Spindle Assembly Checkpoint Gene Expression in Childhood Adrenocortical Tumors (ACT): Overexpression of Aurora Kinases A and B Is Associated With a Poor Prognosis

Spindle Assembly Checkpoint Gene Expression in Childhood Adrenocortical Tumors (ACT): Overexpression of Aurora Kinases A and B Is Associated With a Poor Prognosis

Author Borges, Kleiton Silva Google Scholar
Moreno, Daniel Antunes Google Scholar
Martinelli, Carlos Eduardo Google Scholar
Rauber Antonini, Sonir Roberto Google Scholar
Castro, Margaret de Google Scholar
Tucci, Silvio Google Scholar
Neder, Luciano Google Scholar
Zambelli Ramalho, Leandra Naira Google Scholar
Seidinger, Ana Luiza Google Scholar
Cardinalli, Izilda Google Scholar
Mastellaro, Maria Jose Google Scholar
Yunes, Jose Andres Google Scholar
Brandalise, Silvia Regina Google Scholar
Tone, Luiz Gonzaga Google Scholar
Scrideli, Carlos Alberto Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Ctr Infantil Boldrini
Universidade Estadual de Campinas (UNICAMP)
Abstract BackgroundPediatric adrenocortical tumors (ACT) are rare malignancies and treatment has a small impact on survival in advanced disease and the discovery of potential target genes could be important in new therapeutic approaches.MethodsThe mRNA expression levels of spindle checkpoint genes AURKA, AURKB, BUB, and BUBR1 were analyzed in 60 children with ACT by quantitative real time PCR. the anticancer effect of ZM447439, an experimental AURK inhibitor, was analyzed in a primary childhood ACT culture carrying the TP53 p.R337H mutation.ResultsA significant association was observed between malignancy as defined by Weiss score 3 and higher AURKA (2.0-fold, P=0.01), AURKB (7.0-fold, P=0.007), and BUBR1 (5.8-fold, P=0.007) gene expression, and between unfavorable event (death or relapse) and higher expression of AURKA (6.0-fold, P=0.034) and AURKB (17-fold, P=0.013). Overexpression of AURKA and AURKB was associated with lower event-free survival in uni- (P<0.001 and P=0.006, respectively) and multivariate (P=0.002 and P=0.03, respectively) analysis. Significant lower Event free survival (EFS) was also observed in patients with moderate/strong immunostaining to AURKA (P=0.012) and AURKB (P=0.045). ZM447439 was able to induce inhibition of proliferation and colony formation in a primary childhood ACT culture carrying the TP53 p.R337H mutation.ConclusionOur results suggest that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease and the inhibition of these proteins could be an interesting approach for the treatment of these tumors. Pediatr Blood Cancer 2013;60:1809-1816. (c) 2013 Wiley Periodicals, Inc.
Keywords adrenocortical tumor
AURK
childhood
prognosis
spindle assembly checkpoint genes
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 2010/7020-9
FAPESP: 2010/08699-5
Date 2013-11-01
Published in Pediatric Blood & Cancer. Hoboken: Wiley-Blackwell, v. 60, n. 11, p. 1809-1816, 2013.
ISSN 1545-5009 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 1809-1816
Origin http://dx.doi.org/10.1002/pbc.24653
Access rights Closed access
Type Article
Web of Science ID WOS:000324299800021
URI http://repositorio.unifesp.br/handle/11600/36926

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