In the US, the incidence and mortality rates of prostate cancer (PCa) are higher among African American men compared to European American men. Obesity is an important risk factor of PCa. Obesity is known to alter the gene expression profiles in prostate tumors. This study evaluates the impact of obesity and the expression of obesity-related genes on the progression of PCa in African American men. The primary outcome of interest is biochemical recurrence (BCR) of PCa. There were 48 African American prostate cancer patients in the study. The tissue samples included 42 normal tissues, 40 Prostate Intraepithelial Neoplasia (PIN) and 45 tumor tissues (127 tissue samples in total). We assembled 99 obesity-related genes and determined the levels of their expression in the three types of tissue samples using Nanostring Technologies. An ANOVA test was used to compare the means for gene expression among normal, PIN and tumor tissue samples. Unconditional logistic regression models were used to calculate odds ratios (ORs) and their respective 95% confidence intervals (95% CIs) to determine the association between obesity and BCR as well as gene expression and BCR. Results were regarded as statistically significant if p-values were less than 0.05. A Kaplan Meier Curve was constructed to depict the survival time and time to event (BCR) among obese and non-obese African American prostate cancer patients. Patients were followed up from the date of first surgery to the date of biochemical recurrence or date of last follow-up. Statistical analysis was done with SAS 9.4 software. Forty-three obesity-related genes were statistically significantly associated with biochemical recurrence. There was no association between obesity and biochemical recurrence (BCR) in obese African American men compared to non-obese African American men (OR= 2.03, 95% CI = 0.22 - 18.77, p-value= 0.53). Twenty genes showed an upward trend in gene expression among normal, PIN and tumor tissue samples including ADIPOR1, AKRIC4, ALOX12, ALOX15, CRYBB2, EIF5A, ERG, GNPDA2, HNF1B, HSD3B1, KLK4, LEP, MC4R, MTCH2, PCSK1, PIK3CB, SLC2A2, STAT1, SULT1A1, YY1. The probability of survival (not having BCR) is lower in obese African American men compared to non-obese African American men as indicted in the Kaplan Meier curve. In other words, the probability of developing BCR is higher in obese African American men compared to non-obese African American men. We did not find a significant association between obesity and biochemical recurrence. However, we elucidated some obesity-related genes that could explain PCa carcinogenesis. Further studies are needed to determine functional significance of these selected obesity-related genes and the role they play in encouraging PCa progression in African American men.

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer. Using a quantitative real-time PCR assay(MethyLight), I determined promoter methylation levels of APC, RASSF1A, CYP26A1 and TBX15 in 219 radical prostatectomies diagnosed between 1998-2001, examined their correlation with clinicopathological follow-up data including Gleason Pattern(GP), Gleason Score(GS) and pathological stage, and explored their potential in predicting biochemical recurrence(BR) using univariate and multivariate analyses. I demonstrated that methylation status of all four genes could accurately differentiate normal from cancerous tissues. Quantitative methylation levels of APC and TBX15 correlated strongly with GP, GS, and pathological stage. Both APC and TBX15 methylation levels could significantly predict BR in univariate analysis(p-value=0.028 and 0.003, respectively). The methylation profiles of APC and TBX15 combined could discriminate patients into high, intermediate, and low risk groups of BR(p-value=0.005). My project demonstrated that quantitative increase in promoter methylation levels of APC and TBX15 were associated with PCa progression.

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer. Using a quantitative real-time PCR assay(MethyLight), I determined promoter methylation levels of APC, RASSF1A, CYP26A1 and TBX15 in 219 radical prostatectomies diagnosed between 1998-2001, examined their correlation with clinicopathological follow-up data including Gleason Pattern(GP), Gleason Score(GS) and pathological stage, and explored their potential in predicting biochemical recurrence(BR) using univariate and multivariate analyses. I demonstrated that methylation status of all four genes could accurately differentiate normal from cancerous tissues. Quantitative methylation levels of APC and TBX15 correlated strongly with GP, GS, and pathological stage. Both APC and TBX15 methylation levels could significantly predict BR in univariate analysis(p-value=0.028 and 0.003, respectively). The methylation profiles of APC and TBX15 combined could discriminate patients into high, intermediate, and low risk groups of BR(p-value=0.005). My project demonstrated that quantitative increase in promoter methylation levels of APC and TBX15 were associated with PCa progression.