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Nucleotide Excision Repair Gene Polymorphisms and Recurrence after Treatment for Superficial Bladder Cancer

Departments of ¹ Epidemiology and ² Urology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, and ³ Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut

Requests for reprints: Xifeng Wu, Department of Epidemiology, Unit 1340, The University of Texas MD Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-4657; E-mail: xwu{at}mdanderson.org.

	ABSTRACT

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Purpose: Interindividual differences in DNA repair capacity not only modify individual susceptibility to carcinogenesis, but also affect individual response to cancer treatment. Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells involved in the removal of a wide variety of DNA lesions. Polymorphisms in NER genes may influence DNA repair capacity and affect clinical outcome of bladder cancer treatment.

Experimental Design: To test the influence of NER gene polymorphisms on superficial bladder cancer outcome (recurrence and progression), we conducted a follow-up study of 288 patients with superficial bladder cancer. Median follow-up among patients who were recurrence-free at the end of observation was 21.7 months from diagnosis. The specific polymorphic loci examined include XPA [A/G at 5' untranslated region (UTR)], XPC (poly AT, Ala⁴⁹⁹Val, Lys⁹³⁹Gln), XPD (Asp³¹²Asn, Lys⁷⁵¹Gln), XPG (His¹¹⁰⁴Asp), ERCC 1 (G/T at 3' UTR), and ERCC6 (Met¹⁰⁹⁷Val, Arg¹²³⁰Pro).

Results: The ERCC6 (Met¹⁰⁹⁷Val) polymorphism had a significant impact on recurrence: carriers of at least one variant allele (Val) had a significantly higher recurrence risk than carriers of the wild-type allele (Met/Met; hazard ratio, 1.54; 95% confidence interval, 1.02-2.33). There were no overall statistically significant differences in the distributions of the other polymorphisms between patients with and without recurrence. However, when we combined these variant genotypes, there was a significant trend for an increased recurrence risk with an increasing number of putative high-risk alleles. Using individuals with five or fewer putative high-risk alleles as the reference group, individuals with six to seven risk alleles and individuals with eight or more risk alleles had higher recurrence risks, with hazard ratios of 0.92 (0.54-1.57) and 2.53 (1.48-4.30), respectively (P for trend < 0.001). There was also a significant trend for shorter recurrence-free survival time with increasing number of variant alleles (log rank test, P = 0.0007). When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively). There were no significant individual or joint associations between these polymorphisms and progression.

Conclusions: These data suggest that interindividual differences in DNA repair capacity may have an important impact on superficial bladder cancer recurrence. A pathway-based approach is preferred to study the effects of individual polymorphism on clinical outcomes.

Key Words: bladder cancer • polymorphism • nucleotide excision repair • XPA • ERCC6 • Genotourinary cancers: bladder

	INTRODUCTION

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Bladder cancer is the fifth most commonly diagnosed malignancy in the United States, with more than 55,300 new cases diagnosed in 2004 (1). Superficial bladder cancer accounts for >85% of newly diagnosed cases. These cases comprise a heterogeneous group of tumors whose individual prognoses are difficult to predict (2). Nevertheless, following transurethral resection, tumor recurrence rate is about 70%, and 10% to 15% of such recurrences may be associated with progression to more invasive forms of cancer (3, 4). Clinical and pathologic prediction variables of disease recurrence have been extensively studied. In a patient cohort of 1,529 patients, tumor size, number of tumors, and presence of carcinoma in situ have been correlated with disease recurrence (5). Administration of intravesical Bacille Calmette-Guerin (BCG) has been found to significantly reduce the risk of recurrence and progression. However, the response rate for BCG treatment is only 60% to 70%, and about one-third of responders develop recurrence and progression (6, 7). A number of pathologic and molecular markers have been studied as potential predictors of outcome in bladder cancer. Mutant cell cycle and proliferative markers, including Ki-67, cytokeratin 20 and 34ß, and growth factors, such as epidermal growth factor, vascular endothelial growth factor, and fibroblast growth factor receptor-3, have been found to influence recurrence. p53, p21, RB, cadherins cathepsins, metalloproteinases, BCL-2, cytokeratins, and fibroblast growth factor receptor-3 have been found to be predictors of tumor progression (8).

A possible explanation for the unpredictability of the clinical course of superficial bladder cancer may be related to the fact that host genetic differences may render some individuals at higher risk than others. Functional polymorphisms may account for phenotypic differences that lead to enhanced cancer risk. The associations between genetic polymorphisms and cancer risk have been extensively reported; however, few studies have focused on polymorphisms as predictors of specific clinical events.

