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Item Ocorrência de mutações em loci ligados ao cromossomo Y na prole nascida de indivíduos expostos à radiação ionizante(Universidade Federal de Goiás, 2009-05-13) ARRUDA, Jalsi Tacon; CRUZ, Aparecido Divino da; http://lattes.cnpq.br/7868817504129985In September 1987, in Goiânia-GO, Brazil, one of the most serious radiological accidents occurred at a radiotherapy unit involving a source of cesium-137. An area of 2,000 m2 was contaminated and 249 people were exposed, both externally and internally, to substantial doses of ionizing radiation, resulting in four fatalities due to acute radiation syndrome. The current study examined the occurrence of possible mutations in the Y chromosome of the exposed men and their male offspring divided into two groups: A) eight accidentally exposed men and eight boys; B) twelve occupationally exposed men and sixteen boys; and the control group with 8 men and 8 boys not exposed. DNA was isolated from peripheral blood lymphocytes and 30 loci (SRY, AMELY, ZFY, AZFa-Prox1, SY83, AZFa-Prox2, SY86, SY85, SY84, USP9Y, SY87, DBY, AZFa-Dist1, 12f2, AZFa-Dist2, UTYpe, SY106, SY124, SY127, SY134, SY135, SY143, SY1197, SY1291, SY1125, SY1054, YDAZ3, SY254, SY255, RH65618) were amplified by the polymerase chain reaction. All DNA tests had a probability of paternity of at least 99.99%. All analyzed individuals amplified STS; however, 4 fathers (8.4%) and 8 sons (21.2%) in group A, and 3 fathers (7.1%) and 3 sons (63.3%) in group B showed mutations. The total mutation rates were 0.11. The first generation of the accidentally exposed group showed 7 mutations in SY86, 12 mutations in SY84, and 1 mutation both in 12f2 and SY135. The first generation of the occupationally exposed group showed 2 mutations in SRY, AMELY, AZFa-Prox1, AZFa-Prox2, SY86, SY85, SY84, USP9Y, SY87, AZFa-Dist1, UTYpe, SY106, SY124, SY127, SY134, SY135, SY143, SY1125, SY1054, YDAZ3, SY254, SY255, and RH65618; and 4 mutations in 12f2. In the control group, only one son showed an SY84 deletion. Recombination events between repetitive regions are possibly the cause of the high incidence of de novo mutations in the Y chromosome. The mutations were possibly generated by intrinsic mechanisms that could have been increased by the ionizing radiation from cesium-137. The exposure to ionizing radiation from cesium-137 can be detected in offspring of exposed individuals, and the mutation rate can be attributed to radioactive exposure.Item Estudo da associação do polimorfismo genético em carcinomas da tiróide(Universidade Federal de Goiás, 2010-02-24) REIS, Angela Adamski da Silva; CRUZ, Aparecido Divino da; http://lattes.cnpq.br/7868817504129985Thyroid nodules are common in clinical practice and the incidence of thyroid cancer is increasing throughout the world. Certainly, an important factor for the increase of the incidence is the use of ultrasound and PAFF. The identification of genetic polymosphism is important for understanding the potential mechanisms involved in thyroid carcinogenesis. We hypothesized that polymorphisms of xenobiotic enzyme system (CYP1A1, GSTM1 and GSTT1) and the common germline polymorphism of TP53 gene at codon 72 may be associated with the risk of thyroid cancer. To evaluate the role of such polymorphisms, we investigated 122 cases of thyroid nodules, classified according to the following: 35 malignant neoplasic nodules (MNN), 20 benign neoplasic nodules (BNN) and 67 non-neoplasic nodules (NNN) compared with 134 controls of the healthy individuals randomly selected. The PCR-RFLP was used in the analysis of the CYP1A1m1 and CYP1Am2 genotypes; the multiplex PCR was used in the deletion analysis of the GSTM1 and GSTT1; and for the determination of the polymorphism in the gene TP5372, the samples were submitted to conventional PCR reaction. We included case-control studies that compare the incidence of germline polymorphism of TP5372 in patients with thyroid cancer by DerSimonian-Laird method. Our results demonstrated that CYP1A1m1 and CYP1A1m2 genotypes were frequent not only as neoplasic thyroid nodules and non-neoplasic thyroid nodules but also in the control group, which suggests that those are not associated with thyroid nodules. The null genotype for the GSTT1 gene was predominant in benign nodules compared with the control group (p<0,005) indicated that individuals that possess such null genotypes presented a predisposition to benign thyroid diseases than malignant. The risk analysis, done by Odds Ratio, suggests that the risk genotypes GSTM1 (OR=12,82; p=0,004) and GSTT1 (OR=4,53; p<0,0001) contribute to the development of the BNN and NNN, respectively. The frequency of the p53 Arg allele was significantly higher in both patient and control groups. The genotype p53Arg Arg presents a lower risk to thyroid cancer, indicating that the allele arginine in homozygosis can present a protective effect against thyroid carcinogenesis (OR: 0.15; p<0.0001). The data of the meta-analysis demonstrates that the relation between the genotype and phenotype from the TP5372 polymorphism is not associated with the genetic susceptibility at thyroid cancer. The high incidence of thyroid pathologies among women is a characteristic not completely understood. Therefore, some factors, such as the imbalance of sexual hormones; nutritional deficiencies, especially in iodine; therapeutic exposure to radiation; failures in the control