TY - JOUR
T1 - From genotype to phenotype
T2 - Correlating XRCC1 polymorphisms with mutagen sensitivity
AU - Wang, Yunfei
AU - Spitz, Margaret R.
AU - Zhu, Yong
AU - Dong, Qiong
AU - Shete, Sanjay
AU - Wu, Xifeng
N1 - Funding Information:
This study was supported by National Cancer Institute Grants CA 55769, CA 85576 and CA 86390. Yunfei Wang was supported by the International Association for the Study of Lung Cancer Prevention Fellowship. Affiliation of authors: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center.
PY - 2003/8/12
Y1 - 2003/8/12
N2 - This study correlated the extent of induced in vitro chromosomal damage, assessed by the mutagen sensitivity assay, with genotypes of the X-ray repair cross complementing group 1 (XRCC1) gene, which encodes for a base excision repair protein. There are two common polymorphisms that cause amino acid substitutions in XRCC1, one at codon 194 in exon 6 and another at codon 399 in exon 10. We genotyped these two polymorphisms in 524 healthy subjects and performed mutagen sensitivity assays using both bleomycin and benzo[a]pyrene-diol-epoxide (BPDE) as challenge mutagens. Our results showed that individuals with the wildtype exon 6 Arg/Arg exhibited significantly higher values of chromosomal breaks per cell (b/c) than those with one or two variant Trp alleles (P = 0.005 for bleomycin and P = 0.05 for BPDE). For the exon 10 polymorphism, subjects who were Gln/Gln homozygotes had higher b/c than did those with other genotypes, with evidence of a gene dosage effect. When we combined the two polymorphic sites and used the exon 6 Arg/Trp and Trp/Trp and exon 10 Arg/Arg genotypes as the reference category, these differences were enhanced for bleomycin sensitivity (P for trend = 0.032), but not for BPDE sensitivity (P for trend = 0.821). These data are biologically plausible since codon 399 is located within the BRCA1 C-terminus functional domain and codon 194 is in the linker region of the XRCC1 N-terminal functional domain. To our knowledge, this is the largest study conducted evaluating the functional relevance of these polymorphisms.
AB - This study correlated the extent of induced in vitro chromosomal damage, assessed by the mutagen sensitivity assay, with genotypes of the X-ray repair cross complementing group 1 (XRCC1) gene, which encodes for a base excision repair protein. There are two common polymorphisms that cause amino acid substitutions in XRCC1, one at codon 194 in exon 6 and another at codon 399 in exon 10. We genotyped these two polymorphisms in 524 healthy subjects and performed mutagen sensitivity assays using both bleomycin and benzo[a]pyrene-diol-epoxide (BPDE) as challenge mutagens. Our results showed that individuals with the wildtype exon 6 Arg/Arg exhibited significantly higher values of chromosomal breaks per cell (b/c) than those with one or two variant Trp alleles (P = 0.005 for bleomycin and P = 0.05 for BPDE). For the exon 10 polymorphism, subjects who were Gln/Gln homozygotes had higher b/c than did those with other genotypes, with evidence of a gene dosage effect. When we combined the two polymorphic sites and used the exon 6 Arg/Trp and Trp/Trp and exon 10 Arg/Arg genotypes as the reference category, these differences were enhanced for bleomycin sensitivity (P for trend = 0.032), but not for BPDE sensitivity (P for trend = 0.821). These data are biologically plausible since codon 399 is located within the BRCA1 C-terminus functional domain and codon 194 is in the linker region of the XRCC1 N-terminal functional domain. To our knowledge, this is the largest study conducted evaluating the functional relevance of these polymorphisms.
KW - DNA repair
KW - Mutagen sensitivity
KW - Risk markers
KW - XRCC1
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U2 - 10.1016/S1568-7864(03)00085-5
DO - 10.1016/S1568-7864(03)00085-5
M3 - Article
C2 - 12893086
AN - SCOPUS:0142124401
SN - 1568-7864
VL - 2
SP - 901
EP - 908
JO - DNA Repair
JF - DNA Repair
IS - 8
ER -