One of the pathways for carcinogenesis is related to DNA damage and repair. DNA repair systems are essential for maintaining genomic integrity. The ability to monitor and repair carcinogen-induced DNA damage is an important determinant of susceptibility to carcinogenesis. There is considerable evidence suggesting that reduced DNA repair capacity may play a role in cigarette smoking–related cancer risk (9, 10). Interestingly, in terms of cancer recurrence and survival, efficient DNA repair capacity is not always a favorable prediction factor. Catto et al. (11) reported that reduced expression of two mismatch repair genes, hMLH1 and hMSH2, was associated with fewer recurrences of superficial bladder cancer. In addition, Bosken et al. (12) found that effective host DNA repair capacity was associated with poorer survival in patients with non–small cell lung cancer who were treated with chemotherapy.

Nucleotide excision repair (NER), one of the major DNA repair pathways in mammalian cells, is involved in the removal of a wide variety of DNA lesions, including bulky carcinogen adducts resulting from tobacco exposure. All key NER factors have been cloned, and the core of the "cut-and-paste" reaction has been reconstituted in vitro (13). Most NER genes are polymorphic, and some of the polymorphisms have been extensively studied in terms of their associations with cancer risk as well as clinical outcomes in specific cancer types (14–17). However, most studies have used a candidate gene approach, investigating one single nucleotide polymorphism (SNP) in a single gene. In the current study, we applied a pathway-based approach to systematically examine the individual and joint impact of most relevant genetic polymorphisms in major NER genes on clinical outcomes of superficial bladder cancer.

	MATERIALS AND METHODS

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Study Population. For this study, 288 patients with superficial bladder cancer were identified from The University of Texas MD Anderson Cancer Center in Houston, TX. Because 90.6% (261) of the patients were Caucasians, all analyses were restricted to Caucasians. All cases diagnosed within 1 year preceding enrollment were histologically confirmed, and were previously untreated with chemotherapy or radiotherapy. There were no age, sex, or ethnic restrictions. Through personal interview, each of the 261 patients were asked to provide detailed demographic information using a standardized questionnaire. Each patient also donated a 40 mL sample of blood for laboratory analysis. All patients gave written informed consent, and the protocol was approved by the MD Anderson Cancer Center Institutional Review Board. Patients were followed with periodic cystoscopic examinations and intravesical treatment. This treatment consisted of either BCG for 6 weekly instillations (induction BCG) or induction BCG + maintenance BCG according to the Southwest Oncology Group protocol (induction BCG followed by instillations at 3, 6 and then every 6 months for 3 years). Tumor recurrence was defined as a newly detected bladder tumor following a previous negative follow-up cystoscopy, and tumor progression was defined as the transition from non–muscle-invasive (superficial) to invasive or metastatic disease.

Genotyping. Genomic DNA was first isolated from peripheral blood lymphocytes by proteinase K digestion followed by isopropanol extraction and ethanol precipitation; the sample was then coded and then subjected to genotyping. The specific polymorphic loci examined include XPA (A/G at 5' UTR, rs1800975), XPC (poly AT, Ala⁴⁹⁹Val, Lys⁹³⁹Gln), XPD (Asp³¹²Asn, Lys⁷⁵¹Gln), XPG (His¹¹⁰⁴Asp), ERCC1 (G/T at 3' UTR, rs3212986), and ERCC6 (Met¹⁰⁹⁷Val, Arg¹²³⁰Pro). Most of the polymorphisms, except for XPA, XPC (poly AT in intron 11), and XPD (Asp³¹²Asn), were determined using TaqMan real-time PCR. The primer and probe sequences, which are available upon request, were either obtained from National Cancer Institute's SNP500 database or designed using Primer Express Software. The probes were labeled fluorescently with either FAM or VIC on the 5' end and a nonfluorescent minor groove binder quencher on the 3' end (Applied Biosystems, Foster City, CA). Typical amplification mixes (5 µL) contained sample DNA (5 ng), 1x TaqMan buffer A, 200 µm deoxynucleotide triphosphates, 5 mmol MgCl₂, 0.65 units of AmpliTaq Gold, 900 nmol/L each primer, and 200 nmol/L each probe. The thermal cycling conditions consisted of 1 cycle for 10 minutes at 95°C, 40 cycles for 15 seconds at 95°C, and 1 minute at 60°C. SDS version 2.1 software (Applied Biosystems) was used to analyze end-point fluorescence. Water control, internal controls, and previously genotyped samples were included in each plate to ensure accuracy of genotyping. Genotyping for XPA, XPC (poly AT in intron 11), and XPD (Asp³¹²Asn) were done as described previously using PCR-RFLP (14–16).

