Susceptibility to DNA damage varies among individuals and sensitivity to bleomycin (BLM) may reflect the inter-individual differences. BLM sensitivity in part may be explained by inherited differences in DNA repair genes. We investigated the association between genetic polymorphisms in the GSTT1, GSTM1, XPD, XRCC1 and XRCC3 genes and the levels of spontaneous and BLM-induced DNA damage in peripheral blood lymphocytes from 200 healthy, unexposed individuals. The investigation of BLM sensitivity on cancer- or disease-free subjects and not occupationally exposed to known mutagen represents the strengths of the present study, as the detection of genetic damage is not biased by any disease- and occupational-related factor. The micronucleus (MN) assay was used to detect the spontaneous and BLM-induced genetic damage whereas, genotype analysis was carried out using methods based on polymerase chain reaction. Poisson regression analysis showed that subject's age, gender and smoking status had no effect on the spontaneous and BLM-induced MN frequencies. Genotype analysis revealed a clear association between GSTT1-null and XPD polymorphisms and both spontaneous and BLM-induced MN frequencies, whereas the effect of the XRCC1 polymorphism was marginally significant only with regard to spontaneous MN frequency. Genotype analysis did not reveal a clear association between the other studied SNPs (GSTM1 and XRCC3) and MN frequencies. Poisson regression analysis revealed no association between the score of protective alleles and the frequency of spontaneous MN. However, an increased number of protective alleles was significantly associated with a lower frequency of BLM-induced MN (P = 0.0003). This finding highlights the genetic basis for BLM sensitivity, which could be a valid and useful surrogate for identifying genotypes that might increase susceptibility in population exposed to carcinogens. Further investigations in a large sample size and including more SNPs, reflecting the complexity of DNA repair machinery, might lead to the identification of a genetic profile responsible for the susceptibility to genotoxicants, with a far-reaching long-term impact on primary prevention and early detection of disease associated genes.

Inherited susceptibility to bleomycin-induced micronuclei: Correlating polymorphisms in GSTT1, GSTM1 and DNA repair genes with mutagen sensitivity

ANGELINI, SABRINA;CARBONE, FABIO;MAFFEI, FRANCESCA;CANTELLI FORTI, GIORGIO;HRELIA, PATRIZIA
2008

Abstract

Susceptibility to DNA damage varies among individuals and sensitivity to bleomycin (BLM) may reflect the inter-individual differences. BLM sensitivity in part may be explained by inherited differences in DNA repair genes. We investigated the association between genetic polymorphisms in the GSTT1, GSTM1, XPD, XRCC1 and XRCC3 genes and the levels of spontaneous and BLM-induced DNA damage in peripheral blood lymphocytes from 200 healthy, unexposed individuals. The investigation of BLM sensitivity on cancer- or disease-free subjects and not occupationally exposed to known mutagen represents the strengths of the present study, as the detection of genetic damage is not biased by any disease- and occupational-related factor. The micronucleus (MN) assay was used to detect the spontaneous and BLM-induced genetic damage whereas, genotype analysis was carried out using methods based on polymerase chain reaction. Poisson regression analysis showed that subject's age, gender and smoking status had no effect on the spontaneous and BLM-induced MN frequencies. Genotype analysis revealed a clear association between GSTT1-null and XPD polymorphisms and both spontaneous and BLM-induced MN frequencies, whereas the effect of the XRCC1 polymorphism was marginally significant only with regard to spontaneous MN frequency. Genotype analysis did not reveal a clear association between the other studied SNPs (GSTM1 and XRCC3) and MN frequencies. Poisson regression analysis revealed no association between the score of protective alleles and the frequency of spontaneous MN. However, an increased number of protective alleles was significantly associated with a lower frequency of BLM-induced MN (P = 0.0003). This finding highlights the genetic basis for BLM sensitivity, which could be a valid and useful surrogate for identifying genotypes that might increase susceptibility in population exposed to carcinogens. Further investigations in a large sample size and including more SNPs, reflecting the complexity of DNA repair machinery, might lead to the identification of a genetic profile responsible for the susceptibility to genotoxicants, with a far-reaching long-term impact on primary prevention and early detection of disease associated genes.
ANGELINI S.; KUMAR R.; CARBONE F.; BERMEJO J.L.; MAFFEI F.; CANTELLI FORTI G.; HEMMINKI K.; HRELIA P.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/54578
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