Valor prognóstico e preditivo de genes candidatos selecionados após análise de oligoarrays em carcinomas mamários
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Data
2012-03-16
Autores
Bueno, Renata Camargo [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Neste estudo foi proposto (1) validar a assinatura genética de metástase previamente identificada pelo grupo para cinco genes candidatos (POLR1B, IKBKB, TRIP10, PGM5 e ATM), identificados como centrais em redes biológicas e correlacionar os dados de expressão com os dados clínicos e histopatológicos das pacientes; (2) confirmar o valor prognóstico do gene ATM e o seu mecanismo de regulação pelo miR-203, miR-421, miR- 576-5p, miR-664, miR-26a, miR-26b e miR-18a. Foi utilizada a metodologia de RT-qPCR em 63 amostras de carcinomas mamários (CM) e 5 de tecido mamário normal. Foram observadas correlações positivas entre os níveis de expressão dos genes detectados pela técnica de microarray e RT-qPCR, embora sem significância estatística. Não foram observadas diferenças significativas na expressão destes genes nos CM quando comparados às amostras de mama normais. Nas comparações entre os níveis de expressão e as características clínicas e histopatológicas pode-se observar que os genes IKBKB, POLR1B e PGM5 apresentaram aumento significativo de expressão em tumores ER positivos. Foram observadas diminuições significativas dos transcritos de IKBKB, TRIP10, PGM5 e ATM em tumores HER2 positivos; para os genes PGM5 e ATM houve uma diminuição significativa de expressão nos tumores grau III. A análise da expressão proteica do ATM foi realizada por imunoistoquímica em 926 amostras de CM organizadas em quatro plataformas de microarranjos de tecidos. Foi verificada a diminuição da expressão da proteína ATM nos tumores quando comparados com a amostra de tecido mamário normal e sua diminuição estava associada a tumores de alto grau e metástase à distância. Pacientes com tumores ATM-negativos apresentaram diminuição do tempo de sobrevida livre de doença e de...
The present study aimed: 1) to validate the genetic signatures of metastasis previously detected by our group for five candidate genes (POLR1B, IKBKB, TRIP10, PGM5, and ATM), identified as central in biological networks, and to correlate the findings with clinical-histopathological data; 2) to confirm the prognostic value of the ATM gene and its mechanism of regulation by miR-203, miR-421, miR-576-5p, miR-664, miR-26a, miR- 26b and miR-18a. Sixty-three breast carcinomas (BC) samples and 5 normal breast tissue samples were evaluated by RT-qPCR. Positive correlations were observed between the gene expression levels detected by microarray and RT-qPCR, although not statistically significant. There was no significant difference between BC and normal samples. Overexpression of IKBKB, POLR1B, and PGM5 genes were significantly associated with ER positive tumours. Significant downexpression of IKBKB, TRIP10, PGM5 and ATM transcripts were observed in HER2-positive tumours. PGM5 and ATM downexpression were statistically associated with grade III tumours. ATM protein expression was evaluated by immunohistochemistry in 926 BC samples organized into four tissue microarray platforms. A decreased ATM protein expression was observed in tumours when compared to normal tissue as well as with high grade tumours and distant metastasis. Patients with ATM-negative tumours showed a decrease of diseasefree survival and overall survival. After multivariate analysis, ATM revealed to be an independent prognostic marker in BC and have been associated with lower risk of metastasis and death by disease (P<0.001, HR=0.535, and P<0.001, HR=0.534, respectively). A negative correlation between the transcript levels of ATM and the miR- 664 (P=0.035, r=-0.293), and miR-421 (P=0.075 e r=-0.249, respectively) was verified. The miR-26a... (Complete abstract click electronic access below)
The present study aimed: 1) to validate the genetic signatures of metastasis previously detected by our group for five candidate genes (POLR1B, IKBKB, TRIP10, PGM5, and ATM), identified as central in biological networks, and to correlate the findings with clinical-histopathological data; 2) to confirm the prognostic value of the ATM gene and its mechanism of regulation by miR-203, miR-421, miR-576-5p, miR-664, miR-26a, miR- 26b and miR-18a. Sixty-three breast carcinomas (BC) samples and 5 normal breast tissue samples were evaluated by RT-qPCR. Positive correlations were observed between the gene expression levels detected by microarray and RT-qPCR, although not statistically significant. There was no significant difference between BC and normal samples. Overexpression of IKBKB, POLR1B, and PGM5 genes were significantly associated with ER positive tumours. Significant downexpression of IKBKB, TRIP10, PGM5 and ATM transcripts were observed in HER2-positive tumours. PGM5 and ATM downexpression were statistically associated with grade III tumours. ATM protein expression was evaluated by immunohistochemistry in 926 BC samples organized into four tissue microarray platforms. A decreased ATM protein expression was observed in tumours when compared to normal tissue as well as with high grade tumours and distant metastasis. Patients with ATM-negative tumours showed a decrease of diseasefree survival and overall survival. After multivariate analysis, ATM revealed to be an independent prognostic marker in BC and have been associated with lower risk of metastasis and death by disease (P<0.001, HR=0.535, and P<0.001, HR=0.534, respectively). A negative correlation between the transcript levels of ATM and the miR- 664 (P=0.035, r=-0.293), and miR-421 (P=0.075 e r=-0.249, respectively) was verified. The miR-26a... (Complete abstract click electronic access below)
Descrição
Palavras-chave
Mamas - Cancer, Reação em cadeia de polimerase, Anatomia patologica, Anatomy, Pathological, Polymerase chain reaction, Breast - Cancer
Como citar
BUENO, Renata Camargo. Valor prognóstico e preditivo de genes candidatos selecionados após análise de oligoarrays em carcinomas mamários. 2012. 111 f. Dissertação (mestrado) - Universidade Estadual Paulista, Faculdade de Medicina de Botucatu, 2012.