Alterations in DNA repair genes have been shown to cause a reduction in host DNA repair capacity and may influence host susceptibility to carcinogenesis. The double-strand break repair is a major DNA-repair pathway. This study tested the hypothesis that common sequence variants of the double-strand break pathway genes predispose susceptible individuals to an increased risk for renal cell carcinoma. Toward this end, we evaluated the associations of 13 single-nucleotide polymorphisms in 10 candidate genes involved in the double-strand break pathway with renal cell carcinoma risk in a population-based case-control study that included 326 Caucasian renal cell carcinoma patients and 335 controls. Using the homozygous wild type as the reference group, we observed a significantly increased renal cell carcinoma risk associated with the homozygous variant genotype of NBS1 (rs1805794; odds ratio, 2.13; 95% confidence interval (95% CI), 1.17-3.86). Carrying of at least one copy of the variant XRCC4 allele was also associated with a significantly increased risk (rs1805377; odds ratio, 1.56; 95% CI, 1.08-2.26). Importantly, in pathway analysis, compared with the reference group (1 or less adverse alleles), individuals with two (odds ratio, 1.26; 95% CI, 0.83-1.91), three (odds ratio, 1.00; 95% CI, 0.64-1.56), and more than three adverse alleles (odds ratio, 1.75; 95% CI, 1.03-2.98) were at increased risk for renal cell carcinoma with significant association in subjects carrying more than 3 adverse alleles. Results from this study provide evidence that individuals with a higher number of genetic variations in the DBS repair pathway are at an increased risk for renal cell carcinoma. These findings require further validation in independent populations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2366–73)

Renal cell carcinoma represents the third leading cause of death among genitourinary malignancies and the twelfth leading cause of cancer death overall. It is estimated that in the United States, ∼51,000 people were diagnosed with renal cell carcinoma in 2007, and roughly one third of these patients will ultimately die from this disease (1).

Epidemiologic studies have suggested that gender, obesity, smoking, analgesic, diuretic abuse, and environmental factors are associated with renal cell carcinoma (2). Cigarette smoking, for example, doubles the risk for renal cell carcinoma and contributes to as much as one third of all cases, yet only a fraction of smokers and a low number of nonsmokers develop renal cell carcinoma, which implies influence of host factors on individual susceptibility (3). These interindividual differences in susceptibility to renal cell carcinoma may be attributed to genetic polymorphisms in critical genes, including those involved in DNA repair (4).

DNA repair systems play a critical role in protecting the human genome from damage caused by carcinogens present in the environment (5). The double-strand break pathway is responsible for repairing double-strand breaks caused by a variety of exposures, including ionizing radiation, free radicals, and telomere dysfunction. There are 2 distinct and complementary pathways for double-strand break repair, namely, homologous recombination and nonhomologous end joining (5). Many genes that encode enzymes involved in DNA repair carry single-nucleotide polymorphisms with potential to modulate gene function, and associations between renal cell carcinoma risk and variant alleles in different DNA repair genes have been reported (4).

The conventional single gene–based approach to study the role of genetic variants in carcinogenesis has been fraught with inconsistencies and, sometimes, conflicting data, likely due to the fact that carcinogenesis is a multigenic process. Consequently, a pathway-based approach, which evaluates the combined effects of a panel of single-nucleotide polymorphisms in the same pathway, may amplify the effects of individual polymorphisms and provide enhanced risk assessment. Such pathway-based multigenic approaches have recently been shown to provide robust risk prediction in several solid organ cancers (6-8). In this context, we investigated thirteen potential functional polymorphisms in 10 major double-strand break repair genes (XRCC3, XRCC2, NBS1, BRCA2, RAG1, KU70, KU80, LIG4, XRCC4, and ATM), and used a variety of analytic approaches to identify high-order gene-gene and gene-environment interactions in modulating the risk for renal cell carcinoma.

