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Previous issue date: 2016-03-18 / Introduction: Colorectal cancer is the third most common cancer in men and the second in women worldwide. It presents multifactorial, heterogeneous and complex etiopathogeny, still not fully elucidated. The evolution of the disease is often distinct from the exhaustive surgical and pathological staging, eventually (possibly) patients with focal disease develop an aggressive pattern presenting poor prognosis. Recent evidence shows the molecular heterogeneity of colorectal cancer. In this context the microRNAs (miRNAs), small non-coding RNAs (containing 19-25 nucleotides) capable of regulating gene expression in post-transcriptional level, have been identified with different expressions for numerous diseases, including cancer. Colorectal cancer shows change in expression of several miRNAs. These changes have been associated with the diagnosis, prognosis, gene expression, chemosensitivity and staging, being a potential biomarker. Methods: Clinical and pathological data of patients submited to surgical resection of the primary tumor and regional lymph nodes diagnosed from September 2002 to October 2011 have been reviewed and analyzed, and included in the colorectal cancer tumor bank of the S?o Lucas Hospital's Oncology Department - PUCRS. The analysis of the expression of miRNAs was performed in the laboratory of the Institute of Biotechnology of the Catholic University of Brasilia where they were analyzed in primary tumor and regional lymph nodes for descriptive purposes and versus the clinical-pathological data of the cases studied. The quantification analysis of the following miRNA (mir-570, mir-16, mir-338, Let-7, miR-1, miR-150, mir-183, mir-650 and mir-31) were determined by qPCR. Statistical analysis tests: Fisher's, Wilcoxon and Kruskal Wallis Exact, considered a significance level of 5%. Results: Of the 28 cases studied, 28.6% were less than 60 years old at diagnosis and 71.4% aged 60 or over. The average age was 66.7 years (26 to 86). The mean (average) follow-up (period, age) was 3.9 years (0 to 9), SD= 2.8 and a median of 4 years. The expression of miRNAs in the primary tumor (N=28) showed more homogeneous pattern, with a tendency to overexpression; whereas, in ill lymph nodes (N=15) this pattern was more heterogeneous, with mir-570, mir-338, mir-1, mir-183 and mir-31 being presented overexpressed and mir-16, Let-7, mir-150 and mir-650 with a more repressed expression. The suppressed expression of mir-570 was associated with mortality when evaluated in the primary tumor (N=28), where the prevalence of death in individuals with suppressed expression was 63.64% and those overexpressed was 17.65%, with p=0.020. In the primary tumor of patients with lymph node metastasis (N=15) the median expression of mir-183 was 4.42 with interquartile range (IQR) p25 of 1,66 and p75 of 43.01; whereas in the samples from patients with no ill lymph nodes (N=13) the median expression of mir-183 was 54.17 with IQR p25 of 13.12 and p75 of 223.14, with p=0.01, suggesting focal disease at diagnosis. In the subgroup of patients with lymph node metastasis (N=15), the expression of mir-650 in lymph node was associated with the prevalence of recurrence. The expression of mir-650 showed suppressed expression in 25% of the recurrence cases and was overexpressed in 85% of cases, with p=0.04. Conclusions: The expression pattern of miRNAs differs depending on the site of the disease studied (primary tumor or metastatic disease). The suppressed expression of mir-570 in the primary tumor is likely to be predictor of mortality. Overexpression of mir-183 in the primary tumor suggests focal disease at diagnosis. The overexpression of mir-650 in the metastatic lymph node is a recurrence predictor. New studies including functional tests and meta-analyzes may confirm these findings and optimize the use of these miRNAs in clinical practice. / Introdu??o: O c?ncer colorretal ? o terceiro c?ncer mais comum em homens e o segundo em mulheres no mundo. Apresenta etiopatogenia multifatorial, heterog?nea e complexa, ainda n?o totalmente