title: BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma.
abstract: OBJECTIVE
  Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor the BRAF-KIAA1549 (B-K) fusion gene resulting in constitutive activation of the RAS/MAPK pathway. However, the clinical significance of this genetic alteration is yet to be determined. We aimed to test the prognostic role of the B-K fusion in progression of incompletely resected PLGA.
  
  
  METHODS
  We retrospectively identified 70 consecutive patients with incompletely resected "clinically relevant" PLGA. We added 76 tumors diagnosed at our institution between 1985 and 2010 as controls. We examined BRAF alterations by reverse transcriptase PCR, FISH, and single-nucleotide polymorphism array analysis and correlated that with progression-free survival (PFS).
  
  
  RESULTS
  Overall, 60% of tumors were B-K fusion positive. All patients with B-K fused PLGA are still alive. Five-year PFS was 61% ± 8% and 18% ± 8% for fusion positive and negative patients, respectively (P = 0.0004). B-K fusion resulted in similarly significant favorable PFS for patients who received chemotherapy. Multivariate analysis revealed that B-K fusion was the most significant favorable prognostic factor in incompletely resected PLGA and was independent of location, pathology, and age. In vitro, BRAF overexpression resulted in growth arrest associated with DNA damage (γH2AX expression). Five-year PFS was 68% ± 15% and 0% for patients with B-K fused and γH2AX-expressing PLGA versus negative tumors (P = 0.001).
  
  
  CONCLUSIONS
  These data suggest that B-K fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. Combined analysis of B-K fusion and γH2AX expression can determine prognosis and may be a powerful tool to tailor therapy for these patients.
authors: Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Cynthia
authors: C
authors: Hawkins
authors: Erin
authors: E
authors: Walker
authors: Nequesha
authors: N
authors: Mohamed
authors: Cindy
authors: C
authors: Zhang
authors: Karine
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authors: Jacob
authors: Margret
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authors: Shirinian
authors: Noa
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authors: Alon
authors: Daniel
authors: D
authors: Kahn
authors: Iris
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authors: Fried
authors: Katrin
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authors: Scheinemann
authors: Elena
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authors: Tsangaris
authors: Peter
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authors: Dirks
authors: Robert
authors: R
authors: Tressler
authors: Eric
authors: E
authors: Bouffet
authors: Nada
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authors: Jabado
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authors: Tabori