Study Population

Beginning in 2002, incident renal cell carcinoma cases were recruited from The University of Texas M. D. Anderson Cancer Center in Houston, Texas. All cases were individuals with newly diagnosed, histologically confirmed renal cell carcinoma. There was no age, gender, ethnicity, or cancer stage restrictions on recruitment. M. D. Anderson Cancer Center staff interviewers identified renal cell carcinoma cases through a daily review of computerized appointment schedules for the Departments of Urology and Genitourinary Medical Oncology. Healthy control subjects without a history of cancer, except nonmelanoma skin cancer, were identified and recruited using the random digit dialing methods. In random digit dialing, randomly selected household phone numbers were used to contact potential control volunteers in the same residency of cases accordingly to the telephone directory listings. Controls must have lived in the same county or socioeconomically matched surrounding counties that the case resides in for at least 1 year and have no history of cancer. The controls were frequency matched to the cases by age (±5 years), sex, ethnicity, and county of residence.

Epidemiologic Data

After informed consent was obtained, all study participants completed a 45-min in-person interview that was administered by M. D. Anderson Cancer Center staff interviewers. The interview elicited information on demographics, smoking history, family history of cancer, occupational history and exposures, and medical history. At the conclusion of the interview, a 40-mL blood sample was drawn into coded heparinized tubes and delivered to the laboratory for molecular analysis. The study was approved by the institutional review boards of M. D. Anderson Cancer Center. An individual who had smoked at least 100 cigarettes in his or her lifetime was defined as an ever smoker. Ever smokers include former smokers (those who had quit smoking for at least 1 year), current smokers, and recent quitters (those who had quit within the previous year).

Genotyping

Based on published association studies, we selected 13 potentially functional single-nucleotide polymorphisms from ten double-strand break genes, including 8 single-nucleotide polymorphisms from the homologous recombination pathway and 5 single-nucleotide polymorphisms from the nonhomologous end joining pathway. The selected single-nucleotide polymorphisms include all published common nonsynonymous single-nucleotide polymorphisms (minor allele frequency, >5%) in these genes and a few other potential functional single-nucleotide polymorphisms (5′ UTR, splice site, and one synonymous single-nucleotide polymorphism) that have been investigated in previous cancer association studies (9, 10). Genomic DNA was isolated from peripheral blood lymphocytes by proteinase K digestion, followed by isopropanol extraction and ethanol precipitations. DNA samples were stored at -80°C. Genotyping was done using the Taqman real-time PCR method using 7900 HT sequence detector system (Applied Biosystems). The primer and probe sequences for each single-nucleotide polymorphism are available on request. In probes, fluorescent dye FAM and VIC were labeled on the 5′ end, and a quencher was labeled on the 3′ end. Typical amplification mixes (5 μL) consist of DNA sample (5 ng), 1× TaqMan Buffer A, 200 μm dNTPs, 5 mmol MgCl2, 0.65 units of AmpliTaq Gold, 900 nmol/L primer each and 200 nmol/L probe each. The thermal cycling conditions included 1 cycle for 10 minutes at 95°C and 40 cycles for 15 seconds at 95°C and 1 minute at 60°C. The endpoint fluorescence was analyzed by SDS version 2.1 software (Applied Biosystems). Water control, internal controls, and previously genotyped samples were added into each plate as the calibrator to ensure the accuracy and consistency of the genotyping. Positive and negative controls were used in each genotyping assay, and 5% of the samples were randomly selected and run in duplicates with 100% concordance.