Statistical Analyses. ² analyses and Fisher's exact test were used to assess patient characteristics by NER gene genotypes when appropriate. Survival analysis methods were used to consider the influence of NER gene genotypes on patient recurrence and progression. For each patient, we calculated recurrence-free survival time as the time from diagnosis to recurrence or to the date of last follow-up. We calculated person-years at risk within each genotype category as the sum of recurrence-free survival times of all subjects in that category. Overall recurrence-free survival in relation to NER gene genotype was evaluated by Kaplan-Meier survival function and log-rank tests. Hazard ratios (HRs) for risk of recurrence were estimated from a multivariate Cox proportional hazards model, with adjustments for age, sex, ethnicity, smoking status, tumor grade, and BCG treatment. Stratified analysis was also done according to age, gender, smoking status, and BCG treatment. Stata software (Stata Corp., College Station, TX) was used for statistical analysis.

	RESULTS

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Characteristics of Subjects. Of the 261 Caucasian superficial bladder cancer patients included in this study, 205 (78.54%) were men, and 56 (21.46%) were women. The mean age was 62.37 ± 11.63 years. The median follow-up time was 21.7 months (range, 1-74.5 months). Table 1 summarizes the detailed distribution of demographic characteristics among patients with or without recurrent disease and progression for those Caucasian patients with available data. There were 127 recurrences and 36 developed progressive disease during the follow-up period. Between recurrent and nonrecurrent patients, there were no statistically significant differences in any of the characteristics except BCG treatment (P = 0.049). Clinical factors associated with increased progression risk included aggressive histologic subtypes (P < 0.001), the presence of carcinoma in situ (P = 0.005), and tumor size (P = 0.056). In addition, substantially more men developed progression than women (P = 0.003). Those with recurrent or progressive disease tend to be older, although the differences were not statistically significant (P = 0.056 and 0.143, respectively).

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Fig. 1 Kaplan-Meier survival function for recurrence among bladder cancer patients by number of risk alleles.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Fig. 2 Kaplan-Meier survival function for recurrence among bladder cancer patients by BCG treatment with XPA genotypes.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Fig. 3 Kaplan-Meier survival function for recurrence among bladder cancer patients by BCG treatment with ERCC6 genotypes.

	DISCUSSION

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There have been many studies about the associations of genetic polymorphisms with clinical outcomes in cancer (18–20), most of which have focused on one SNP in a certain gene resulting in often contradictory results. Most importantly, because the prognosis of cancer patients likely involves multistep, multigenic pathways, it is unlikely that any one single genetic polymorphism would have a dramatic effect on clinical outcome. In addition, association studies of clinical outcomes often have small sample sizes compared with case-control studies. The limits of the candidate gene approach study mandate a better approach for such association studies. The pathway-based approach would reflect the combined effects of a panel of polymorphisms in a molecular pathway and thus increase the chance of finding minor effects by evaluating a combination of polymorphisms in genes involved in multiple pathways.

We found significant associations between the ERCC6 polymorphism and increased recurrence risk and some other interesting associations in stratified analysis, which are biologically plausible. For example, we found that that XPD and ERCC6 polymorphisms conferred more evident effects on recurrence risk in older individuals and smokers, which might be because these two groups typically have accumulated more DNA damage than younger individuals and nonsmokers. However, because stratified analysis often deals with smaller sample sizes, these observations warrant further corroboration. More significantly, although each individual polymorphism had a minor effect on recurrence, when combining the putative risk alleles, individuals with higher numbers of putative risk alleles had a 2.53-fold increased risk of recurrence in a multivariate model. In addition, there was a significant association between increased variant alleles and shorter overall recurrence-free survival time for superficial bladder cancer patients (P = 0.0007).

