Expressão de antígenos Câncer-Testículo em Glioblastoma
Data
2013
Autores
Freitas, Marcelo Roberto Pereira 
Orientadores
Vettore, André Luiz
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: O glioblastoma (GBM) e o mais comum e agressivo entre os tumores primarios malignos do sistema nervoso em adultos. Apesar dos avancos terapeuticos, o prognostico dos pacientes que recebem o tratamento baseado em cirurgia, radioterapia e quimioterapia e sombrio, com uma mediana de sobrevida global de 15 meses. Portanto, o desenvolvimento de novas terapias se faz necessario, sendo a manipulacao do sistema imune contra o tumor uma alternativa promissora. Os antigenos cancer-testiculo (CTA) formam um grupo de peptideos cuja expressao esta restrita a tumores e as celulas da linhagem germinativa, o que os coloca como excelentes candidatos a alvos de vacinas antitumorais. Entretanto, poucos estudos avaliaram sistematicamente a expressao genica dos CTA em GBM. Objetivo: Avaliar o perfil de expressao de um grande numero de CTA em GBM. Metodo: Dentre os 153 genes CTA descritos, foram selecionados 30 potencialmente expressos em GBM e seus padroes de expressao foram avaliados por RT-PCR em uma serie de 48 GBM e 5 amostras de cerebro normal. A expressao da proteina CTCFL tambem foi avaliada por imuno-histoquimica. Resultados: Entre os CTA sem expressao no cerebro normal, ACTL8 (57%), OIP5 (54%), XAGE3 (44%) e CTCFL (15%) estavam frequentemente expressos em GBM, enquanto que mais de 85% dos tumores expressavam ao menos um destes quatro CTA. A coexpressao de dois ou mais CTA ocorreu em 49% dos casos. A expressao da proteina CTCFL foi detectada em 13% dos casos de GBM e foi negativa em amostras cerebrais normais. A expressao de OIP5 e a expressao de 3-4 CTA foram associadas a melhor sobrevida global, mediana de 48 versus 23 semanas (HR 0.53; IC 95% 0.28-1.01; p=0.032) e mediana de 100 versus 26 semanas (HR 0.36; IC 95% 0.17-0.74; p=0.017), respectivamente. Pela analise multivariada, a positividade para 3-4 CTA (p=0.044), radioterapia (p=0.010) e quimioterapia (p=0.001) foram fatores prognosticos independentes para sobrevida global. Conclusao: GBM frequentemente expressa ACTL8, OIP5, XAGE3 e CTCFL, sendo que uma porcentagem elevada de tumores expressa pelo menos um destes quatro CTA, o que abre uma perspectiva para a sua utilidade como alvos para imunoterapia. Alem disso, a positividade de RNAm para 3-4 CTA foi um preditor independente de melhor sobrevida global para pacientes com GBM
Background: Glioblastoma (GBM) is the most common and deadliest of malignant primary brain tumors in adults. GBM confers a dismal prognosis despite advances in current therapy, with a median survival of 15 months with standard-of-care surgery, radiation and chemotherapy. Therefore, the development of new therapeutic options is desired. Cancer immunotherapy is a promising approach. Cancer/testis antigens (CTA) are a group of peptides whose expression is restricted to tumors and germ cells, which puts them as excellent candidates for targets of anti-tumor vaccines. However, few studies have systematically evaluated the CTA gene expression in GBM. Objective: The aim of this study was to determine the expression profile of a large number of CTA genes in GBM. Method: We selected, from 153 CTA genes, those genes potentially expressed in GBM. The expression pattern of 30 CTA was then evaluated by RT-PCR in a series of 48 GBM and 5 normal brain samples. The presence of CTCFL protein was also evaluated by immunohistochemical staining. Results: Among the genes with no expression in normal brain, ACTL8 (57%), OIP5 (54%), XAGE3 (44%) and CTCFL (15%) were frequently expressed in GBM, while over 85% of the tumors expressed at least 1 of these four CTA. Coexpression of two or more CTA occurred in 49% of cases. CTCFL protein expression was detected in 13% of the GBM and was negative in normal brain samples. GBM cases expressing OIP5 and 3-4 CTA was associated with significantly better median overall survival (OS) rates, 48 versus 23 weeks (HR 0.53; 95% CI 0.28-1.01; p=0.032) and 100 versus 26 weeks (HR 0.36; 95% CI 0.17 to 0.74; p=0.017), respectively. By multivariate analysis, mRNA positivity for 3-4 CTA (p=0.044), radiotherapy (p=0.010) and chemotherapy (p=0.001) were independent prognostic factors for OS. Conclusion: GBM frequently express ACTL8, OIP5, XAGE3 and CTCFL. A relatively high percentage of tumors expressed at least one of these four CTA, opening the perspective for their utility in antigen-specific immunotherapy. Furthermore, mRNA positivity for 3-4 CTA is an independent predictor of better OS for GBM patients.
Background: Glioblastoma (GBM) is the most common and deadliest of malignant primary brain tumors in adults. GBM confers a dismal prognosis despite advances in current therapy, with a median survival of 15 months with standard-of-care surgery, radiation and chemotherapy. Therefore, the development of new therapeutic options is desired. Cancer immunotherapy is a promising approach. Cancer/testis antigens (CTA) are a group of peptides whose expression is restricted to tumors and germ cells, which puts them as excellent candidates for targets of anti-tumor vaccines. However, few studies have systematically evaluated the CTA gene expression in GBM. Objective: The aim of this study was to determine the expression profile of a large number of CTA genes in GBM. Method: We selected, from 153 CTA genes, those genes potentially expressed in GBM. The expression pattern of 30 CTA was then evaluated by RT-PCR in a series of 48 GBM and 5 normal brain samples. The presence of CTCFL protein was also evaluated by immunohistochemical staining. Results: Among the genes with no expression in normal brain, ACTL8 (57%), OIP5 (54%), XAGE3 (44%) and CTCFL (15%) were frequently expressed in GBM, while over 85% of the tumors expressed at least 1 of these four CTA. Coexpression of two or more CTA occurred in 49% of cases. CTCFL protein expression was detected in 13% of the GBM and was negative in normal brain samples. GBM cases expressing OIP5 and 3-4 CTA was associated with significantly better median overall survival (OS) rates, 48 versus 23 weeks (HR 0.53; 95% CI 0.28-1.01; p=0.032) and 100 versus 26 weeks (HR 0.36; 95% CI 0.17 to 0.74; p=0.017), respectively. By multivariate analysis, mRNA positivity for 3-4 CTA (p=0.044), radiotherapy (p=0.010) and chemotherapy (p=0.001) were independent prognostic factors for OS. Conclusion: GBM frequently express ACTL8, OIP5, XAGE3 and CTCFL. A relatively high percentage of tumors expressed at least one of these four CTA, opening the perspective for their utility in antigen-specific immunotherapy. Furthermore, mRNA positivity for 3-4 CTA is an independent predictor of better OS for GBM patients.
Descrição
Citação
FREITAS, Marcelo Roberto Pereira. Expressão de antígenos Câncer-Testículo em Glioblastoma. 2013. 45 f. Tese (Doutorado em Hematologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo. São Paulo, 2013.