Statistical Analysis

The Pearson's χ2 test and the Wilcoxon rank sum test were used to test the differences in characteristics between cases and controls. The Hardy-Weinberg equilibrium was tested by the goodness-of-fit χ2 test. To evaluate the main effect of individual single-nucleotide polymorphisms, we did a multivariate unconditional logistic regression analysis to estimate odds ratios and the 95% confidence intervals (95% CI), adjusting for age, sex, smoking status (never or ever smoker), and history of hypertension (yes or no). The single-nucleotide polymorphisms were tested in association with renal cell carcinoma risk in additive, dominant, and recessive models. The combined effects of minor alleles were analyzed as a categorical variable by grouping the subjects according to the number of minor alleles in each pathway. We treated the minor allele at each locus as the “adverse” allele and tallied the total number of adverse alleles for each individual. For genes with multiple single-nucleotide polymorphisms assayed, only one single-nucleotide polymorphism was included in this pathway analysis. A trend test was done to test for a linear trend in the odds ratios. All statistical analyses were two sided. To account for multiple comparisons, we used the false discovery rate function based on the Benjamini-Hochberg method (11). We calculated the false discovery rate–adjusted P values at 5%, 10%, and 15% levels to assess whether the resulting P values were still significant after adjusting for multiple comparisons. All analyses were done using the Intercooled Stata 8.0 statistical software package (Stata Co.). To assess renal cell carcinoma risk in the context of multiple genes, we applied a recursive partitioning technique (12). The recursive partitioning was derived from the methodology of Classification and Regression Tree. In Classification and Regression Tree, a tree-based model is created by recursive partitioning the data and enables to identify effect modifications between variables that are less visible by traditional logistic regression. The algorithm splits the study sample into a number of homogenous subgroups based on risk factors. The final model is a tree structure with terminal nodes defining a range of risk subgroups. Classification and Regression Tree analysis was done using the Recursive Partitioning and Regression Trees (RPART) package in the R software (version 2.5). We calculated odds ratios for each terminal node adjusting for age, sex, smoking status, and history of hypertension.

Subject Characteristics

Because of the small number of the minority cases, we restricted our analysis to Caucasians only in this study. There were 326 renal cell carcinoma patients and 335 matched cancer-free controls available for this analysis (Table 1). Cases and controls were well matched on age (cases versus controls, 59.4 versus 59.7 years; P = 0.66), gender (cases versus controls: males, 66.5% versus 61.2%; females, 33.5% versus 38.8%; P = 0.16). There were no significant differences in smoking status (cases: never smoker, 48.5%; ever smoker, 46.0%; controls: never smoker, 44.5%; ever smoker, 55.2%; P = 0.09). Among ever smokers, there were no differences in smoking duration, number of cigarettes smoked per day or pack-years of smoking (P = 0.87, P = 0.51, and P = 0.72, respectively). Cases reported a significantly higher prevalence of hypertension than controls (cases versus controls, 57.4% versus 42.8%; P = 0.003).

Effects of Individual Polymorphisms on Risk for Renal Cell Carcinoma

All tested single-nucleotide polymorphisms were in Hardy-Weinberg equilibrium in controls (data not shown). The overall renal cell carcinoma risks associated with the individual polymorphisms are listed in Table 2. When compared with the homozygous wild-type reference group, a significantly increased renal cell carcinoma risk was observed for the homozygous variant genotype of NBS1 E185Q (odds ratio, 2.13; 95% CI, 1.17-3.86) and for heterozygous variant genotype of XRCC4 rs1805377 (odds ratio, 1.70; 95% CI, 1.15-2.52). In addition, the variant allele of NBS1 E185Q also exhibited a significantly increased risk under a recessive model (homozygous variant genotype compared with wild type–containing genotype: odds ratio, 2.18; 95% CI, 1.23-3.85) and the variant allele of XRCC4 rs1805377 was associated with an increased risk under a dominant model (variant-containing genotype compared with homozygous wild-type genotype: odds ratio, 1.56; 95% CI, 1.08-2.26). After adjusting for multiple comparisons at 15% level, the associations with NBS1 E185Q and the XRCC4 rs1805377 heterozygous variant genotype remained significant (Table 2).

When stratified by smoking status, in ever smokers, we observed a significant 1.76-fold increased risk for variant-containing genotype of XRCC4 rs1805377 in the dominant model (odds ratio, 1.76; 95% CI, 1.00-3.11). The homozygous variant genotype of NBS1 E185Q was associated with 3.45-fold increased risk (95% CI, 1.47-8.11). None of the associations were observed in never smokers (data not shown).