systems of the cellular cycle; and the genetic polymorphism could explain the high incidence of thyroid disease among women. Although the interindividual variation in the susceptibility to thyroid diseases could indicate new perspectives to an early diagnostic and prognostic, the polymorphic profile requires additional studies.Item O polimorfismo do gene p5372(RP) no câncer de cabeça e pescoço: estudo de associação e meta-análise(Universidade Federal de Goiás, 2009-10-20) SILVA, Antonio Márcio Teodoro Cordeiro; CRUZ, Aparecido Divino da; http://lattes.cnpq.br/7868817504129985Head and neck cancer arises in the oral cavity and nearby regions, larynx, pharynx, including oropharynx, nasopharynx, and hipopharynx. Extensive epidemiologic studies have revealed that chronic tobacco smoking and alcohol consumption as the two main risk factors associated with the multifactorial etiology of head and neck cancers. Additionally, nutritional status, HPV infection, and genetic polymorphism were also related with the disease. A frequently studied polymorphism in Squamous Cell Carcinoma (SCC) of head and neck is a G-to-C SNP (Single Nucleotide Polymorphism) at codon 72 in the p53 gene, which codes for an Arg or Pro (Arginine or Proline) in P53 protein. In order to investigate the distribution and potential association of that SNP in SCC, biological samples were obtained from 331 cases of head and neck SCC from Araújo Jorge Hospital and 271 healthy control individuals from Goiânia (Brazil) population. DNA was isolated and subsequently used for PCR amplification to genotype cases and controls with respect to their p5372 SNP. Additionaly, a meta-analysis was carried out using 29 relevant case-control studies that used p5372 SNP genotyping in SCC of the head and neck. Allelic frequencies for cases were 73.3% and 27.7% for Arg and Pro, respectively. On the other hand, control allelic frequencies were 74.2% and 25.8% for Arg and Pro, respectively (p = 0.119). Genotypic frequencies were 56.8% Arg/Arg, 32.9% Arg/Pro, and 10.3% Pro/Pro for all cases. The control genotypic frequencies were 61.3% Arg/Arg, 25.8% Arg/Pro and 12.9% Pro/Pro (p = 0,137). According to the current data and meta-analysis, no association between p5372 SNP and the development of SCC of the head and neck was found. Although, the homozygous genotype Arg/Arg was found as an important oncogenic risk factor associated with the carcinoma of the oropharynx.Item Avaliação Genético-Molecular do Carcinoma das Células Escamosas da Laringe(Universidade Federal de Goiás, 2009-10-21) SILVA, Cláudio Carlos da; CRUZ, Aparecido Divino da; http://lattes.cnpq.br/7868817504129985The larynx is a structure of the upper aerodigestive tract responsible for the production of sounds as well as protecting the lower airways and helping during the normal act of swallowing. Any pathology which affects the larynx can impose several challenges that disrupt its normal physiological function, and consequently and directly resulting in reduction of the patient s quality of life. Among the different diseases that affect the larynx, cancer is one of the most serious. The squamous cell carcinoma (SCC) of the larynx is a multifactorial disease, influenced by environmental factors and individual behavioral, habits, and susceptibility. The current study describes the molecular and genetic assessment of 20 patients with the squamous cell carcinoma of the larynx. In summary, the study strategy included the analyses of the genetic polymorphism of codon 72 of the TP53, the detection and genotyping of HPV genome, assessing genomic instability (MIS and LOH) and random chromosomal imbalances using PCR and CGH approaches. Regarding to the polymorphism of the TP53 gene, arginine homozygous genotypes (p53AA) and arginine-proline heterozygous genotypes (p53PA) were found in 65% (13/20) and 35% (7 / 20) of cases, respectively. HPV genome was found in association with tumor cells in 20% of SCC cases. HPV 16, 11, and 45 were the genotypes identified. Moreover, co-infection of HPV 11 and 45 was also observed. Both samples found positive for HPV genome were associated with p53AA at the TP53 gene. Our results corroborated the data published in the literature that described an increased susceptibility to the virus-induced carcinogenesis of the larynx in arginine homozygous genotypes. Here in we report genomic instability for a panel of 8 microsatellite markers distributed in 5 chromosomes. One locus (D8S135) was found in homozygous for all cases. On the other hand, RH-92600 was not included in the analysis mainly because it was also found homozygous for most cases. We found 76.2% (244/320) of informative loci. Thus the mean frequency of MIS was 9.0% (22/244) and LOH was 6.1% (15/244). The frequency of MIS was found higher than the LOH, suggesting that the tumorigenesis of SCC of the larynx follows a mechanism of mutator phenotype. Using CGH, chromosomal gains were observed in 1q21qter. On the other hand, chromosomal losses occurred in chromosome 3p21p28, 11q23, 16p16, 16q12, 17p13pter and 22q13. The techniques of comparative genomic hybridization have improved the understanding of genetic alterations in squamous cell carcinoma of the larynx, especially for characterizing the relationship between early precursors of laryngeal carcinomas, as well as to identify genomic regions that may contain oncogenes and tumor suppressor genes involved in the tumorigenesis of this anatomical site.