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Carcinogenesis Advance Access originally published online on May 25, 2006
Carcinogenesis 2006 27(10):2083-2089; doi:10.1093/carcin/bgl061
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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 genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity

Min Shen1,*, Qing Lan1, Luoping Zhang2, Stephen Chanock1,3, Guilan Li4, Roel Vermeulen1, Stephen M. Rappaport5, Weihong Guo2, Richard B. Hayes1, Martha Linet1, Songnian Yin4, Meredith Yeager1,3, Robert Welch1,3, Matthew S. Forrest2, Nathaniel Rothman1 and Martyn T. Smith2

1 Division of Cancer Epidemiology and Genetics, NCI NIH, DHHS, Bethesda, MD 20892, USA
2 School of Public Health, University of California Berkeley, CA 94720, USA
3 Center for Cancer Research, NCI NIH, DHHS, Bethesda, MD 20892, USA
4 Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention Beijing, China
5 School of Public Health, University of North Carolina Chapel Hill, NC 27599, USA

*To whom correspondence should be addressed at: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, MSC 7240, 6120 Executive Boulevard, Bethesda, MD 20892-7240, USA. Tel: 301 451 8791; Fax: 301 402 1819; Email: shenmi{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 References
 
Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage. DNA double-strand breaks (DSB) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. DSB may lead to chromosome aberrations, apoptosis and hematopoietic progenitor cell suppression. We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity. We analyzed one or more single nucleotide polymorphisms (SNPs) in each of seven candidate genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4) in a study of 250 workers exposed to benzene and 140 controls in China. Four SNPs in WRN (Ex4 –16 G > A, Ex6 +9 C > T, Ex20 –88 G > T and Ex26 –12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) were associated with a statistically significant decrease in total white blood cell (WBC) counts among exposed workers. The SNPs in WRN and TP53 remained significant after accounting for multiple comparisons. One or more SNPs in WRN had broad effects on WBC subtypes, with significantly decreased granulocyte, total lymphocyte, CD4+-T cell, CD8+-T cell and monocyte counts. Haplotypes of WRN were associated with decreased WBC counts among benzene-exposed subjects. Likewise, subjects with TP53 Ex4 +119 C > G variant had reduced granulocyte, CD4+-T cell and B cell counts. The effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes. These results suggest that genetic polymorphisms in WRN, TP53 and BRCA2 that maintain genomic stability impact benzene-induced hematotoxicity.

Abbreviations: BMI, body mass index; DSB, double-strand break; LD, linkage disequilibrium; SNP, single nucleotide polymorphism; WBC, white blood cell


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary material
 References
 
Benzene is an important industrial chemical and is a component of cigarette smoke, gasoline, crude oil and automobile emissions. Several million workers worldwide are exposed to benzene in the oil industry, shipping, automobile repair, shoe manufacture, and so on. (1). Epidemiological studies have shown that exposure to benzene results in an increased risk of aplastic anemia, myelodysplastic syndromes, leukemia and other blood disorders (1).

Benzene must be metabolized in order to elicit toxicity to the blood and bone marrow (2). These benzene metabolites, that is, reactive quinones, are capable of binding to and damaging macromolecules including DNA, glutathione, tubulin, histones, topoisomerase II and other DNA-related proteins. Additionally, benzene metabolites may give rise to reactive oxygen species (ROS) (3).

Direct attack by ROS and benzene metabolites or replication of unrepaired DNA damage can result in DNA double-strand breaks (DSB) (4). DSBs are repaired in vivo by non-homologous end joining or, after replication when a second identical DNA copy is present, homologous recombination (5). DSB is especially genotoxic because (i) it affects both DNA strands and no intact template is available for repair; (ii) the repair is intrinsically more difficult than other types of DNA repair mechanisms because erroneous rejoining of broken DNA may occur. Therefore, a DNA DSB is potentially highly cytotoxic and can induce chromosomal aberrations (CA) and disrupt the genomic integrity of a cell. It was observed that chromosomal instability can be induced by the benzene metabolite, hydroquinone, and may contribute to the development of acute myeloid leukemia by increasing the number of genetic lesions in hematopoietic cells (6). Therefore, the prompt and efficient repair of DSBs is fundamental for genomic stability and cancer prevention in the presence of benzene (7).