Combined Effects of Multiple Single-Nucleotide Polymorphisms

To test the hypothesis that multiple single-nucleotide polymorphisms in the same pathway may have an additive effect on renal cell carcinoma risk, we estimated the combined effect of these single-nucleotide polymorphisms and stratified the analyses by host characteristics (Table 3). The same combination of genes or single-nucleotide polymorphisms was used in the overall analysis and in the stratified analysis. For those genes with multiple single-nucleotide polymorphisms assayed, only one single-nucleotide polymorphism was included in this combined analysis and others were excluded because of linkage disequilibrium.

In the homologous recombination pathway, compared with the reference group (1 or less adverse alleles), individuals with two (odds ratio, 1.26; 95% CI, 0.83-1.91), three (odds ratio, 1.00; 95% CI, 0.64-1.56), and more than adverse alleles (odds ratio, 1.75; 95% CI, 1.03-2.98) were at increased risk for renal cell carcinoma with significant association in subjects carrying more than three adverse alleles (Table 3). Stratified analysis showed that a significant gene-dosage trend was evident in ever smokers, hypertensive, and female subjects. Compared with the reference group (0 and 1 adverse alleles), ever smokers with 2, 3, and >3 adverse alleles had odds ratios that increased to 1.09 (95% CI, 0.62-1.94), 1.38 (95% CI, 0.73-2.59), and 2.31 (95% CI, 1.12-4.76), respectively (P for trend = 0.02; Table 3). Female individuals with 2, 3, and >3 adverse homologous recombination alleles had odds ratios of 1.67 (95% CI, 0.81-3.43), 1.31 (95% CI, 0.60-2.89), and 3.48 (95% CI, 1.44-8.40), respectively (P for trend = 0.02), compared with the reference group. Similarly, subjects with history of hypertension had odds ratios of 2.71 (95% CI, 1.43-5.13), 1.87 (95% CI, 0.96-3.65), and 2.96 (95% CI, 1.27-6.88) when 2, 3, and >3 adverse homologous recombination alleles were respectively present (P for trend = 0.02; Table 3).

For the nonhomologous end joining pathway, a statistically significant cumulative gene-dosage trend was observed in female subjects and individuals >59 (median age of the control subjects) years of age. Females with 2, 3, and >3 adverse nonhomologous end joining alleles had odds ratios of 1.17 (95% CI, 0.59-2.30), 1.28 (95% CI, 0.57-2.89), and 3.69 (95% CI, 1.27-10.43), respectively (P for trend = 0.04). Likewise, subjects >59 years with 2, 3, and >3 adverse nonhomologous end joining pathway alleles had odds ratios that increased to 1.75 (95% CI, 1.01-3.03), 1.58 (95% CI, 0.82-3.05), and 2.60 (95% CI, 1.13-5.99), respectively (P for trend = 0.02; Table 3).

Finally, when all the double-strand break pathway genes were combined, compared with the reference group of three or less adverse alleles, hypertensive subjects, ever smokers, older, and female subjects showed significant gene-dosage trends in renal cell carcinoma risk (Table 3).

Classification and Regression Tree Analysis

Figure 1 depicts the tree structure generated using the Classification and Regression Tree analysis, which all investigated genetic variants of the double-strand break pathway. The final tree structure contained seven terminal nodes as defined by single-nucleotide polymorphisms of the DBS pathway. The terminal nodes represent a range of low- versus high-risk subgroups. The NBS1 genotype was singled out in the first splitting node, separating individuals with the wild type–containing genotypes (low risk) from subjects with the homozygous variant genotype (high risk). Individuals with the variant genotypes of ATM and BRCA2 exhibited the lowest renal cell carcinoma risk with a 32% case rate. Using this terminal node as the reference, the odds ratios of the other 5 terminal nodes ranged from 1.16 to 3.59. Subjects with the variant genotype of NBS1 exhibited a 3.59-fold (95% CI, 1.67-7.72) increased risk for renal cell carcinoma (Fig. 1).

