TY - JOUR
T1 - Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity
AU - Shen, Min
AU - Lan, Qing
AU - Zhang, Luoping
AU - Chanock, Stephen
AU - Li, Guilan
AU - Vermeulen, Roel
AU - Rappaport, Stephen M.
AU - Guo, Weihong
AU - Hayes, Richard B.
AU - Linet, Martha
AU - Yin, Songnian
AU - Yeager, Meredith
AU - Welch, Robert
AU - Forrest, Matthew S.
AU - Rothman, Nathaniel
AU - Smith, Martyn T.
N1 - Funding Information:
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.
PY - 2006/10
Y1 - 2006/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33749553917&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749553917&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgl061
DO - 10.1093/carcin/bgl061
M3 - Article
C2 - 16728435
AN - SCOPUS:33749553917
VL - 27
SP - 2083
EP - 2089
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 10
ER -