Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity.

2.50
Hdl Handle:
http://hdl.handle.net/10146/57574
Title:
Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity.
Authors:
Shen, Min; Lan, Qing; Zhang, Luoping; Chanock, Stephen; Li, Guilan; Vermeulen, Roel; Rappaport, Stephen M.; Guo, Weihong; Hayes, Richard B.; Linet, Martha; Yin, Songnian; Yeager, Meredith; Welch, Robert; Forrest, Matthew S.; Rothman, Nathaniel; Smith, Martyn T.
Abstract:
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.
Citation:
Carcinogenesis 2006, 27 (10):2083-2089
Journal:
Carcinogenesis
Issue Date:
Oct-2006
URI:
http://hdl.handle.net/10146/57574
DOI:
10.1093/carcin/bgl061
PubMed ID:
16728435
Additional Links:
http://carcin.oxfordjournals.org/cgi/content/full/27/10/2083
Type:
Article
Language:
en
Description:
Biomarker: single nucleotide polymorphisms (SNPs) in each of seven genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4); alleles studied: WRN (Ex4 -16 G > A, Ex6 +9 C > T, Ex20 -88 G > T and Ex26 -12 T > G); TP53 (Ex4 +119 C > G); BRCA2 (Ex11 +1487 A > G)Effect studied: DNA damage. Tissue/biological material/sample size: blood. Method of analysis: TaqMan-based real-time PCR. Study design: case-control studyStudy size: 250 workers exposed to benzene and 140 unexposed controlsImpact on outcome (including dose-response): 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. keywords - classification: Adult;Alleles;analysis;Benzene;biomarkers of individual susceptibility: field studies;blood;Blood Cells;China;Cross-Sectional Studies;DNA Helicases;DNA Repair;drug effects;Epidemiology;Female;field studies;Genes,Brca2;Genes,p53;genetic;Genetic Predisposition to Disease;genetics;Haplotypes;history;Humans;Male;Polymorphism,Single Nucleotide;RecQ Helicases;Research;toxicity;
ISSN:
0143-3334
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorShen, Min-
dc.contributor.authorLan, Qing-
dc.contributor.authorZhang, Luoping-
dc.contributor.authorChanock, Stephen-
dc.contributor.authorLi, Guilan-
dc.contributor.authorVermeulen, Roel-
dc.contributor.authorRappaport, Stephen M.-
dc.contributor.authorGuo, Weihong-
dc.contributor.authorHayes, Richard B.-
dc.contributor.authorLinet, Martha-
dc.contributor.authorYin, Songnian-
dc.contributor.authorYeager, Meredith-
dc.contributor.authorWelch, Robert-
dc.contributor.authorForrest, Matthew S.-
dc.contributor.authorRothman, Nathaniel-
dc.contributor.authorSmith, Martyn T.-
dc.date.accessioned2009-03-27T11:35:30Z-
dc.date.available2009-03-27T11:35:30Z-
dc.date.issued2006-10-
dc.identifier.citationCarcinogenesis 2006, 27 (10):2083-2089en
dc.identifier.issn0143-3334-
dc.identifier.pmid16728435-
dc.identifier.doi10.1093/carcin/bgl061-
dc.identifier.urihttp://hdl.handle.net/10146/57574-
dc.descriptionBiomarker: single nucleotide polymorphisms (SNPs) in each of seven genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4); alleles studied: WRN (Ex4 -16 G > A, Ex6 +9 C > T, Ex20 -88 G > T and Ex26 -12 T > G); TP53 (Ex4 +119 C > G); BRCA2 (Ex11 +1487 A > G)Effect studied: DNA damage. Tissue/biological material/sample size: blood. Method of analysis: TaqMan-based real-time PCR. Study design: case-control studyStudy size: 250 workers exposed to benzene and 140 unexposed controlsImpact on outcome (including dose-response): 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. keywords - classification: Adult;Alleles;analysis;Benzene;biomarkers of individual susceptibility: field studies;blood;Blood Cells;China;Cross-Sectional Studies;DNA Helicases;DNA Repair;drug effects;Epidemiology;Female;field studies;Genes,Brca2;Genes,p53;genetic;Genetic Predisposition to Disease;genetics;Haplotypes;history;Humans;Male;Polymorphism,Single Nucleotide;RecQ Helicases;Research;toxicity;en
dc.description.abstractBenzene 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.en
dc.language.isoenen
dc.relation.urlhttp://carcin.oxfordjournals.org/cgi/content/full/27/10/2083en
dc.subject.meshAdult-
dc.subject.meshBenzene-
dc.subject.meshBlood Cells-
dc.subject.meshCross-Sectional Studies-
dc.subject.meshDNA Helicases-
dc.subject.meshDNA Repair-
dc.subject.meshExodeoxyribonucleases-
dc.subject.meshFemale-
dc.subject.meshGenes, BRCA2-
dc.subject.meshGenes, p53-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshHaplotypes-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshPolymorphism, Single Nucleotide-
dc.subject.meshRecQ Helicases-
dc.titlePolymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity.en
dc.typeArticleen
dc.identifier.journalCarcinogenesisen

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