Stem cells in bone marrow undergo active cell proliferation and differentiation throughout life and are sensitive to DNA-damaging factors. Hematopoietic progenitor cells have been found to be suppressed after benzene exposure (8,9). In addition, DNA DSB repair genes may be implicated in hematopoiesis (10). In a study by Bender et al. (11) mice with defects in DSB repair genes demonstrated progressive hematopoietic stem cell failure.

Genetic polymorphism in genes involved in the repair of DSB may modify the function of DNA DSB repair and confer genetic susceptibility to hematotoxicity caused by benzene. We, therefore, examined the association between a number of single nucleotide polymorphisms (SNPs)/haplotypes in seven genes, which are either DSB repair genes (NBS1, BRCA1, BRCA2, XRCC3, and XRCC4) or genes that play an important role in this pathway (WRN and TP53), and benzene-induced hematotoxicity in a cross-sectional study in China.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary material
 References
 
Study population and exposure assessment
The details of this cross-sectional study have been described elsewhere (8). Briefly, the study population included 250 workers who were exposed to benzene in two shoe manufacturing factories, and 140 unexposed controls from comparable populations who worked in three clothing-manufacturing factories in the same region of China. Data were obtained from 28 benzene-exposed workers in both study years (2000 and 2001) and are treated as independent observations in the study. Controls were frequency-matched by sex and age to exposed workers. Blood samples were collected from all workers. Individual exposure to benzene and toluene, as well as other organic solvents, was monitored repeatedly up to 16 months before phlebotomy by wearing an organic vapor passive monitor badge, and post-shift urine samples were collected from each subject (8). Subjects were administered a questionnaire for information on lifetime occupational history, hobbies, environmental exposures, medical history and current medications, and past and current tobacco and alcohol use. Individuals carrying out exposure assessment activities were blinded with regard to hematologic data on study subjects.

Hematology
All subjects provided a 29 ml peripheral blood sample and a buccal cell mouth rinse sample, and underwent a physical exam. Blood samples were delivered to the lab within 6 h of being collected; the complete blood cells (CBC) and differentials were analyzed using a T540 blood counter, and the major lymphocyte subsets were analyzed by an FACS Calibur flow cytometer (Software: SimulSET v3.1).

Genotyping
DNA was extracted from blood samples using phenol–chloroform extraction (12) and genotyped by TaqMan-based real-time PCR at Core Genotyping Facility of NCI (http://snp500cancer.nci.nih.gov) (13). SNPs were selected for study on the basis of a minimum allele frequency of 0.05, and evidence of association in previous epidemiology studies, evidence of function, or to extend genomic coverage for a given gene. Individuals carrying out genotyping were blinded with regard to hematologic data on study subjects. DNA was successfully extracted from all samples, and >95% of the DNA samples were successfully genotyped for all candidate SNPs except for three SNPs in WRN [Ex6 +9 C > T (91%), Ex20 –88 G > T (90%) and IVS33 –95 C > T (81%)] and four SNPs in BRCA2 [Ex11 +1487 A > G (88%), Ex11 +1898 T > C (90%), Ex14 –194 A > G (90%) and Ex2 +14 A > G (88%)]. Blind replicate samples were randomly interspersed, and the concordance rates were 99–100% for all assays.

Statistical analysis
The Hardy–Weinberg equilibrium for each SNP was tested with a Pearson {chi}2 or exact test. Measure of pairwise linkage disequilibrium (LD) and the test for LD at one gene were carried out using the HaploView program (http://www.broad.mit.edu/personal/jcbarret/haploview/). Genotype data were analyzed with the homozygotes of the common allele as the reference group. Generalized Estimating Equations (GEE) were used to model the relationship between SNPs and blood cell counts, adjusting for age, sex, body mass index (BMI), any recent smoking and alcohol consumption for controls, plus occupational exposure to benzene and toluene on a log scale 1 month before phlebotomy for exposed subjects. Interaction was estimated by adding a multiplicative term between SNP (variant carriers versus Wild-type carriers) and benzene exposure (yes/no) into a model with all subjects.

