TY - JOUR
T1 - BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma
AU - Hawkins, Cynthia
AU - Walker, Erin
AU - Mohamed, Nequesha
AU - Zhang, Cindy
AU - Jacob, Karine
AU - Shirinian, Margret
AU - Alon, Noa
AU - Kahn, Daniel
AU - Fried, Iris
AU - Scheinemann, Katrin
AU - Tsangaris, Elena
AU - Dirks, Peter
AU - Tressler, Robert
AU - Bouffet, Eric
AU - Jabado, Nada
AU - Tabori, Uri
PY - 2011
Y1 - 2011
N2 - 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 RelevancePediatric 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.
AB - 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 RelevancePediatric 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.
U2 - 10.1158/1078-0432.CCR-11-0034
DO - 10.1158/1078-0432.CCR-11-0034
M3 - Article
SN - 1557-3265
VL - 17
SP - 4790
EP - 4798
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -