Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and MethodsA combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180).Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P , .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. ConclusionBRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. response to therapy and clinical outcome is still not known. As a result, as far as nonsurgical treatment is concerned, all patients with PLGGs receive similar treatment independent of their tumor's molecular alterations. 6 For deeply located tumors, such as hypothalamic/chiasmatic LGGs, the need for biopsy before treatment decisions are made for these children is still debated.The BRAF V600E mutation, which is observed in a variety of adult 7 and pediatric neoplasms, is thought to be present in only a small percentage of PLGGs.8 Controversy still exists as to whether BRAF V600E-mutant PLGG constitutes a unique subgroup with respect to natural history and outcome. 9,10 We have previously reported that PLGGs that transform to high-grade gliomas have a high incidence of BRAF V600E mutations in combination with CDKN2A deletion.11 CDKN2A is a tumor suppressor gene and a key regulator of the cell cycle. CDKN2A alterations act as a secondary hit, which allows for escape from cell cycle regulation and malignant behavior in multiple cancer types. 12,13 In PLGGs, CDKN2A loss has been reported to be associated with escape from oncogene-induced senescence, 14 especially when combined with BRAF mutations.To better define the clinical significance of BRAF V600E in these tumors, we performed a combined clinical and genetic analysis in an institutional discovery cohort of patients with PLGG who were diagnosed and treated in southern Ontario. 15 We then asse...

This study expands the spectrum of mutations in the GBE gene and confirms that the neuromuscular presentation of GSD-IV is clinically and genetically heterogeneous.

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.