SUMMARY The Cancer Genome Atlas Network recently catalogued recurrent genomic abnormalities in glioblastoma (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical and Mesenchymal subtypes and integrate multi-dimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define Classical, Mesenchymal, and Proneural, respectively. Gene signatures of normal brain cell types show a strong relation between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype with greatest benefit in Classical and no benefit in Proneural. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

Competing Interests Statement RMS, TAC and LGTM are inventors on a provisional patent application (62/569,053) filed by MSK, relating to the use of TMB in cancer immunotherapy.MDH, NAR and TAC are inventors on a PCT patent application (PCT/US2015/062208) filed by MSK, relating to the use of TMB in lung cancer immunotherapy.MSK and the inventors may receive a share of commercialization revenue from license agreements relating to these patent applications. CHL received research funding from Eisai, BMS, Exelixis, Pfizer, Calithera and consulting fees from Exelixis and Eisai. ANS has received research support from Bristol Myers Squibb, Immunocore, Astra-Zeneca, Xcovery and serves on the advisory board for Bristol Myers Squibb, Immunocore, Castle Biosciences; he also receives royalties from UpToDate. MDH receives research funding from Bristol-Myers Squibb; is paid consultant to Merck

Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.Malignant gliomas are classified and subtyped on the basis of histopathological features and clinical presentation (Fig. 1). The most common and biologically aggressive of these is glioblastoma (GBM), World Health Organization (WHO) grade IV, and is defined by the hallmark features of uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, and rampant genomic instability. As reflected in the old moniker "multiforme," GBM presents with significant intratumoral heterogeneity on the cytopathological, transcriptional, and genomic levels. This complexity, combined with a putative cancer stem cell (CSC) subpopulation and an incomplete atlas of (epi)genetic lesions driving GBM pathogenesis, has conspired to make this cancer one of the most difficult to understand and to treat. Despite implementation of intensive therapeutic strategies and supportive care, the median survival of GBM has remained at 12 mo over the past decade.In this review, we summarize current basic and translational challenges and highlight the striking scientific advances that promise to improve the clinical course of this lethal disease. These advances include a more comprehensive view of the altered genes and pathways in glioma and how such alterations drive the hallmark pathobiological features of the disease, the identification of new molecular subtypes in GBM, an improved understanding of the cellular origins of the disease and how CSCs may influence therapeutic responses, refined model systems for use in research and preclinical experimental therapeutics, and novel therapeutic strategies for targeting keystone genetic lesions and their pathways. For reasons of length, we have not discussed the advances in such important areas as tumor immunology, the blood-brain barrier, and tumor imaging. For the first time, there is a strong sentiment that meaningful therapeutic advances will soon flow from this explosion of new molecular and biological knowledge; the remarkable technological advances in

Glioblastoma multiforme (GBM) comprises several molecular subtypes including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend upon colony stimulating factor (CSF)-1 for differentiation and survival. A CSF-1R inhibitor was used to target TAMs in a mouse proneural GBM model, which dramatically increased survival, and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors including GM-CSF and IFN-γ facilitated TAM survival in the context of CSF-1R inhibition. Alternatively activated/ M2 macrophage markers decreased in surviving TAMs, consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in proneural GBM patients. Our results identify TAMs as a promising therapeutic target for proneural gliomas, and establish the translational potential of CSF-1R inhibition for GBM.