Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-08-25T20:42:57Z No. of bitstreams: 1 EdilmarDeMouraSantos_TESE.pdf: 2404882 bytes, checksum: 5eff55db010b690ecc915ee6c24050f0 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-08-26T19:45:12Z (GMT) No. of bitstreams: 1 EdilmarDeMouraSantos_TESE.pdf: 2404882 bytes, checksum: 5eff55db010b690ecc915ee6c24050f0 (MD5) / Made available in DSpace on 2016-08-26T19:45:12Z (GMT). No. of bitstreams: 1 EdilmarDeMouraSantos_TESE.pdf: 2404882 bytes, checksum: 5eff55db010b690ecc915ee6c24050f0 (MD5) Previous issue date: 2016-02-24 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Falhas nos genes respons?veis por reparos no DNA podem influenciar no surgimento de c?ncer ou afetar a resposta aos tratamentos. Estudos t?m demonstrado que a varia??o na capacidade de reparo do DNA pode ser resultado de polimorfismos funcionais nestes genes, e alguns destes experimentos sugerem que a presen?a de polimorfismos de nucleot?deos simples (SNPs), em genes de reparo, est? relacionada ao desenvolvimento e resposta ao tratamento de v?rios c?nceres, incluindo o Carcinoma Epidermoide Oral (CEO) e o Carcinoma Epidermoide de Orofaringe (CEOR). Nesta pesquisa avaliou-se a frequ?ncia de tr?s SNPs em dois genes de reparo do DNA RAD51 172G>T (c.-61 G>T, rs1801321), RAD51 135G>C (c.-98 G>C, rs1801320) e XRCC3 T241M (c. 722 C>T, rs861539) em indiv?duos saud?veis (n=130) e indiv?duos com CEO e CEOR (n=126) e investigou-se poss?veis rela??es de tais achados com os desfechos cl?nicos: resposta tumoral ao tratamento com radioterapia e quimioterapia, recidiva, e sobrevida global. Constatou-se frequ?ncia al?lica e genot?pica em equil?brio. A presen?a dos SNPs analisados n?o revelou ser um fator de risco para o desenvolvimento de CEO ou CEOR; contudo, quando associado ao h?bito de fumar ou beber, aumentou o risco de desenvolver o c?ncer de tr?s a cento e cinquenta vezes (p<000,1). A resposta tumoral ao tratamento de radioterapia e quimioterapia foi semelhante nos pacientes com ou sem SNPs. Nenhum polimorfismo demonstrou signific?ncia estat?stica em rela??o ? sobrevida livre de recidiva ou sobrevida global. Os gen?tipos AA e AC do SNP rs861539 no gene XRCC3, os gen?tipos CC e CG do SNP rs1801320 e GG e GT do SNP 1801321 no gene RAD51, aumentam o risco do desenvolvimento de carcinoma epidermoide oral e de orofaringe, quando associados ao h?bito de beber ou fumar. Os polimorfismos estudados nos genes XRCC3 e RAD51 n?o est?o associados ? resposta ? radioterapia, sobrevida livre de recidiva ou sobrevida global. / Faults in the genes responsible for repairs to the DNA can influence the onset of cancer or affect the response to treatment. This research evaluated the frequency of three single nucleotide polymorphisms (SNPs) in two repair genes DNA RAD51 172g> T (rs1801321), RAD51 135G> C (rs1801320) and XRCC3 T241M (rs861539) in individuals without cancer (n = 130) and patients with oral squamous cell carcinoma (OSC) and carcinoma oropharyngeal squamous (ORSC) (n = 126) and investigated possible relationships of these findings with clinical and pathological data and clinical outcomes: tumor response to radiotherapy and chemotherapy, disease-free survival, and overall survival. It was found that the allele and genotype frequencies were in equilibrium Hard-Weinberg equilibrium. The presence of at least one polymorphic allele in XRCC3 (rs861539) gene is associated with histological grade (WHO) higher (p = 0.007). We observed a higher recurrence rate trend (p = 0.08) and more advanced stage (p = 0.08) in the group that had at least one polymorphic allele of RAD51 gene (rs1801321). The presence of the analyzed SNPs not proved to be a risk factor for the development of CEO or CEOR; however, when combined with smoking or drinking, increased the risk of developing cancer from three to one hundred and fifty times. The tumor response to radiotherapy and chemotherapy was similar in patients with and without SNPs. No polymorphism showed statistical significance in relation to recurrence-free survival or overall survival. We conclude that the presence of at least one polymorphic allele of the SNPs rs861539 in XRCC3 gene, rs1801320 and rs1801321 in the RAD51 gene increase the risk of development of OSC and ORSC, when associated with the habit of drinking or smoking. Polymorphisms studied in XRCC3 and RAD51 genes are not associated with response to radiation therapy, relapse-free survival or overall survival.