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-09-30T12:24:37Z No. of bitstreams: 1 adrianadesouzasergioferreira.pdf: 4960629 bytes, checksum: b90d61012929ce42f060b1462cf6d78c (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-09-30T13:38:39Z (GMT) No. of bitstreams: 1 adrianadesouzasergioferreira.pdf: 4960629 bytes, checksum: b90d61012929ce42f060b1462cf6d78c (MD5) / Made available in DSpace on 2016-09-30T13:38:39Z (GMT). No. of bitstreams: 1 adrianadesouzasergioferreira.pdf: 4960629 bytes, checksum: b90d61012929ce42f060b1462cf6d78c (MD5) Previous issue date: 2010-06-24 / Este estudo teve como objetivo analisar e comparar a sobrevida livre de recidiva bioquímica em cinco anos e fatores prognósticos em pacientes portadores de câncer de próstata submetidos à braquiterapia ou cirurgia radical. Foram analisados 129 pacientes com câncer de próstata, destes 64 foram submetidos à braquiterapia permanente com sementes de Iodo 125 e 75 pacientes foram tratados com prostatovesiculectomia radical, no período de janeiro de 2002 a dezembro de 2005, em um hospital da rede privada da cidade de Juiz de Fora-MG. As principais variáveis analisadas, coletadas dos prontuários dos pacientes, foram: idade, data de nascimento, PSA inicial, escore de Gleason à biópsia prostática e na peça cirúrgica para os pacientes operados, estadiamento clínico e patológico para os casos cirurgicos, volume da próstata ao pré-planejamento e no momento da braquiterapia, atividade das sementes de Iodo 125 e dosagens seriadas de PSA após o tratamento. Os pacientes foram classificados, segundo D’Amico, em grupos de risco: baixo, intermediário e alto. A recidiva bioquímica foi definida como níveis de PSA> 0,4ng/ml para os casos de prostatectomia radical e três elevações consecutivas de PSA para os pacientes implantados (ASTRO). Para estudo do efeito do tratamento na sobrevida livre de recidiva bioquímica foram geradas curvas de Kaplan-Meier, e teste de log-rank foi usado para determinar diferenças entre as curvas. A influência de múltiplas variáveis na sobrevida livre de recidiva bioquímica, como Gleason, estadiamento, iPSA, categoria de risco e idade foram estimados por regressão de Cox. No primeiro artigo, foi observada taxa de sobrevida livre de recidiva bioquímica superior (p=0,0056) para os pacientes submetidos à braquiterapia 79,70% (IC95%:66,87-87,99) quando comparado aos pacientes submetidos à cirurgia 44,30% (IC95%:23,28-63,47) sendo identificados como fatores prognósticos associados de forma independente à sobrevida livre de recidiva bioquímica a modalidade terapêutica (HR= 3,33 ;IC95% :1,41-7,88), os níveis séricos de iPSA (HR=2,54;IC95%:1,11-5,78) e a categoria de risco (HR=4,18 ;IC95%:1,89-9,23). No segundo artigo, que avaliou somente os pacientes submetidos à braquiterapia, foi verificada uma taxa de sobrevida livre de recidiva bioquimica em cinco anos, significativamente superior (p=0,0012) para os pacientes do grupo de baixo risco 91,6% (IC 95%:75,92-97,24), quando comparada com àquela dos pacientes do grupo de risco intermediário/alto 59,19% (IC 95%:36,00-76,40). A sobrevida livre de recidiva bioquimica também foi significativamente superior nos pacientes com iPSA ≤ 10ng/ml (p=0,0084) e com escore de Gleason ≤ 6 à biópsia prostática (p=0,0057). Na análise multivariada, o risco de falha bioquímica também se manteve maior nos pacientes que pertenciam ao grupo de risco moderado/alto e para pacientes com iPSA superior a 10ng/ml. Os dados de sobrevida livre de recidiva bioquimica em cinco anos, para os pacientes desta análise, tratados com braquiterapia, foram comparáveis aos da literatura. / This study aimed to analyze and compare the biochemical relapse-free survival at five years and prognostic factors in patients with prostate cancer undergoing radical surgery or brachytherapy. We analyzed 129 patients with prostate cancer, these 64 underwent brachtherapy with permanent seeds implantation and 75 patients were treated with radical prostatectomy, from January 2002 to December 2005 in a private hospital network in the city of Juiz de Fora-MG. The main variables analyzed were collected from medical records and were: age, date of birth, initial PSA, Gleason score of prostate biopsy and of surgical specimens, clinical and pathologic staging on surgical cases, the prostate volume pre-planning and at the time of brachytherapy, seed activity of lodine 125 and serial measurements of PSA after treatment. Patients were classified according to D’Amico, at risk groups; low, intermediate and high. The biochemical recurrence was defined as PSA levels>0.4 ng/ml for cases of radical prostatectomy and three consecutive elevations of PSA for patients implanted (ASTRO). For the study of the effect of the treatment on biochemical relapse-free survival Kaplan-Meier curves were generated, and log rank test was used to determine the differences among the curves. The influence of multiple variables in the biochemical relapse-free survival as age, initial PSA, Gleason score, staging and risk category was estimated by Cox regression. In the first article, was observed rate of biochemical relapse-free survival superior (p = 0.0056) for patients undergoing brachytherapy 79.70% (CI95% :66,87-87, 99) when compared with patients undergoing surgery 44.30% (CI95% :23,28-63, 47) and were identified as prognostic factors independently associated with survival free of biochemical recurrence modality therapy (HR = 3.33, CI95% :1,41-7 88), serum levels of IPSA (HR = 2.54, CI95% :1,11-5, 78) and risk category (HR = 4.18, CI95% :1,89-9, 23). In the second article, which evaluated only the patients who underwent brachytherapy, there was a rate of biochemical relapse-free survival at five years, significantly higher (p = 0.0012) for patients with low-risk group 91.6% (CI 95% :75,92-97, 24), when compared with that of patients in the intermediate/high risk group 59.19% (CI95% :36,00-76, 40).The biochemical relapse-free survival was also significantly higher in patients with IPSA ≤ 10ng/ml (p = 0.0084) and Gleason score ≤ 6 on prostate biopsy (p = 0.0057). In multivariate analysis, the risk of biochemical failure also remained higher in patients who belonged to the group of moderate / high risk and patients with IPSA more than 10ng/ml. Data from biochemical relapse-free survival at five years for the patients of this analysis were comparable to literature.

