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PURPOSE: Pediatric secondary high grade glioma (sHGG), which result from malignant transformation of low grade glioma (PLGG), are a poorly understood group of tumors with devastating outcomes. PATIENTS AND METHODS: We performed a population-based study combined with long-term follow-up of PLGG that transformed to sHGG. Exonic-sequencing and copy number alterations were investigated on a discovery cohort, followed by detailed genetic analysis of all tumors. Clinical and outcome data analysis of a genetically distinct subgroup was performed. RESULTS: sHGG were observed in 28/888 (3.2%) patients treated in Southern Ontario for PLGG with a median latency of 2.74 years (range, 0.18-20.3 years). sHGG were characterized by a high somatic mutation load (23 per genome). Alterations in chromatin modifying genes and major telomere maintenance pathways were observed in 57% and 54% of sHGG respectively. However, specific mutations in IDH1, H3F3A G34 and ATRX were extremely rare. The most recurrent somatic alterations were the oncogenic BRAF V600E mutation and deletion of the tumor suppressor gene CDKN2A, observed in 39% and 57% of sHGG respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced to the patient-matched PLGG counterparts. These early alterations were rarely observed in non-transformed PLGG (p < 0.0001) and primary childhood high grade glioma (p = 0.0023). The BRAF mutant sHGG subgroup was characterized by longer latency periods to transformation than non-BRAF mutant sHGG (median 6.59 versus 1.62 years; p < 0.0001). Furthermore, 5-year overall survival of children with BRAF mutant and wild-type PLGG that transformed were 75% ± 15% and 29% ± 12% respectively (p = 0.024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation provides a window of opportunity for aggressive surgical interventions, targeted therapy against oncogenic BRAF, and extended surveillance to potentially mitigate the devastating transformation event.

DEAD box proteins are putative RNA helicases that have been implicated in cellular processes involving alteration of RNA secondary structure, such as translation initiation and splicing. These proteins share eight conserved amino acid motifs, including Asp(D)-Glu-(E)-Ala(A)-Asp(D) which is part of a more extended motif. Recently, we have shown that the novel DDX1 gene containing a DEAD box motif maps to the same chromosome band as MYCN at 2p24 and is co-amplified with MYCN in retinoblastoma cell lines. Here, we show that the DDX1 gene is co-amplified with the MYCN gene in 2 of three neuroblastoma cell lines and that DDX1 RNA levels correlate with DDX1 gene copy number. Since amplification of MYCN is an indicator of poor prognosis in neuroblastoma, it was of interest to determine whether co-amplification with DDX1 occurred in clinical samples of neuroblastoma and whether such a finding carried any additional prognostic significance. We determined the gene copy number of DDX1 in 32 neuroblastoma patient samples (representative of all stages): 13 were MYCN amplified and 19 had normal copy numbers of the MYCN gene. Of the 13 neuroblastomas that were MYCN amplified, seven were also DDX1 amplified. Of the 19 that were not MYCN amplified, none were DDX1 amplified. This is the first example of a gene that is co-amplified with MYCN at a high frequency in neuroblastoma. While there was a trend towards a worse clinical outcome with co-amplification, the numbers were too small to reach significance.

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 Methods A 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. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Regional and local structural controls on the emplacement of 1326 Southern African kimberlites and related rocks (kimberlites sensu lato, 11% of which are dated) are analysed using a framework of lineaments defined by combining geology, aeromagnetics, gravity and geomorphological data. Spatial analysis of occurrences within clusters of kimberlites less than 100km across resolves variable trends, depending on the age and position of the cluster; but on a regional scale the distribution of these clusters is statistically controlled by four lineament trends: 040°, 096°, 134° and 165°. Similar regional trends are observed as aspect lineaments that can be followed over large distances from modelling the variation in dip direction of the Southern African topography. These observations suggest that different geological parameters exert a control on the distribution of kimberlites. Local structures may include en-echelon fault arrays, Riedel, R’-, P- or T-structures within trans-continental lithosphere structures (cryptic continental corridors). Many cryptic continental corridors are collinear with fracture zones along the Atlantic and Indian continental margins of Southern Africa, and may have found their origin in events resulting from plate reorganization during the break-up of the supercontinent Gondwana. Fault resistance may have rapidly changed the stress state of the African continent causing the deep lithospheric faults to be the loci of episodic extension, allowing kimberlite fluids to ascend through the faults and cluster within near-surface structures. A progressive age variation of kimberlite magmatism in Southern Africa may be attributed to stress propagation along deep lithospheric fractures.