In this study, we used a polygenic approach to investigate the combined effects of 13 common potentially functional variants in ten double-strand break repair genes on renal cell carcinoma risk. Multivariate logistic regression revealed that the NBS1 E185Q and XRCC4 splicing variant allele exhibited a statistically significant association with the risk for renal cell carcinoma. More importantly, the combined analysis of multiple single-nucleotide polymorphisms showed an increasing risk for renal cell carcinoma with an increasing number of adverse alleles. The results of the current study are in concordance with our previous report, wherein using a comet assay, a significantly higher level of DNA damage at baseline and after mutagen induction was seen in renal cell carcinoma patients compared with control subjects, suggesting a functional correlation between DNA damage repair capacity and risk for renal cell carcinoma (13). To the best of our knowledge, this is the first study to examine associations between a panel of double-strand break repair single-nucleotide polymorphisms and renal cell carcinoma risk.

Main effects on the risk for renal cell carcinoma were observed for the NBS1 E185Q single-nucleotide polymorphism in subjects with the homozygous variant genotype, which exhibited a 2.17-fold increased risk for renal cell carcinoma. Homozygous germline mutations of the NBS1 gene lead to the Nijmegen breakage syndrome, a rare autosomal recessive disease characterized by microcephaly, growth and mental retardation, radiosensitivity, immunodeficiency, high incidence of malignancies at an early age, and elevated rates of chromosomal abnormalities (14). Nibrin, the protein encoded by NBS1, is part of a nuclear multiprotein complex that also contains the DNA repair proteins Mre11 and Rad50. Upon irradiation, this complex redistributes within the nucleus, forming foci that have been implicated as sites of DNA repair. Distinct domains of nibrin are required for focus formation, nuclear localization, and functional interactions with other DNA repair proteins (15). In accordance, the variant allele of the NBS1 E185Q single-nucleotide polymorphism was also associated with altered renal cell carcinoma risk under a recessive model, consistent with the role as a tumor suppressor gene in an autosomal recessive genetic disease. This single-nucleotide polymorphism has also been previously shown to be associated with increased risk for skin and lung cancer; however, the exact molecular mechanism remains to be determined (16, 17). The XRCC4 gene is necessary for DNA ligation in nonhomologous end joining, and XRCC4 variant allele in intron 7 (rs1805377) may have functional significance because the nucleotide change from G to A potentially abolishes an acceptor splice site at exon 8 (18, 19). In a recent study of 696 bladder cancer cases and 629 controls, XRCC4 variant allele in intron 7 was associated with an increased risk for bladder cancer (20). Likewise, we observed a significant increase in risk for renal cell carcinoma among carriers of the variant allele compared with common homozygotes (odds ratio, 1.6; 95% CI, 1.08-2.26). However, these findings need to be replicated in additional study populations because homozygote variants were rare in the control populations and did not show significant associations with risk. Furthermore, after adjustment for multiple comparisons, the associations were only significant at 15% false discovery rate level.

Interestingly, we also noticed that consistent with the main effect logistic regression analysis, the NBS1 E185Q and XRCC4 splicing polymorphisms were also identified in the Classification and Regression Tree analysis as important genetic variants modulating renal cell carcinoma risk. NBS1 E185Q was the most prominent single-nucleotide polymorphism to discriminate between cases and controls. Moreover, subsets of individuals with higher cancer risks were identified through Classification and Regression Tree modeling, based on differential combinations of double-strand break genotypes. The Classification and Regression Tree analysis used in this study shows proof-of-principle ability for rapid identification of potential gene-gene interactions when dealing with a large number of variables in a complex disease process such as cancer.