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O câncer de próstata é o quinto tipo mais comum de câncer no mundo e o mais comum em homens. Fatores clínicos e anatomopatológicos atualmente usados na clínica não são capazes de distinguir entre a doença indolente e a agressiva. Existe uma grande necessidade de novos marcadores de prognóstico, a fim de melhorar o gerenciamento clínico de pacientes de câncer de próstata. Além das anormalidades em genes codificadores de proteínas, alterações em RNAs não codificadores (ncRNAs) contribuem para a patogênese do câncer e, portanto, representam outra fonte potencial de biomarcadores de câncer de próstata. Entretanto, até o momento, poucos estudos de perfis de expressão de ncRNAs foram publicados. Este projeto teve como principal objetivo identificar perfis de expressão de genes codificadores e não codificadores de proteína correlacionados com recorrência de tumor de próstata, a fim de gerar um perfil prognóstico com potencial uso como biomarcadores e elucidar o possível papel de ncRNAs no desenvolvimento do câncer. Para isso, foram analisados os perfis de expressão de genes codificadores e não codificadores de proteína de um conjunto de 42 amostras de tecido tumoral de câncer de próstata de pacientes de amostras de pacientes submetidos à prostatectomia radical, com longo acompanhamento clínico (cinco anos) e conhecida evolução da doença Nós utilizamos microarranjos por nós desenhados e fabricados pela Agilent sob encomenda, interrogando aproximadamente 18.709 transcritos não codificadores longos (>500 nt), sem evidência de splicing, que mapeiam em regiões intrônicas dentro de 5.660 loci genômicos. Os dados de expressão foram extraídos de cada arranjo, normalizados entre todas as 42 amostras de pacientes. Usando uma estratégia de múltipla amostragem, foi identificado um perfil de expressão de mau prognóstico, contendo 51 transcritos intrônicos não codificadores de proteína. O perfil prognóstico de ncRNAs foi aplicado a um conjunto teste independente de 22 pacientes, classificando corretamente 82% das amostras. Uma análise de Kaplan-Meier dos pacientes do conjunto teste indicou que as curvas de sobrevida dos grupos de alto e baixo risco foram significativamente distintas (Log-rank test p = 0,0009; Hazard ratio = 23,4, 95% CI = 3,62 a 151,2), confirmando assim que este classificador é útil para identificar pacientes com alto risco de recorrência. Além disso, estas descobertas indicam um potencial papel destes RNAs intrônicos não codificadores na progressão do tumor de próstata e apontam para os RNAs intrônicos como potenciais novos marcadores de câncer / Prostate cancer is the fifth most common type of cancer in the world, and the most common in men. Clinical and anatomo-pathological factors currently used in clinic are not able to distinguish between the indolent and the aggressive disease. There is a major need of new prognostic makers in order to improve the clinical management of prostate cancer patients. Apart from abnormalities in protein-coding genes, changes in non-coding RNAs (ncRNAs) contribute to the pathogenesis of cancer and thus represent another potential source of prostate cancer biomarkers. However, few studies of expression profiles of ncRNAs have been published. This project aimed to identify expression profiles of protein-coding and non-coding genes correlated to prostate cancer biochemical recurrence. For this, we analyzed the expression profile of 42 prostate cancer samples from patients undergoing radical prostatectomy, with long follow-up (five years), and know disease outcome. We used a custom microarray designed by us and printed by Agilent, that probes 18,709 long (>500 nt) ncRNAs mapping to intronic regions within 5,660 genomic loci. The expression data were extracted from each array and normalized across all 42 samples. Using a multiple random sampling validation strategy, we identified an expression profile of poor prognosis, comprising 51 ncRNAs. The prognostic profile of ncRNAs was applied to an independent test set of 22 patients, correctly classifying 82% of the samples. A Kaplan-Meier analysis of the test set of patients indicated that the survival curves of high and low risk groups were significantly different (Log-rank test p = 0.0009, Hazard ratio = 23.4, 95% CI = 3.62 to 151.2) thus confirming that this classifier is useful for identifying patients at high risk of recurrence. Furthermore, these findings indicate a potential role of these intronic non-coding RNAs in the progression of prostate tumors and points to the intronic ncRNAs as potential new markers of cancer.

