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...

CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3′ Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.

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