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. 2015 Jul;74(7):743-54.
doi: 10.1097/NEN.0000000000000213.

KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas

Aline Paixão Becker  1 , Cristovam Scapulatempo-Neto, Adriana C Carloni, Alessandra Paulino, Jamie Sheren, Dara L Aisner, Evelyn Musselwhite, Carlos Clara, Hélio R Machado, Ricardo S Oliveira, Luciano Neder, Marileila Varella-Garcia, Rui M Reis
Affiliations

KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas

Aline Paixão Becker et al. J Neuropathol Exp Neurol. 2015 Jul.

Abstract

Up to 20% of patients with pilocytic astrocytoma (PA) experience a poor outcome. BRAF alterations and Fibroblast growth factor receptor 1 (FGFR1) point mutations are key molecular alterations in Pas, but their clinical implications are not established. We aimed to determine the frequency and prognostic role of these alterations in a cohort of 69 patients with PAs. We assessed KIAA1549:BRAF fusion by fluorescence in situ hybridization and BRAF (exon 15) mutations by capillary sequencing. In addition, FGFR1 expression was analyzed using immunohistochemistry, and this was compared with gene amplification and hotspot mutations (exons 12 and 14) assessed by fluorescence in situ hybridization and capillary sequencing. KIAA1549:BRAF fusion was identified in almost 60% of cases. Two tumors harbored mutated BRAF. Despite high FGFR1 expression overall, no cases had FGFR1 amplifications. Three cases harbored a FGFR1 p.K656E point mutation. No correlation was observed between BRAF and FGFR1 alterations. The cases were predominantly pediatric (87%), and no statistical differences were observed in molecular alterations-related patient ages. In summary, we confirmed the high frequency of KIAA1549:BRAF fusion in PAs and its association with a better outcome. Oncogenic mutations of FGFR1, although rare, occurred in a subset of patients with worse outcome. These molecular alterations may constitute alternative targets for novel clinical approaches, when radical surgical resection is unachievable.

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Figures

FIGURE 1
FIGURE 1
Molecular alterations in BRAF. (A, B) FISH assay for detection of KIAA1549:BRAF fusion showing a positive (A) and a negative (B) case (white arrows). (C, D) Point mutations detected by Sanger sequencing for V600E (C) and V600K (D).
FIGURE 2
FIGURE 2
Immunohistochemical expression of FGFR1. (A) In normal cerebellum, expression is limited to Purkinje cells. (B) Neoplastic cells show overexpression when compared with nonneoplastic astrocytes (bottom). (C) Oligodendroglial pattern of PA, showing moderate FGFR1 expression. (D) Piloid pattern of PA with similar FGFR1 expression.
FIGURE 3
FIGURE 3
Molecular alterations of FGFR1. (A) Electropherogram showing the point mutation K656E. (B, C) FISH assay displaying a normal pattern (B), and a case with low-copy number gain of the FGFR1 signal (C). The amount of FGFR1 signals (green) did not reach the cutoff value needed for the diagnosis of gene amplification.
FIGURE 4
FIGURE 4
(A–D) Kaplan-Meier curves showing the impact of KIAA1549:BRAF (K:B) fusion (A, B) and FGFR1 p.K656E point mutation (C, D) in the overall survival and event-free survival of the patients.
FIGURE 5
FIGURE 5
Kaplan-Meier curves comparing the simultaneous impact of KIAA1549:BRAF (K:B) fusion and FGFR1 alterations on the overall survival of patients. (A) Impact of FGFR1 p.K656E point mutation. (B) Impact of FGFR1 expression assessed by immunohistochemistry (positive score ≥3; negative score ≤2).
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