Made available in DSpace on 2014-08-20T13:32:46Z (GMT). No. of bitstreams: 1 Tese_Ludmila_Goncalves_Entiauspe.pdf: 1808464 bytes, checksum: 8834f78745c1e2d7f757d36d4797ef5c (MD5) Previous issue date: 2013-03-08 / Estimates show that approximately 80% of sexually active women will be infected by the Human Papillomavirus (HPV) in some point of their life course, and HPV DNA has been found in 99,7% of cervical cancer (CC) cases. Thus, several factors may contribute to CC development, including co-infections with Human Immunodeficiency Virus (HIV), as well as genetic factors, including TP53 and MDM2 polymorphisms. Some authors have associated CC development risk, among women infected with oncogenic HPV strains, with the Arg72Pro TP53 SNP. The MDM2 protein plays an important role in p53 protein regulation and, thus, a MDM2 SNP referred as SNP309 may also be implicated in CC risk in association with high-risk HPV genotypes. The present work aimed at determining the frequencies of HPV infection and identification of its genotypes, as well as the frequencies of the SNPs Arg72Pro and SNP309 and their associations with CC risk in female HIV-positive and negative populations in the city of Pelotas. It has been observed a prevalence of HPV infection of 30% among HIV-negative women, and 68% in the positive group. The HPV-16 genotype was the most prevalent in the HIV-negative group, and HPV-6 in the positive group. Among HPV-positive women, the TP53 Arg/Arg genotype was the most prevalent in both HIV groups, and the SNP309 TT genotype was the most prevalent in the HIV negative group, and the TG genotype in the positive group. These findings suggest that future investigations in larger populations are necessary and of interest to better understand the potential roles of these SNPs in HPV infected women. / Estimativas mostram que cerca de 80% das mulheres sexualmente ativas estarão infectadas pelo Vírus do Papiloma Humano (HPV) em algum momento de suas vidas, o que DNA-HPV tem sido encontrado em 99,7% dos casos de câncer cervical (CC). Assim, vários fatores podem contribuir para o desenvolvimento do CC, incluindo coinfecções como o vírus da Imunodeficiência Humana (HIV), bem como fatores genéticos, incluindo os polimorfismos nas proteínas p53 e MDM2. Alguns autores relacionam um maior risco ao desenvolvimento de CC em mulheres infectadas com genótipos oncogênicos do HPV e que apresentam polimorfismo do gene supressor de tumor TP53 (SNP Arg72Pro). A proteína MDM2 apresenta um papel importante na regulação da p53, e assim como o SNP Arg72Pro da p53, o SNP309 da MDM2 (substituição de T por G) também pode favorecer o desenvolvimento de CC quando associado a genótipos de HPV de alto risco. O presente trabalho objetivou conhecer o grau da extensão de infecção pelo HPV e identificação de seus genótipos, frequência do SNP Arg72Pro e MDM2 SNP309 e associação ao risco de CC, na população feminina HIV positiva e negativa residente em Pelotas. Foi observada uma prevalência de infecção por HPV em 30% no grupo HIV negativo e 68% no grupo HIV positivo. O genótipo de HPV mais prevalente no grupo HIV negativo foi o HPV-16, e HPV-6 no grupo HIV positivo. Nas HPV positivas, o genótipo Arg72Arg foi o mais prevalente em ambos os grupos, e o SNP309 TT para o grupo HIV negativo e TG para HIV positivo. Os resultados encontrados mostram que futuros estudos em populações maiores são necessários para um melhor entendimento destes SNPs em mulheres infectadas por HPV.

Made available in DSpace on 2014-08-20T13:32:57Z (GMT). No. of bitstreams: 1 tese_helena_strelow_thurow.pdf: 807973 bytes, checksum: 9ce5f5a742c1cda1d087be4eaaf27eae (MD5) Previous issue date: 2011-07-15 / A proteína p53,codificada pelo gene TP53, vem sendo estudada há mais de 30 anos e já foi denominada de "guardiã do genoma.

The presence of TP53 mutations has been associated with inferior outcome in diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In DLBCL, the impact of the TP53 codon 72 polymorphism and MDM2 SNP309 has not been clearly elucidated, whereas MDM2 SNP309 was suggested as a poor-prognostic marker in CLL. In addition, p16INK4a promoter hypermethylation has been implicated as a negative prognostic factor in DLBCL. The aim of this thesis was to further evaluate these molecular markers in well-characterised materials of DLBCL and CLL. In paper I, we investigated the prognostic role of TP53 mutation, codon 72 polymorphism and MDM2 SNP309 in DLBCL (n=102). The presence of TP53 mutations (12.7%) correlated with a poor lymphoma-specific and progression-free survival, and a particularly pronounced effect was observed in the germinal center subtype. Neither the MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. In paper II, we applied pyrosequencing to measure the level of p16INK4a methylation in DLBCL (n=113). Thirty-seven percent of cases displayed p16INK4a methylation; however, no clear association could be observed between degree of methylation and clinical characteristics or lymphoma-specific survival. In papers III–IV, we investigated the prognostic role of MDM2 SNP309 (n=418) and TP53 mutation (n=268) in CLL. No correlation was observed between any particular MDM2 SNP309 genotype and time to treatment and overall survival. Furthermore, no association was found between the different MDM2 SNP309 genotypes and established CLL prognostic markers. TP53 mutations were detected in 3.7% of CLL patients; where the majority showed a concomitant 17p-deletion and only three carried TP53 mutations without 17p-deletion. We confirmed a significantly shorter overall survival and time to treatment in patients with both TP53 mutation and 17p-deletion. Altogether, our studies could confirm the negative prognostic impact of TP53 mutations in DLBCL, whereas MDM2 SNP309 and TP53 codon 72 polymorphisms appear to lack clinical relevance. We also question the role of p16INKa methylation as a poor-prognostic factor in DLBCL. Finally, the presence of TP53 mutation in CLL appears to be rare at disease onset and instead arise during disease progression.