Another interesting finding of this study is that polymorphisms in XPA and ERCC6 genes were associated with BCG response. It is well established that deficient DNA repair capacity increases cancer susceptibility. However, little is known about the effects of deficient DNA repair capacity on treatment outcome. Several studies have shown that polymorphisms in DNA repair genes modulate response to cisplatin-based therapy (18–20) because NER is the major pathway repairing cisplatin-induced DNA damage. Although BCG intravesical instillation is the dominant and most effective method for treating superficial bladder cancer and preventing recurrence, its mechanism of action is not yet fully understood (21). The antitumor effects of BCG are mostly related to local immunologic events, which might include two pathways. In the first pathway, after incubation with BCG, normal and malignant urothelial cells produce an array of cytokines, including interleukin-1, tumor necrosis factor-, and interleukin-6. The cytotoxic response to tumor necrosis factor- has features of both apoptotic and necrotic cell death. One immediate cause of cell death is believed to be the production of oxygen-free radicals by mitochondria following tumor necrosis factor- action. Moreover, several lines of evidence suggest that tumor necrosis factor- stimulation induce extensive oxidative DNA damage; for instance, Nathan et al. (22) found that tumor necrosis factor- induced wide chromosome damage in DNA repair-deficient cells. In the second possible pathway, BCG stimulation of human peripheral blood mononuclear cells leads to the generation of tumor cytotoxic natural killer cells. IFN- and interleukin 2 are essential for BCG-induced cytotoxicity. Some recent studies suggest that the antitumor effect of IFN- could possibly be mediated by induction of reactive oxidative species (ROS; refs. 23, 24). Watanabe et al. (23) reported that IFN--induced generation of ROS leads to apoptosis in primary hepatocytes. Besides local immune response, BCG treatment also induces a systemic activation of the immune system and consequent systemic production of oxygen free-radicals (25). It is known that in many cases, ROS are the primary cause of tumor cell death (26). Therefore, ROS production might be an important pathway in the mediation of BCG treatment response.

ROS causes a wide range of DNA damage, and the accumulation of irreparable DNA damage leads to cell death. The majority of ROS-induced DNA damage is repaired by base excision repair. However, NER seems to also have a function in the repair of oxidative lesions (27). Reardon et al. (28) showed the removal of 8-oxodG by NER. A recent study suggests that NER represents a plausible mechanism by which 8-oxodG and oligomers containing 8-oxodG appear extracellularly in cell culture supernatant, plasma, or urine (29). XPA was previously reported to be actively involved in the dual incision step of repairing ROS-induced 5',8-purine cyclodeoxynucleosides, which is formed by intramolecular cross-linking between the C-8 position of adenine or guanine and the 5' position of 2-deoxyribose (30). ERCC6 (CSB) protein plays an important role in transcription-coupled and global genome-DNA repair, as well as base excision repair of some types of oxidative damage, including the aforementioned 8-oxodG (31). Therefore, the interindividual variability in DNA repair capacity that affects ROS-induced DNA damage is likely to impact the treatment effect of BCG. Optimal DNA repair capacity will lead to decreased ROS-induced DNA damage, which subsequently results in less tumor cell death and worse clinical outcome. On the contrary, suboptimal DNA repair capacity will lead to increased ROS-induced DNA damage, which subsequently translates into more tumor cell death and better clinical outcome. In this regard, it is biologically plausible that the G allele of the XPA polymorphism is associated with a poorer outcome (shorter time to recurrence after BCG treatment), because a previous study showed that the G allele, compared with the A allele, was associated with more efficient DNA repair capacity (14). The functional significance of ERCC6 polymorphisms has not been reported in any studies; however, because patients with G alleles had worse outcomes after BCG treatment, it would be interesting to find out whether the G allele is associated with better DNA repair capacity.

Since 1976, BCG has remained the most effective treatment against superficial bladder cancer leading to improved recurrence and progression-free survival, yet about one-third of patients do not respond to BCG treatment, and another one-third develop recurrence and progression despite initial response. Early identification of BCG nonresponders may allow these patients to be saved from recurrence and progression by timely radical cystectomy. The functional impacts on BCG response of SNPs in XPA and ERCC6, as observed in our study, may help identify BCG nonresponders early.

This is the first molecular epidemiologic study to investigate the association between genetic polymorphisms in DNA repair genes and risk of bladder cancer recurrence. The pathway-based approach is more promising in finding predictors of clinical outcomes. However, the magnitude of the associations found in our study is far from clinically relevant. In the future, more comprehensive genotyping and haplotyping are warranted for using genomic polymorphisms as clinically applicable predictive markers.

	FOOTNOTES

 
Grant support: National Cancer Institute grants CA 74880, CA 85576 (X. Wu), CA 91846(C. Dinney and X. Wu),and CA 86390 (M. Spitz).

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

Received 6/ 4/04; revised 1/ 7/05; accepted 1/13/05.

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