RESUMEN
Radio-adaptive response (RAR) is a biological mechanism, where cells primed with a low dose exhibit reduced DNA damage with a high challenging dose. Single nucleotide polymorphisms (SNPs) of DNA repair genes including base excision repair (BER) pathway are known to be associated with radio-sensitivity but involvement in RAR is not yet understood. In the present study, attempt was made to correlate genotype frequencies of four BER SNPs [hOGG1(Ser326Cys), XRCC1(Arg399Gln), APE1(Asp148Glu) and LIGASE1(A/C)] with DNA damage, repair and mRNA expression level among 20 healthy donors (12 adaptive and 8 nonadaptive). Our results revealed that LIGASE1 (p = .002) showed significant correlation with DNA damage and mRNA expression level with increasing dose. hOGG1 (Ser326Cys), XRCC1 (Arg399Gln) and LIGASE1(A/C) polymorphisms showed significant difference with DNA damage (%T) and mRNA expression profile in primed cells among adaptive donors. In conclusion, BER gene polymorphisms play important role in identifying donors with radio-sensitivity and RAR in human cells.
Asunto(s)
ADN Glicosilasas/genética , ADN Ligasa (ATP)/genética , Reparación del ADN/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Rayos gamma , Leucocitos Mononucleares/metabolismo , Tolerancia a Radiación/efectos de la radiación , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Daño del ADN/genética , ADN Glicosilasas/sangre , ADN Ligasa (ATP)/sangre , Reparación del ADN/efectos de la radiación , ADN-(Sitio Apurínico o Apirimidínico) Liasa/sangre , Regulación de la Expresión Génica , Frecuencia de los Genes/genética , Genotipo , Humanos , Leucocitos Mononucleares/efectos de la radiación , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Tolerancia a Radiación/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/sangreRESUMEN
BACKGROUND: Cervical cancer is the 4th highest cause of female reproductive tract malignancies. Multiple loci have been identified as important determinant factors for tumor susceptibility. In this report, we aimed to explore the roles of gene polymorphisms affecting x-ray repair cross complementing 1 (XRCC1), the tumor protein p53 (TP53), and fibroblast growth factor receptor 3 (FGFR3) in the context of susceptibility to cervical cancer. Additionally, we assessed the impact of single nucleotide polymorphism-single nucleotide polymorphism (SNP-SNP) interaction of these three genes in the context of cervical cancer risk in Chinese women. METHODS: A case-control study consisted of 340 women located in Chongqing. Of these women, 121 were diagnosed with cervical cancer, 118 served as healthy controls, and 101 were specifically recruited elderly patients above the age of 80 who showed no history of cervical cancer. Three SNPs (XRCC1 rs25487, TP53 rs1042522, and FGFR3 rs121913483) were examined using mutation analysis of mismatch amplification PCR (MAMA-PCR) on samples obtained from peripheral blood. RESULTS: Our results indicated that females from southwestern China all exhibited a wild-type phenotype at FGFR3 rs121913483. We also observed that the rs25487 mutation was significantly increased within the cervical cancer population. A 2-locus SNP-SNP interaction pattern (rs25487 and rs1042522) was significantly associated with cervical cancer risk (cases vs. negative controls: OR = 4.63, 95% CI = 1.83-11.75; cases vs. elderly group: OR = 17.61, 95% CI = 4.34-71.50). CONCLUSIONS: This is the first study to identify a novel interaction between the XRCC1 and TP53 genes that is highly associated with susceptibility to cervical cancer risk in a female population in southwestern China.
Asunto(s)
Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteína p53 Supresora de Tumor/sangre , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/epidemiología , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/sangreRESUMEN
Although a plethora of studies have examined tobacco smoke-cancer disease association, the involvement of cellular genetic toxicity remains unclear. Therefore, the present study provides molecular evidence for a pathway involved in the DNA damage induced by long-term cigarette and waterpipe smoke in human subjects. The study population consisted of 45 subjects who were divided into three groups; healthy nonsmokers group, cigarette smokers group, and waterpipe smokers group. A questionnaire and consent form was distributed and signed by all participants. Total RNA was extracted from the blood using PAXgene Blood RNA Kit and mRNA expression levels of target genes were quantified by RT-PCR. Our results showed that 80% of the participants smoke 20-39 cigarettes/day, whereas 12% smoke more than 40 cigarettes/day. With regard to waterpipe smoke, the majority (46%) smoke more than 5 times/week. Both cigarette and waterpipe smokers showed increased the plasma levels 8-hydroxy-2'-deoxyguanosine (8-OHdG), of DNA damage marker. In addition, the mRNA expression levels of DNA repair genes (OGG1 and XRCC1) were significantly inhibited in both cigarette and waterpipe smokers groups by 30% and 60%, respectively. This was associated with a marked decrease (50%) in the expression of detoxifying genes (NQO1 and GSTA1) with an increase in CYP1A1 mRNA expression, a cancer-activating gene. Both cigarette and waterpipe smokers increased in the plasma concentrations of several toxic heavy metals such as Cd (130%), Pb (47%), and Ni (30%). In conclusion: the present findings clearly explore the genotoxic effect of cigarette and waterpipe smoking on human DNA.