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

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    Astrocytoma
    Pediatrics
    Disease-Free Survival
    Neoplasms
    Gene Fusion
    DNA Damage
    Central Nervous System Neoplasms
    Growth
    Reverse Transcriptase Polymerase Chain Reaction
    Single Nucleotide Polymorphism
    Molecular Biology
    Chronic Disease
    Research Design
    Multivariate Analysis
    Observation
    Pathology

    Cite this

    Hawkins, C., Walker, E., Mohamed, N., Zhang, C., Jacob, K., Shirinian, M., ... 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
    Hawkins, Cynthia ; Walker, Erin ; Mohamed, Nequesha ; Zhang, Cindy ; Jacob, Karine ; Shirinian, Margret ; Alon, Noa ; Kahn, Daniel ; Fried, Iris ; Scheinemann, Katrin ; Tsangaris, Elena ; Dirks, Peter ; Tressler, Robert ; Bouffet, Eric ; Jabado, Nada ; Tabori, Uri. / BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 14. pp. 4790-4798.
    @article{a16d12e91dbc4e68a4d1b32c7eae1f0d,
    title = "BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma",
    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. {\circledC}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.",
    author = "Cynthia Hawkins and Erin Walker and Nequesha Mohamed and Cindy Zhang and Karine Jacob and Margret Shirinian and Noa Alon and Daniel Kahn and Iris Fried and Katrin Scheinemann and Elena Tsangaris and Peter Dirks and Robert Tressler and Eric Bouffet and Nada Jabado and Uri Tabori",
    year = "2011",
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    language = "English",
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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, vol. 17, no. 14, pp. 4790-4798. https://doi.org/10.1158/1078-0432.CCR-11-0034

    BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. / Hawkins, Cynthia; Walker, Erin; Mohamed, Nequesha; Zhang, Cindy; Jacob, Karine; Shirinian, Margret; Alon, Noa; Kahn, Daniel; Fried, Iris; Scheinemann, Katrin; Tsangaris, Elena; Dirks, Peter; Tressler, Robert; Bouffet, Eric; Jabado, Nada; Tabori, Uri.

    In: Clinical Cancer Research, Vol. 17, No. 14, 2011, p. 4790-4798.

    Research output: Contribution to journalArticle

    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.

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    DO - 10.1158/1078-0432.CCR-11-0034

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    JO - Clinical Cancer Research

    JF - Clinical Cancer Research

    SN - 1078-0432

    IS - 14

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