Haplotype block structure was examined for SNPs within the same gene using HaploView. Overall association between quantitative blood cell counts and haplotypes was assessed separately for unexposed and exposed subjects adjusting for the potential confounders using the HaploStats program (14) in R (Version 2.0.1) (15). Individual haplotypes were estimated using SAS/Genetics, and the effects of each haplotype were estimated using the best haplotype pairs in a GEE model with the most common haplotype as the reference.

We controlled for multiple hypothesis testing by calculating the false discovery rate, using the Benjamini–Hochberg method (16), which was defined as the expected ratio of erroneous rejections of the null hypothesis to the total number of rejected hypotheses. An FDR of 0.05 was used as a critical value to assess if the obtained P-values are still significant. Those SNPs demonstrating significant gene-dosage effects (i.e. trend test) among workers exposed to benzene were further explored for their influence on specific white blood cell (WBC) subtypes. All P-values presented are two-sided and data were analyzed using the Statistical Analysis Software, version 8.02 (SAS Institute Inc, 1996) if not specified elsewhere.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary material
 References
 
Demographic characteristics were essentially the same between controls and benzene-exposed workers. The majority of the study subjects were females (65%) and relatively young (30 ± 8). The subjects in the benzene-exposed and non-exposed groups were comparable in alcohol use, recent infection, smoking status and BMI (8). The benzene-exposed workers had been employed an average of 6.1 ± 2.9 years. The average benzene air exposure in the month before phlebotomy was 5.4 (SD: 12.1) p.p.m. in the exposed group (Table I). WBCs and most WBC subtypes as well as the platelet counts were significantly reduced in benzene-exposed workers compared with controls (Table I). Natural killer (NK) cell counts and hemoglobin levels were significantly decreased only among the most highly exposed workers (8), and CD8+-T cells did not vary with benzene-exposure levels.


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  		Table I Hematological characteristics of study population by benzene-exposure statusa

 
Twenty-four SNPs in seven genes involved in the DNA DSB repair pathway were genotyped, covering substitutions in the coding and non-coding regions (Table II). Only those SNPs that are associated with total WBC counts in benzene-exposed group are shown in Table III. Those SNPs that were not associated with total WBC counts in benzene-exposed group are shown in a Supplementary Table. In the exposed group, homozygous variants in four SNPs in WRN (Ex4 –16 G > A, Ex6 +9 C > T, Ex20 –88 G > T and Ex26 –12 T > G) had significantly reduced WBCs in the range of 8–18%. For the TP53 Ex4 +119 C > G polymorphism, the magnitude of reduction in WBC counts was ~12%, and subjects homozygous for the uncommon allele of BRCA2 Ex11 +1487 A > G had a 7% greater reduction in WBCs. There was a linear trend of reduced WBC counts associated with the increase of carried variant for WRN Ex6 +9 C > T, Ex20 –88 G > T, Ex26 –12 T > G, TP53 Ex4 +119 C > G and BRCA2 Ex11 +1487 A > G. Although most SNPs located within the same gene were in LD and as such do not constitute true independent tests, we assessed all 24 SNP associations for possible FDR and found that the five SNPs in WRN and TP53 remained significantly associated with total WBC counts. There was a statistically significant interaction (P = 0.021) between benzene exposure and the WRN Ex26 –12 T > G polymorphism. All these SNPs were not found to influence WBC counts among unexposed subjects except that the polymorphism of BRCA2 Ex11 +1487 A > G was associated with increased WBCs with borderline significance. SNPs in other genes were not associated with reduced WBC counts in exposed subjects.


