects of the C–C and T–A haplotypes were more evident in younger subjects. We previously observed that case subjects who were young at diagnosis exhibited lower DRCs and higher lung cancer risks (29). Moreover, the C–C haplotype was associated with significantly decreased risk in men but not women (Table IV); this is in agreement with our previous finding that DRC was significantly lower in women than men for both lung cancer case and control subjects (42). Other studies have shown that women might have higher bladder cancer risk and higher levels of 3- and 4-aminobiphenyl-hemoglobin adducts than men (43). Moreover, more men than women are ever-smokers, so the sex difference in risk may actually reflect the modulatory effect of smoking.

It should be noted that high-grade lesions are over-represented in our study population because as a large referral center, M. D. Anderson received many patients with high-grade lesions referred to by local physicians for treatments.

Collectively, we found that specific haplotypes and diplotypes constructed by PAT, Ala499Val and Lys939Gln polymorphisms of the XPC gene were associated with reduced bladder cancer risk, suggesting the presence of interactions among XPC genetic variants, smoking status and specific subject characteristics. Further studies are warranted to validate these observations with phenotypic-based study and investigate the molecular mechanism of the interactions.


   Acknowledgments
 
We thank Dr Angelique Siy for her scientific editing. This work was supported by National Cancer Institute grants CA74880, CA91846 and CA110928.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

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Received March 20, 2006; revised October 9, 2006; accepted October 11, 2006.


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J. Lin, G. E. Swan, P. G. Shields, N. L. Benowitz, J. Gu, C. I. Amos, M. de Andrade, M. R. Spitz, and X. Wu
Mutagen Sensitivity and Genetic Variants in Nucleotide Excision Repair Pathway: Genotype-Phenotype Correlation
Cancer Epidemiol. Biomarkers Prev., October 1, 2007; 16(10): 2065 - 2071.
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