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-02-29T22:55:50Z No. of bitstreams: 1 StefaniaJeronimoFerreira_TESE.pdf: 1963411 bytes, checksum: 83b197f2ea9b0bdbd5ac4b4732412733 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-03-02T19:57:46Z (GMT) No. of bitstreams: 1 StefaniaJeronimoFerreira_TESE.pdf: 1963411 bytes, checksum: 83b197f2ea9b0bdbd5ac4b4732412733 (MD5) / Made available in DSpace on 2016-03-02T19:57:46Z (GMT). No. of bitstreams: 1 StefaniaJeronimoFerreira_TESE.pdf: 1963411 bytes, checksum: 83b197f2ea9b0bdbd5ac4b4732412733 (MD5) Previous issue date: 2015-02-24 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq / As vias de reparo por excis?o de base (BER) e por excis?o de nucleot?deo (NER) desempenham um papel crucial na manuten??o da integridade gen?mica. Polimorfismos em genes das vias BER e NER, que modulam a capacidade de reparo do DNA, podem estar relacionados ao risco de desenvolvimento e progn?stico do c?ncer oral. O presente trabalho teve como objetivo investigar a frequ?ncia de polimorfismos de nucleot?deos simples, em dois genes da via de reparo do DNA por excis?o de base (XRCC1 ? rs25487 e APEX1 ? rs1130409) e dois genes da via de reparo por excis?o de nucleot?deo (XPD ? rs13181 e XPF ? rs1799797), em pacientes com carcinoma de c?lulas escamosas oral (CCEO), buscando associa??es com o risco de desenvolver esta neoplasia maligna e o seu progn?stico. Um total de 92 amostras de DNA de pacientes com CCEO e 130 controles foram genotipadas utilizando o m?todo da rea??o em cadeia da polimerase em tempo real. O software estat?stico GraphPad Prism version 6.0.1. foi utilizado para a aplica??o dos testes apropriados. Odds ratio (OR) e hazard ratio (HR), e seus intervalos de confian?a (IC) de 95%, foram calculados pela regress?o log?stica. A avalia??o do progn?stico foi realizada por meio da curva de Kaplan-Meier e an?lise multivariada de Cox. A presen?a das variantes polim?rficas nos genes XRCC1, APEX1, XPD, e XPF n?o foram associadas ao risco de desenvolver CCEO. A intera??o da presen?a da variante polim?rfica com o h?bito de fumar n?o foi significativa para nenhum dos polimorfismos analisados. J? a presen?a do polimorfismo em XPD, somada ao h?bito de beber, aumentou o risco de desenvolver CCEO (OR 1,86, 95% IC: 0,86 ? 4,01, p=0,03). Apenas o SNP do APEX1 (rs1130409) esteve associado a uma diminui??o da sobrevida espec?fica (HR 3,94, 95% IC: 1,31 ? 11,88, p=0,01). O presente estudo sugere uma intera??o entre o consumo de ?lcool e a presen?a do polimorfismo estudado no gene XPD. Al?m disso, indica um pior progn?stico para pacientes que possuem o polimorfismo estudado em APEX1. / Base excision repair (BER) and nucleotide excision repair (NER) pathways play critical role in maintaining genome integrity. Polymorphisms in BER and NER genes which modulate the DNA repair capacity may affect the susceptibility and prognosis of oral cancer. This study was conducted with genomic DNA from 92 patients with oral squamous cell carcinomas (OSCC) and 130 controls. The cases were followed up to explore the associations between BER and NER genes polymorphisms and the risk and prognosis of OSCC. Four single-nucleotide polymorphisms (SNPs) in XRCC1 (rs25487), APEX1 (rs1130409), XPD (rs13181) and XPF (rs1799797) genes were tested by polymerase chain reaction ? quantitative real time method. The GraphPad Prism version 6.0.1 statistical software was applied for statistical analysis of association. Odds ratio (OR), hazard ratio (HR), and their 95 % confidence intervals (CIs) were calculated by logistic regression. Kaplan-Meier curve and Cox proportional hazard model were used for prognostic analysis. The presence of polymorphic variants in XRCC1, APEX1, XPD and XPF genes were not associated with an increased risk of OSCC. Gene-environment interactions with smoking were not significant for any polymorphism. The presence of polymorphic variants of the XPD gene in association with alcohol consumption conferred an increased risk of 1.86 (95% CI: 0.86 ? 4.01, p=0.03) for OSCC. Only APEX1 was associated with decreased specific survival (HR 3.94, 95% CI: 1.31 ? 11.88, p=0.01). These results suggest an interaction between polymorphic variants of the XPF gene and alcohol consumption. Additionally APEX1 may represent a prognostic marker for OSCC.