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  		Table II Genes and SNPs assessed in this study

 

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  		Table III Effect on total WBC counts of SNPs in WRN, TP53 and BRCA2 by benzene-exposure statusa

 
We further evaluated the influence on several major WBC subtypes of the SNPs that had significant gene-dosage effects on total WBC counts among exposed workers (Table IV). One or more SNPs in WRN had broad effects on WBC subtypes, with significant decreases of granulocyte, total lymphocyte, CD4+-T cell, CD8+-T cell and monocytes counts. Likewise, TP53 Ex4 +119 C > G was associated with reduced granulocyte, CD4+-T cell and B cell counts, while the effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes.


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  		Table IV Effect on WBC subsets of SNPs in WRN, TP53 and BRCA2 among benzene-exposed subjectsa

 
Haplotype analysis of genes in which two or more SNPs in LD were available (i.e. WRN, BRCA1, BRCA2 and XRCC4) was carried out. Six SNPs in WRN constituted one haplotype block. There was an overall association between WBC counts and haplotypes of WRN (P = 0.007) in the benzene-exposed group (Table V). A haplotype with substitutions in three SNPs (Ex4 –16 G > A, Ex20 –88 G > T and Ex26 –12 T > G) was associated with a 20% reduction in WBCs following benzene exposure.


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  		Table V Haplotype analysis of WRN on total WBC counts by benzene-exposure status

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary material
 References
 
We studied the effect of 24 SNPs in 7 genes that survey the genome and participate in DNA DSB repair on peripheral WBC counts among 250 benzene-exposed workers and 140 unexposed controls. Of these genes, our results demonstrate that four SNPs in WRN (Ex4 –16 G > A, Ex6 +9 C > T, Ex20 –88 G > T and Ex26 –12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) are associated with decreased WBCs and particular WBC subtypes in benzene-exposed workers. The effect of all SNPs on WBC counts in controls was not statistically significant after adjustment for multiple comparisons using the FDR method. In addition, the two unadjusted borderline associations between WRN (IVS33 –95 C > T) and XRCC4 (Ex6 –7 G > T) and lower WBC count are based on small numbers of observations.

The gene WRN encodes a member of the RecQ subfamily and the DEAH (Asp-Glu-Ala-His) subfamily of DNA and RNA helicases. It possesses an intrinsic 3'–5' DNA helicase activity, and is also a 3'–5' exonuclease. WRN plays an important role in monitoring genome integrity and controlling the cell's response to genotoxic stress (17). Initially, together with other related factors, WRN helps recruit the proper DNA repair factors to the site of the lesion. However, the WRN complex may direct the activation of the apoptotic pathway if the damage is excessive. Lack of WRN may result in deregulation of DNA damage monitoring and anomalous activation of DNA repair or apoptosis in response to certain types of DNA damage (18). Specifically, WRN has been found to play a key role in DSB repair (19). Mutations in this gene produce truncated proteins and result in Werner syndrome, an autosomal recessive disorder characterized by premature aging and genomic instability.

Four significant SNPs are located in the functional domains of WRN, with the Ex4 –16 G > A and Ex6 +9 C > T being in the exonuclease domain, Ex20 –88 G > T in the helicase domain and Ex26 –12 T > G located in the vicinity of the RecQ C-terminal domain (17,20). These polymorphisms may modify the function of these functional domains, particularly for Ex26 –12 T > G, which is located in a region that interacts with multiple proteins (21). Even though the four SNPs are in LD, there may be an accumulation of effects based on the haplotype analysis, indicating that the effects may not be attributable to one particular SNP. However, available reports for the impact of these SNPs on longevity and aging-related diseases demonstrated only weak and inconsistent associations (22,23), and, moreover, the WRN Ex26 –12 T > G polymorphism displayed little change in helicase/exonuclease activities relative to wild-type WRN in an in vitro assay (24). This region in WRN (Ex4–Ex26) warrants further investigation for the accountable polymorphic position(s) and their precise role in susceptibility to benzene hematotoxicity.

