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Carcinogenesis Advance Access published online on October 31, 2008
Carcinogenesis, doi:10.1093/carcin/bgn249
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Published by Oxford University Press 2008.

Large-scale evaluation of candidate genes identifies associations between DNA repair and genomic maintenance and development of benzene hematotoxicity

Qing Lan1, Luoping Zhang2, Min Shen1, William J. Jo2, Roel Vermeulen3, Guilan Li4, Christopher Vulpe2, Sophia Lim2, Xuefeng Ren2, Stephen M. Rappaport2, Sonja I. Bernedt1, Meredith Yeager1, Jeff Yuenger1, Richard B. Hayes1, Martha Linet1, Songnian Yin3, Stephen Chanock1, Martyn T. Smith2 and Nathaniel Rothman1

1 Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, MD 20892
2 School of Public Health, University of California, Berkeley, CA 94720
3 Utrecht University, the Netherlands
4 Chinese Center for Disease Control and Prevention, Beijing, China

Address for correspondence: Qing Lan, M.D., Ph.D., Occupational & Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Blvd., Bethesda, Maryland 20892, Telephone: 301-435-4706, Fax: 301-402-1819, E-mail: qingl{at}mail.nih.gov

Benzene is an established human hematotoxicant and leukemogen but its mechanism of action is unclear. To investigate the role of single nucleotide polymorphisms (SNPs) on benzene-induced hematotoxicity, we analyzed 1,395 SNPs in 411 genes using an Illumina GoldenGate assay in 250 benzene-exposed workers and 140 unexposed controls. Highly significant findings clustered in five genes (BLM, TP53, RAD51, WDR79, and WRN) that play a critical role in DNA repair and genomic maintenance, and these regions were then further investigated with tagSNPs. One or more SNPs in each gene were associated with highly significant 10-20% reductions (p values ranged from 0.0011 to 0.0002) in the white blood cell (WBC) count among benzene-exposed workers but not controls, with evidence for gene-environment interactions for SNPs in BLM, WRN, and RAD51. Further, among workers exposed to benzene, the genotype-associated risk of having a WBC count<4,000 cells/µl increased when using individuals with progressively higher WBC counts as the comparison group, with odds ratios of more than 8-fold. In vitro functional studies revealed that deletion of SGS1 in yeast, equivalent to lacking BLM and WRN function in humans, caused reduced cellular growth in the presence of the toxic benzene metabolite hydroquinone, and knockdown of WRN using specific shRNA increased susceptibility of human TK6 cells to hydroquinone toxicity. Our findings suggest that SNPs involved in DNA repair and genomic maintenance, with particular clustering in the homologous DNA recombination pathway, play an important role in benzene-induced hematotoxicity.

Key Words: Benzene • genomic maintenance • genetic polymorphism

Received September 13, 2008; revised October 26, 2008; accepted October 28, 2008.


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H D Hosgood III, L Zhang, M Shen, S I Berndt, R Vermeulen, G Li, S Yin, M Yeager, J Yuenger, N Rothman, et al.
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