RESUMO
BACKGROUND: DNA helicases maintain genome stability, and their deficiency is associated with disorders resembling premature aging as well as contributes to carcinogenesis. Their functions are determined by the respective genes encoding nucleotide excision repair initiating proteins, e.g. XPD and CSB. OBJECTIVE: The present study aimed to investigate the influence of genetic variations in ERCC2/XPD (rs1799793, rs13181) and ERCC6/CSB (rs2228526, rs2228528) loci on lifespan and developing age-related bladder cancer focusing on homozygous wild type alleles. METHOD: The allelic variants were identified in 354 clinically healthy controls and 418 bladder cancer patients using the PCR-RFLP method. RESULTS: The age-depended increase in frequencies of homozygous carriers of wild-type XPD 312Asp and XPD 751Lys alleles was observed among controls, especially among subjects over 80 years (r = 0.67, p = 0.012). The statistically significant correlation was also found between the frequency of homozygous wild type alleles at all tested loci and age in healthy population over 60 years (r = 0.35, p = 0.046) suggesting the relationship between lifespan and longevity, on one hand, and normal functioning of these genes and their products, on the other hand. Homozygous carriers of wild type alleles were less susceptible to bladder cancer, tumor invasion, increase in grade of malignancy and recurrence, but their effects were specific with respect to clinicopathological and lifestyle characteristics. CONCLUSION: Homozygous wild type alleles encoding XPD and CSB proteins with optimal properties were shown to affect human lifespan, risk of developing bladder cancer, its progression and recurrence under certain conditions.
Assuntos
Envelhecimento/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Variação Genética , Neoplasias/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Longevidade/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Neoplasias/prevenção & controle , Fenótipo , Prognóstico , Fatores de Proteção , Fatores de RiscoRESUMO
Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H2O2-treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H2O2-induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03-1.81), p = 0.031. The frequency of the XPD 312Asn allele was significantly higher in T ≥ 2 high grade than in T ≥ 2 low grade tumors (p = 0.036); the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle-invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression.
Assuntos
Dano ao DNA , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Reparo do DNA , Proteínas de Neoplasias/genética , Polimorfismo de Fragmento de Restrição , Neoplasias da Bexiga Urinária/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , DNA Helicases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Oxirredução , Proteínas de Ligação a Poli-ADP-Ribose , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Proteína Grupo D do Xeroderma Pigmentoso/metabolismoRESUMO
CONTEXT: The study of DNA base and nucleotide excision repair gene polymorphisms in bladder cancer seems to have a predictive value because of the evident relationship between the DNA damage response induced by environmental mutagens and cancer predisposition. OBJECTIVE: The objective was to determine OGG1 Ser326Cys, XRCC1 Arg399Gln, XPD Asp312Asn, and ERCC6 Met1097Val polymorphisms in bladder cancer patients as compared to controls. METHODS: Both groups were predominantly represented by Belarusians and Eastern Slavs. DNA samples from 336 patients and 370 controls were genotyped using a PCR-RFLP method. RESULTS: The genotype distributions were in agreement with the Hardy-Weinberg equilibrium. The minor allele frequencies in the control population were in the range of those in Caucasians in contrast to Asians. The OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes were inversely associated with cancer risk (OR [95% CI] = 0.69 [0.50-0.95] and 1.35 [1.0-1.82], respectively). The contrasting effects of these genotypes were potentiated due to their interactions with smoking habit or age. CONCLUSIONS: Among four DNA repair gene polymorphisms, the OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes might be recognized as potential genetic markers modifying susceptibility to bladder cancer in Belarus.
Assuntos
Carcinoma de Células de Transição/genética , DNA Glicosilases/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias da Bexiga Urinária/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Reparo do DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose , Polimorfismo de Nucleotídeo Único , República de Belarus , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
CONTEXT: The study of genome integrity in some genetic disorders has diagnostic and prognostic importance because of the evident relationship between genome instability and both DNA repair deficiencies and cancer predisposition. OBJECTIVE: The objective was to compare the chromosomal and DNA damage responses in lymphocytes from patients with Nijmegen breakage syndrome (NBS), Fanconi anemia (FA) and Williams-Beuren syndrome (WBS) to find additional biomarkers of genome instability. METHODS: The cytogenetic approaches were combined with the alkaline Comet assay to estimate genome integrity in cultured or freshly isolated and H(2)O(2)-treated lymphocytes. RESULTS: Basal frequencies of chromosome aberrations were significantly increased in NBS/FA probands and NBS heterozygous carriers. The NBS diagnosis was confirmed by detecting site-specific rearrangements, while the mitomycin C (MMC)-stress test was highly positive in a FA patient. Among patients with suspected WBS, 12 individuals had a 7q11.23 microdeletion. In the Comet assay, genome instability was revealed in all three disorders, impaired capacity to repair oxidative damage being observed in NBS and WBS in contrast to FA and controls. CONCLUSION: The results indicate that the estimates of DNA damage response may be proposed as efficient biomarkers for detecting and characterizing genome instability in the genetic disorders under study.