Abstract

<div>Abstract<p><b>Purpose:</b> Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor the <i>BRAF-KIAA1549</i> (B-K) fusion gene resulting in constitutive activation of the <i>RAS/MAPK</i> 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.</p><p><b>Experimental Design:</b> 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 <i>BRAF</i> alterations by reverse transcriptase PCR, FISH, and single-nucleotide polymorphism array analysis and correlated that with progression-free survival (PFS).</p><p><b>Results:</b> 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 (<i>P</i> = 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. <i>In vitro</i>, 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 (<i>P</i> = 0.001).</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 17(14); 4790–8. ©2011 AACR</i>.</p></div>

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