Because we observed only modest effects of individual variant double-strand break genotypes, they are expected to have limited practical value in predicting renal cell carcinoma risk, further supporting the role of a multigenic approach over the single–candidate gene approach. In concordance with this hypothesis, we found a significant trend of increased renal cell carcinoma risk with increasing numbers of adverse alleles in the homologous recombination pathway, nonhomologous end joining pathway, and the entire double-strand break pathway. The gene-dosage effect of all the double-strand break pathway genes observed in this study was restricted to specific subpopulations, namely, subjects with smoking history, females, older individuals, and subjects with a history of hypertension.

We observed that carrying more than five adverse alleles of the entire double-strand break pathway was associated with significant increased risk for renal cell carcinoma in ever smokers, but not in never smokers. Oxidative stress due to cigarette smoking can induce oxidative DNA damage and double-strand break, and our data indicates that smokers with less efficient double-strand break capacity are more likely to develop renal cell carcinoma (21, 22). This finding is well supported by several other studies that have reported similar interactions between DNA repair capacity and dose or duration of smoking (20, 23). Although our data indicates that smoking may modify the effects of all the double-strand break pathway genes examined, we observed no statistically significant interactions between smoking and individual single-nucleotide polymorphisms. The moderate sample size in this study may not allow sufficient statistical power to detect gene-environment interactions.

We also observed that carrying more than five adverse alleles of the double-strand break pathway was at significantly increased risk for renal cell carcinoma in older subjects (=59 years), but not in younger subjects (<59 years old). The observation of significant double-strand break gene-dosage effect in older individuals is well supported by a large body of evidence linking DNA damage accumulation with age in mammals (24). The precise mechanism of cancer susceptibility in the elderly is not well understood, but immune function and DNA repair efficiency have been shown to decrease with age, which reduces protection against environmental carcinogens (22). Thus, there is emerging belief that the intrinsic fidelity of DNA repair mechanisms such as double-strand break may influence age-associated cancer risk.

In addition, women carrying more than five adverse alleles in the double-strand break pathway were at increased risk, while the association was not observed in men. Our finding of a significantly increased risk for renal cell carcinoma in women carrying increased numbers of the variant DBS alleles is in line with evidence suggesting that women are inherently more susceptible to certain carcinogens than men (25). A number of epidemiologic studies, for example, indicate that women smokers are 1.7 to 3 times as likely as male smokers to develop lung cancer given the same amount of exposure (25). Possible mechanisms that may underlie the enhanced susceptibility of women are greater activity of CYP P450 enzymes, enhanced formation of DNA adducts and P53 mutations and hormonal effects on tumor promotion (26).

Finally, significant DBS gene-dosage effect observed in hypertensive individuals is particularly intriguing but biologically plausible. Although most epidemiologic studies have not been able to distinguish the effects of hypertension from those of diuretics or other antihypertensive drugs on the risk for renal cell carcinoma, a variety of angiogenic and other growth factors, the levels of which are increased in persons with hypertensive disease, may be involved in renal carcinogenesis (27). Conversely, only a small fraction of hypertensive patients develop renal cell carcinoma, and our data suggest that decreased efficacy of DNA repair machinery may place these individuals at an incrementally increased risk for renal cell carcinoma.

Several potential limitations of this study merit discussion. First, given the small sample size in some of the terminal nodes and in stratified analysis, the results should be interpreted with caution. Second, the inclusion of single-nucleotide polymorphisms was based on potential functional single-nucleotide polymorphisms in genes with higher possibilities of being related to cancer risk and a more comprehensive approach including tagging single-nucleotide polymorphisms would provide more convincing evidence for the associations.

In summary, our study is one of the first to use a polygenic strategy to evaluate the involvement of double-strand break polymorphisms in renal cell carcinoma. We found that, in the context of specific host characteristics, variations in genes responsible for double strand DNA break repair may influence susceptibility to renal cancer.

No potential conflicts of interest were disclosed.

Grant support: National Cancer Institute grant CA 98897.

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.

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