Carcinogenesis Advance Access published online on May 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgl061
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1 Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, MD 20892
* To whom correspondence should be addressed. 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 (SNP) in each of 7 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, 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 monocytes 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.
Received January 8, 2006
Revised April 10, 2006
Accepted April 21, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Polymorphisms in genes involved in DNA double strand break repair pathway and susceptibility to benzene-induced hematotoxicity
Min Shen 1 *,
Qing Lan 1,
Luoping Zhang 2,
Stephen Chanock 3,
Guilan Li 4,
Roel Vermeulen 1,
Stephen M. Rappaport 5,
Weihong Guo 2,
Richard B. Hayes 1,
Martha Linet 1,
Songnian Yin 4,
Meredith Yeager 3,
Robert Welch 3,
Matthew S. Forrest 2,
Nathaniel Rothman 1,
and
Martyn T. Smith 2
2 School of Public Health, University of California, Berkeley, CA 94720
3 Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, MD 20892; Center for Cancer Research, NCI, NIH, DHHS, Bethesda, MD 20892
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
Min Shen, E-mail: shenmi{at}mail.nih.gov
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