BRAF – Anaplastic Astrocytoma

BRAF encodes a serine/threonine kinase in the RAS–RAF–MEK–ERK signaling cascade and is a well-established oncogene in melanoma, colorectal carcinoma, and papillary thyroid carcinoma. Somatic activating mutations at codon 600, most commonly c.1799T>A (p.Val600Glu), confer constitutive kinase activity and downstream ERK activation, driving tumorigenesis. In anaplastic astrocytoma (MONDO:0016684), BRAF V600E has emerged as a diagnostic marker and therapeutic target. The association between BRAF V600E and anaplastic astrocytoma is supported by multiple lines of evidence, including a multicenter cohort and individual case reports of durable responses to BRAF inhibitors.

In a cohort of 223 primary brain tumors—including 28 anaplastic astrocytomas—16.1% harbored BRAF V600E, with 14.3% of anaplastic astrocytomas showing the mutation (PMID:23323158). Three pediatric and adult case reports confirmed recurrent V600E in distinct anaplastic astrocytoma presentations: a circumscribed pediatric high-grade glioma with 26-year survival (PMID:28185325), an epithelioid glioblastoma evolving from anaplastic astrocytoma treated with dabrafenib (PMID:29621181), and a spinal cord anaplastic astrocytoma with 8-year recurrence-free survival (PMID:31986557). Together, these account for at least seven unrelated probands with confirmed V600E variants.

All reported anaplastic astrocytoma cases involve heterozygous, somatic c.1799T>A (p.Val600Glu) mutations. No germline segregation data are available, and no familial clustering has been described. Variant spectrum in anaplastic astrocytoma remains narrow, with V600E predominating; other BRAF alterations in this context have not been reported.

Functional studies establish the oncogenic mechanism of BRAF V600E by mimicking activation segment phosphorylation, leading to high basal kinase activity, constitutive MEK–ERK signaling, and oncogenic transformation (PMID:12781369; PMID:12917419). BRAF V600E–specific siRNA and small-molecule inhibitors (e.g., dabrafenib) selectively suppress ERK phosphorylation and tumor cell proliferation, confirming targetability and informing therapeutic strategies.

Conflicting evidence in anaplastic astrocytoma is limited; no studies have refuted the presence or functional impact of V600E in this setting. However, the prevalence of BRAF V600E is lower in high-grade gliomas versus low-grade gliomas, underscoring the need for systematic screening and larger cohorts to refine mutation prevalence and prognostic implications.

In summary, somatic BRAF V600E is a moderate-strength biomarker for anaplastic astrocytoma, supported by cohort frequencies and multiple independent case reports demonstrating functional oncogenicity and therapeutic responsiveness. Routine molecular testing for V600E should be integrated into the diagnostic workup of anaplastic astrocytoma to guide precision treatment with BRAF inhibitors.

References

• Translational oncology • 2012 • Analysis of the BRAF(V600E) Mutation in Central Nervous System Tumors. PMID:23323158
• Neuropathology • 2017 • A case of high-grade astrocytoma with BRAF and ATRX mutations following a long-standing course over two decades. PMID:28185325
• International journal of molecular sciences • 2018 • Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. PMID:29621181
• Neuropathology • 2020 • Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature. PMID:31986557
• Biochimica et biophysica acta • 2003 • Raf proteins and cancer: B-Raf is identified as a mutational target. PMID:12781369
• The Journal of biological chemistry • 2003 • Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. PMID:12917419

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