BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma

Cynthia Hawkins, Erin Walker, Nequesha Mohamed, Cindy Zhang, Karine Jacob, Margret Shirinian, Noa Alon, Daniel Kahn, Iris Fried, Katrin Scheinemann, Elena Tsangaris, Peter Dirks, Robert Tressler, Eric Bouffet, Nada Jabado, Uri Tabori

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Abstract


Purpose: 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.

Experimental Design: 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).

Conclusion: 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. Clin Cancer Res; 17(14); 4790–8. ©2011 AACR.


Translational Relevance

Pediatric low-grade astrocytomas (PLGA) are the most common pediatric central nervous system neoplasm. PLGA represents a chronic disease in which the timing and modality of intervention, especially at progression, are still controversial. Recent studies have revealed that the majority of 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 show that objective genetic and molecular tools can help clinicians predict the risk of tumor progression and the need for a more aggressive approach or careful observation. Combining B-K fusion and measurement of DNA damage can segregate these tumors into 4 different clinically relevant groups. This study represents a change in the current paradigm as biopsies of PLGA may be encouraged upfront but also at further progression to determine treatment decisions for these devastated children.
Original languageEnglish
Pages (from-to)4790-4798
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number14
DOIs
Publication statusPublished - 2011
Externally publishedYes

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    Hawkins, C., Walker, E., Mohamed, N., Zhang, C., Jacob, K., Shirinian, M., Alon, N., Kahn, D., Fried, I., Scheinemann, K., Tsangaris, E., Dirks, P., Tressler, R., Bouffet, E., Jabado, N., & Tabori, U. (2011). BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clinical Cancer Research, 17(14), 4790-4798. https://doi.org/10.1158/1078-0432.CCR-11-0034