title: Spindle assembly checkpoint gene expression in childhood adrenocortical tumors (ACT): Overexpression of Aurora kinases A and B is associated with a poor prognosis.
abstract: BACKGROUND
  Pediatric 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Kleiton Silva
authors.initials: KS
authors.lastname: Borges
authors.forename: Daniel Antunes
authors.initials: DA
authors.lastname: Moreno
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Martinelli
authors.forename: Sonir Roberto Rauber
authors.initials: SR
authors.lastname: Antonini
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Silvio
authors.initials: S
authors.lastname: Tucci
authors.forename: Luciano
authors.initials: L
authors.lastname: Neder
authors.forename: Leandra Naira Zambelli
authors.initials: LN
authors.lastname: Ramalho
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Seidinger
authors.forename: Izilda
authors.initials: I
authors.lastname: Cardinalli
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Mastellaro
authors.forename: José Andres
authors.initials: JA
authors.lastname: Yunes
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
mesh_terms: D000293:Adolescent; D018268:Adrenocortical Carcinoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D053208:Kaplan-Meier Estimate; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases
keywords: AURK; adrenocortical tumor; childhood; prognosis; spindle assembly checkpoint genes