elucidada. A evolu??o da doen?a ? muitas vezes distinta do exaustivo estadiamento cir?rgico e patol?gico, eventualmente pacientes com doen?a localizada evoluem com padr?o agressivo apresentando mal progn?stico. Evid?ncias recentes demonstram a heterogeneidade molecular do c?ncer colorretal. Neste contexto os microRNAs (miRNAs), pequenos RNAs com 19-25 nucleot?deos n?o codificadores, que s?o capazes de regular a express?o de genes em n?vel p?s-transcricional, t?m sido identificados com diferentes express?es em diversas doen?as, inclusive no c?ncer. O c?ncer colorretal apresenta altera??o na express?o de diversos miRNAs. Estas altera??es t?m sido associadas ao diagn?stico, progn?stico, express?o de genes, quimiossensibilidade e estadiamento, sendo potencial biomarcador. M?todos: Foram revisados e analisados dados cl?nicos e anatomopatol?gicos de pacientes submetidos a ressec??o cir?rgica do tumor prim?rio e linfonodos regionais diagnosticados de setembro de 2002 ? outubro de 2011 e inclu?dos no banco de tumores de c?ncer colorretal do Servi?o de Oncologia do Hospital S?o Lucas ? PUCRS. A an?lise da express?o dos miRNAs foi realizada no laborat?rio do Instituto de Biotecnologia da Universidade Cat?lica de Bras?lia onde foram analisadas nos tumores prim?rios e nos linfonodos regionais, com fins descritivos e frente aos dados cl?nico-patol?gicos dos casos estudados. A an?lise da quantifica??o dos seguintes miRNA (mir-570, mir-16, mir-338, Let-7, mir-1, mir-150, mir-183, mir-650 e mir-31) foi realizada por qPCR. Para an?lise estat?stica os testes: Exato de Fisher, Wilcoxon e de Kruskal Wallis, considerado n?vel de signific?ncia de 5%. Resultados: Dos 28 casos estudados, 28,6% tinham menos de 60 anos na ocasi?o do diagn?stico e 71,4% 60 anos ou mais. A idade m?dia foi de 66,7 anos (26 ? 86). A m?dia de seguimento foi de 3,9 anos (0 ? 9), DP=2,8 e mediana de 4 anos. A express?o dos miRNAs no tumor prim?rio (N=28) apresentou padr?o mais homog?neo, com uma tend?ncia a superexpress?o; enquanto que, nos linfonodos doentes (N=15) este padr?o foi mais heterog?neo, com o mir-570, mir-338, mir-1, mir-183 e mir-31 apresentando-se superexpressos e mir-16, Let-7, mir-150 e mir-650 com express?o reprimida. A express?o reprimida do mir-570 apresentou associa??o com mortalidade quando avaliado no tumor prim?rio (N=28), onde a preval?ncia de ?bito nos indiv?duos com express?o reprimida foi de 63,64% e naqueles superexpressos foi de 17,65%, com valor p=0,020. No tumor prim?rio dos pacientes com met?stase linfonodal (N=15) a mediana de express?o do mir-183 foi de 4,42 com intervalo interquartil p25 de 1,66 e p75 de 43,01; enquanto que, nas amostras de pacientes com linfonodos n?o doentes (N=13) a mediana de express?o do mir-183 foi de 54,17 com intervalo interquartil p25 de 13,12 e p75 de 223,14, com valor p= 0,01, sugerindo doen?a localizada ao diagn?stico. No subgrupo de pacientes com met?stase linfonodal (N=15), a express?o do mir-650 no linfonodo foi associada a preval?ncia de recidiva. A express?o do mir-650 esteve reprimida em 25% dos casos que recidivaram e superexpresso em 85% dos casos, com valor p=0,04. Conclus?es: O padr?o de express?o dos miRNAs difere conforme o s?tio da doen?a estudada (tumor prim?rio ou doen?a metast?tica). A express?o reprimida do mir-570 no tumor prim?rio provavelmente seja preditora de mortalidade. Superexpress?o do mir-183 no tumor prim?rio sugere doen?a localizada ao diagn?stico. A superexpress?o do mir-650 no linfonodo metast?tico ? preditor de recidiva. Novos estudos incluindo testes funcionais e metan?lises poder?o ratificar estes achados e otimizar a utiliza??o destes miRNAs na pr?tica cl?nica.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/6805 |
| Date | 18 March 2016 |
| Creators | Petrarca, Cristiane Rios |
| Contributors | Silva, Vinicius Duval da, Andrade, Ros?ngela Vieira de |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, Brasil, Faculdade de Medicina |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 7620745074616285884, 600, 600, 600, -8624664729441623247, -969369452308786627 |
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