Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which ...interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
B‐lymphoblastic leukemia/lymphoma (B‐ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B‐ALL, ...with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B‐ALL. A cohort of investigational B‐ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B‐ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N‐terminus of the DUX4 protein was performed. N‐DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA‐seq DUX4‐fusion positivity. One N‐DUX4 immunohistochemistry positive case lacked a definitive DUX4‐fusion by RNA‐seq, though demonstrated a gene expression profile characteristic of DUX4‐rearranged B‐ALLs, a CD2+ immunophenotype, and a lack of staining by C‐terminus DUX4 antibody immunohistochemistry. At least 83.3% 5/6 positive predictive value. N‐DUX4 immunohistochemistry was negative in blasts of three RNA‐seq DUX4‐fusion‐negative cases (3/3; 100% negative predictive value). B‐ALLs with mutually exclusive cytogenetic profiles were all N‐DUX4 negative (0/10, specificity 100%). N‐DUX4 immunohistochemistry is reliable for the distinction of DUX4‐rearranged B‐ALLs from other B‐ALLs. We recommend its use for subclassification of B‐ALLs in adolescents and young adults and in B‐ALLs that remain “not otherwise specified.”
High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed ...the genomes of 134 high-grade meningiomas and compared this information with data from 587 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from
. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Meningiomas previously treated with adjuvant radiation had significantly more copy number alterations than radiation-induced or radiation-naïve meningiomas. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas, correlated with subsequent progression to a higher grade. In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor. While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value.
Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas, but the complete spectrum of genetic changes remains ...undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
Abstract Oncolytic herpes simplex virus (oHSV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them, and deliver anticancer agents. However, the host responds to ...oHSV by inducing intratumoral infiltration of macrophages that can engulf the virus, limiting the potential of this therapeutic strategy. Hypervascularity is a pathognomonic feature of glioblastoma (GBM) and is a promising therapeutic target. Antiangiogenic treatments have multiple benefits, including the capacity to increase oHSV efficacy by suppressing macrophage extravasation and infiltration into the tumor. Angiostatin is an antiangiogenic polypeptide, and interleukin-12 (IL-12) is an immunostimulatory cytokine with strong antiangiogenic effects. Clinical use of each has been limited by delivery issues and systemic toxicity.We tested a combination treatment strategy using oHSVs expressing angiostatin (G47Δ-mAngio) and IL-12 (G47Δ-mIL12) in two orthotopic human GBMmodels. Intratumoral injection of G47Δ-mAngio and G47Δ-mIL12 in mice bearing intracranial U87 or tumors derived from glioblastoma stem cells significantly prolonged survival compared to each armed oHSV alone. This was associated with increased antiangiogenesis and virus spread and decreased macrophages. These data support the paradigm of using oHSV expressing different antiangiogenic agents and show for the first time that oHSVs expressing angiostatin and IL-12 can improve efficacy in human GBM models.
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. ...Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
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•Human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression•TAZ/YAP hyperactivity in Schwann cells potently induces high-grade nerve tumors•Lats1/2 dysregulation activates oncogenic programs, including PDGFR signaling•Co-targeting TAZ/YAP and PDGFR pathways inhibits MPNST tumor growth
Wu et al. find that HIPPO-TAZ/YAP expression is elevated in malignant peripheral nerve sheath tumors (MPNST). Lats1/2 deficiency in Schwann cells induces hyperactivation of TAZ/YAP and increased PDGFR signaling, leading to the development of MPNST in mice. Inhibition of TAZ/YAP and PDGFR reduces MPNST growth.
Schwannomatosis is the third major form of neurofibromatosis and is characterized by the development of multiple schwannomas in the absence of bilateral vestibular schwannomas. The 2011 ...Schwannomatosis Update was organized by the Children's Tumor Foundation (www.ctf.org) and held in Los Angeles, CA, from June 5-8, 2011. This article summarizes the highlights presented at the Conference and represents the "state-of-the-field" in 2011. Genetic studies indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40-50% of familial cases and in 8-10% of sporadic cases of schwannomatosis. Tumorigenesis is thought to occur through a four-hit, three-step model, beginning with a germline mutation in SMARCB1 (hit 1), followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3), followed by mutation of the remaining wild-type NF2 allele (hit 4). Insights from research on HIV and pediatric rhabdoid tumors have shed light on potential molecular pathways that are dysregulated in schwannomatosis-related schwannomas. Mouse models of schwannomatosis have been developed and promise to further expand our understanding of tumorigenesis and the tumor microenvironment. Clinical reports have described the occurrence of intracranial meningiomas in schwannomatosis patients and in families with germline SMARCB1 mutations. The authors propose updated diagnostic criteria to incorporate new clinical and genetic findings since 2005. In the next 5 years, the authors expect that advances in basic research in the pathogenesis of schwannomatosis will lead toward clinical investigations of potential drug therapies.
Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks ...tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs.
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•Elimination of mitotic Olig2+ cells inhibits glioma initiation and progression•Olig2 loss reduces glioma growth and causes proneural-to-astrocytic phenotype shift•Olig2 deletion causes PDGFR downregulation and reciprocal EGFR upregulation•Inactivation of Olig2 potentiates sensitization of glioma cells to EGFR inhibition
Lu et al. show that ablation of dividing Olig2-expressing cells in a glioma model reduces tumor initiation and growth. Olig2 deletion in glioma also delays growth, changes the gene expression profile from proneural to astrocyte-associated classical phenotype, and leads to increased EGFR expression and sensitivity to EGFR inhibitors.
OBJECTIVE Patients with atypical and malignant (WHO Grade II and III) meningiomas have a worse prognosis than patients with benign (WHO Grade I) meningiomas. However, there is limited understanding ...of the pathological risk factors that affect long-term tumor control following combined treatment with surgery and radiation therapy. Here, the authors identify clinical and histopathological risk factors for the progression and/or recurrence (P/R) of high-grade meningiomas based on the largest series of patients with atypical and malignant meningiomas, as defined by the 2007 WHO classification. METHODS Patients diagnosed with WHO Grade II and III meningiomas between 2007 and 2014 per the WHO 2007 criteria and treated with both surgery and external beam radiation therapy were retrospectively reviewed for clinical and histopathological factors at the time of diagnosis and assessed for P/R outcomes at the last available follow-up. RESULTS A total of 76 patients met the inclusion criteria (66 Grade II meningiomas, 10 Grade III meningiomas). Median follow-up from the time of pathological diagnosis was 52.6 months. Three factors were found to predict P/R: Grade III histology, brain and/or bone invasion, and a Ki-67 proliferation rate at or above 3%. The crude P/R rate was 80% for patients with Grade III histology, 40% for those with brain and/or bone involvement (regardless of WHO tumor grade), and 20% for those with a proliferative index ≥ 3% (regardless of WHO tumor grade). The median proliferation index was significantly different between patients in whom treatment failed and those in whom it did not fail (11% and 1%, respectively). CONCLUSIONS In patients with atypical or malignant meningiomas, the presence of Grade III histology, brain and/or bone involvement, and a high mitotic index significantly predicted an increased risk of treatment failure despite combination therapy. These patients can be stratified into risk groups predicting P/R. Patients with high-risk features may benefit from more treatment and counseling than is typically offered currently.
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