O câncer de próstata é o quinto tipo mais comum de câncer no mundo e o mais comum em homens. Fatores clínicos e anatomopatológicos atualmente usados na clínica não são capazes de distinguir entre a doença indolente e a agressiva. Existe uma grande necessidade de novos marcadores de prognóstico, a fim de melhorar o gerenciamento clínico de pacientes de câncer de próstata. Além das anormalidades em genes codificadores de proteínas, alterações em RNAs não codificadores (ncRNAs) contribuem para a patogênese do câncer e, portanto, representam outra fonte potencial de biomarcadores de câncer de próstata. Entretanto, até o momento, poucos estudos de perfis de expressão de ncRNAs foram publicados. Este projeto teve como principal objetivo identificar perfis de expressão de genes codificadores e não codificadores de proteína correlacionados com recorrência de tumor de próstata, a fim de gerar um perfil prognóstico com potencial uso como biomarcadores e elucidar o possível papel de ncRNAs no desenvolvimento do câncer. Para isso, foram analisados os perfis de expressão de genes codificadores e não codificadores de proteína de um conjunto de 42 amostras de tecido tumoral de câncer de próstata de pacientes de amostras de pacientes submetidos à prostatectomia radical, com longo acompanhamento clínico (cinco anos) e conhecida evolução da doença Nós utilizamos microarranjos por nós desenhados e fabricados pela Agilent sob encomenda, interrogando aproximadamente 18.709 transcritos não codificadores longos (>500 nt), sem evidência de splicing, que mapeiam em regiões intrônicas dentro de 5.660 loci genômicos. Os dados de expressão foram extraídos de cada arranjo, normalizados entre todas as 42 amostras de pacientes. Usando uma estratégia de múltipla amostragem, foi identificado um perfil de expressão de mau prognóstico, contendo 51 transcritos intrônicos não codificadores de proteína. O perfil prognóstico de ncRNAs foi aplicado a um conjunto teste independente de 22 pacientes, classificando corretamente 82% das amostras. Uma análise de Kaplan-Meier dos pacientes do conjunto teste indicou que as curvas de sobrevida dos grupos de alto e baixo risco foram significativamente distintas (Log-rank test p = 0,0009; Hazard ratio = 23,4, 95% CI = 3,62 a 151,2), confirmando assim que este classificador é útil para identificar pacientes com alto risco de recorrência. Além disso, estas descobertas indicam um potencial papel destes RNAs intrônicos não codificadores na progressão do tumor de próstata e apontam para os RNAs intrônicos como potenciais novos marcadores de câncer / Prostate cancer is the fifth most common type of cancer in the world, and the most common in men. Clinical and anatomo-pathological factors currently used in clinic are not able to distinguish between the indolent and the aggressive disease. There is a major need of new prognostic makers in order to improve the clinical management of prostate cancer patients. Apart from abnormalities in protein-coding genes, changes in non-coding RNAs (ncRNAs) contribute to the pathogenesis of cancer and thus represent another potential source of prostate cancer biomarkers. However, few studies of expression profiles of ncRNAs have been published. This project aimed to identify expression profiles of protein-coding and non-coding genes correlated to prostate cancer biochemical recurrence. For this, we analyzed the expression profile of 42 prostate cancer samples from patients undergoing radical prostatectomy, with long follow-up (five years), and know disease outcome. We used a custom microarray designed by us and printed by Agilent, that probes 18,709 long (>500 nt) ncRNAs mapping to intronic regions within 5,660 genomic loci. The expression data were extracted from each array and normalized across all 42 samples. Using a multiple random sampling validation strategy, we identified an expression profile of poor prognosis, comprising 51 ncRNAs. The prognostic profile of ncRNAs was applied to an independent test set of 22 patients, correctly classifying 82% of the samples. A Kaplan-Meier analysis of the test set of patients indicated that the survival curves of high and low risk groups were significantly different (Log-rank test p = 0.0009, Hazard ratio = 23.4, 95% CI = 3.62 to 151.2) thus confirming that this classifier is useful for identifying patients at high risk of recurrence. Furthermore, these findings indicate a potential role of these intronic non-coding RNAs in the progression of prostate tumors and points to the intronic ncRNAs as potential new markers of cancer.

No description available.