Normal function of TP53 is essential in DNA damage response, cell cycle control and cell apoptosis, and mutations in TP53 are the most common genetic alterations in human tumors. It is activated when genetic material is altered, initiating a range of biological defense pathways. In response to DNA damage, TP53-mediated cell cycle is arrested to allow sufficient time for DNA repair before DNA replication or mitosis. It also directly participates in DNA repair, particularly in homologous recombination and non-homologous end joining (25,26). It has been found that bone marrow cells in p53-deficient mice expressed significantly reduced levels of many key genes involved in the p53-regulated DNA damage response pathways after chronic exposure to benzene (27). In cDNA microarray analyses, Yoon et al. (28) demonstrated that p53 appears to play a key role in benzene-induced hematotoxicity.

The TP53 codon 72 polymorphism is functional. The Ex4 +119 C > G non-conservative substitution is located in a proline-rich region (residues 64–92) of the p53 protein, where the 72Pro amino acid constitutes one of five PXXP (where P represents Pro and X any amino acid) motifs resembling an Src homology 3 (SH3) binding domain (29). The polymorphic variant of wild-type p53 has been shown to have different biochemical properties and biological functions (30–32). Significantly higher levels of p53 expression in lymphocytes were detected in subjects bearing the Arg/Arg allele than in subjects with Pro/Pro and Arg/Pro alleles among healthy humans exposed to low doses of ionizing radiation (33). These findings provide support for a model in which loss of p53 function due to Ex4 +119 C > G polymorphism is associated with benzene-induced hematotoxicity.

BRCA2 is a tumor-suppressor protein directly implicated in familial breast cancer. It maintains genome stability by participating in multiple biological pathways including DNA transcription, recombination and cell cycle control (34,35). A particular spectrum of bi-allelic mutations in BRCA2 is connected to a rare hematological disorder, Fanconi anemia, characterized by aplastic anemia and hypoplasia of the bone marrow (36). BRCA2 has an important role in DNA recombination reactions mediated by RAD51 in DNA DSB repair (34). Two structural features of BRCA2 were revealed with eight BRC repeats interacting with RAD51 and three oligonucleotide/oligosaccharide-binding (OB) fold domains binding single-strand DNA (37). The BRCA2 Ex11 +1487 A > G polymorphism is located in exon 11, which is the largest exon and encodes the eight BRC motifs (38). The exon 11 and BRC motifs are essential for BRCA2's function and homologous recombination (38,39). The eight BRC repeats are highly conserved and the four BRC repeats in 5' are the most conserved sequences (38). The BRCA2 Ex11 +1487 A > G is located between BRC1 and BRC2 in 5' of Exon 11. As it leads to a synonymous substitution, the observed hematotoxic effect may be attributable to a linked functional polymorphism in that region that can modify the function of BRC repeats and impact DNA DSB repair.

In summary, we report that common genetic polymorphisms in WRN, TP53 and BRCA2 may confer susceptibility to hematotoxicity in workers exposed to benzene. All these genetic variants appear to influence granulocytes, while variants in WRN also altered cells of the lymphoid lineage, suggesting that effects may trace back to earlier progenitor and possibly stem cells. The three gene products play an important role in multiple mechanisms including DNA damage recognition, replication, recombination, repair and cell cycle regulation, all of which are critical to maintain genomic integrity. In addition, BRCA2, TP53 and WRN perhaps act synergistically to prevent accumulation of genomic lesions (40,41). Decreased function of WRN, TP53 or BRCA2 due to genetic polymorphisms may result in genomic instability and increase predisposition to cancer in the presence of a carcinogen such as benzene.

Although this is the largest cross-sectional study of DNA repair SNPs and benzene-induced hematotoxicity in the literature, to the best of our knowledge, and our key findings were highly statistically significant, it is possible that some associations are false-positives, particularly those based on small numbers of subjects carrying at-risk alleles. As such, replication of key findings in other benzene-exposed populations is critical.


   Supplementary material
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
References
 
Supplementary material is available online at http://www.carcin.oupjournals.org/.


   Acknowledgments
 
This study is supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute and NIH grants R01ES06721, P42ES04705, P30ES01896 (to M.T.S.), P42ES05948 and P30ES10126 (to S.M.R.). We thank Dr Bingshu Eric Chen for the statistical consultation for the study.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 References
 

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Received January 8, 2006; revised April 10, 2006; accepted April 21, 2006.


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