SUMMARY Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)”, “CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)”, and “CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)”, will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

SUMMARY We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

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% AE 8% and 18% AE 8% for fusion positive and negative patients, respectively (P ¼ 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 (gH2AX expression). Five-year PFS was 68% AE 15% and 0% for patients with B

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

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Optic pathway gliomas account for 3-5% of all pediatric CNS tumors and represent the most common intrinsic optic nerve tumors. These tumors occur preferentially during the first decade of life and are particularly frequent in children with neurofibromatosis type 1. Although optic pathway gliomas are low-grade tumors, their behavior can be aggressive, and their management is often challenging. Their management includes observation, surgery, chemotherapy and radiation. The role of each modality is discussed as well as current and future developments in treatment, in particular targeted therapies that are currently being investigated.

BACKGROUND:The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown. METH-ODS: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n 5 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTS: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% 6 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P <.001) and a thalamic location (P <.001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P 5.001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P 5.013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P 5.012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P 5 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P <.001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONS: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. Cancer 2016;122:1261-9.

We have examined three functional polymorphisms, serotonin transporter promoter region polymorphism (5-HTTLPR), dopamine D4 exon III repeat region (DRD4), and catechol-O-methyltransferase (COMT), in a small family-based design toward identifying candidate genes that confer risk for autism. A significant excess of the long/long 5-HTTLPR genotype was observed (likelihood ratio = 7.18; P = 0.027; 2 df; n = 33 families) as well as preferential transmission of the long allele of the 5-HTTLPR (TDT chi-square = 5.44; P<0.025; 1 df). No association was observed between the COMT and DRD4 polymorphisms and autism in this sample. Some previous studies have observed linkage between autism and the 5-HTTLPR polymorphism and the current results are similar to those first reported by Klauck et al. [1997: Hum Genet 100:224-229; 1997: Hum Mol Genet 6:2233-2238]. Additionally, elevated serotonin levels have been consistently found in 30%-50% of autistic patients and may represent a marker for familial autism. Hyperserotonemia in autism appears to be due to enhanced 5-HT uptake, as free 5-HT levels are normal and the current report of an excess of the long/long 5-HTTLPR genotype in autism could provide a partial molecular explanation for high platelet serotonin content in autism.