Publications by authors named "Melike Pekmezci"

100 Publications

Histopathologic findings in malignant peripheral nerve sheath tumor predict response to radiotherapy and overall survival.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa131. Epub 2020 Oct 1.

Department of Radiation Oncology, University of California, San Francisco, California, USA.

Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown.

Methods: We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018.

Results: Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) ( = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate ( = .004) in response to radiation.

Conclusions: Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.
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http://dx.doi.org/10.1093/noajnl/vdaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044670PMC
October 2020

Loss of fidelity in scanned digital images compared to glass slides of brain tumors resected using cavitron ultrasonic surgical aspirator.

Brain Pathol 2021 Feb 11:e12938. Epub 2021 Feb 11.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Conversion of glass slides to digital images is necessary to capitalize on advances in computational pathology and could potentially transform our approach to primary diagnosis, research, and medical education. Most slide scanners have a limited maximum scannable area and utilize proprietary tissue detection algorithms to selectively scan regions that contain tissue, allowing for increased scanning speed and reduced file size compared to scanning the entire slide at high resolution. However, very small and faintly stained tissue fragments may not be recognized by these algorithms, leading to loss of fidelity in the digital image compared to the glass slides. Cavitron ultrasonic surgical aspirator (CUSA) is frequently used in brain tumor resections, resulting in highly fragmented specimens that are used for primary diagnosis. Here we evaluated the rate of loss of fidelity in 296 digital images from 40 CUSA-resected brain tumors scanned using a Philips Ultra Fast Scanner. Overall, 54% of the slides (at least one from every case) showed loss of fidelity, with at least one tissue fragment not scanned at high resolution. The majority of the missed tissue fragments were small (<0.5 mm), but rare slides were missing fragments greater than 5 mm in greatest dimension. In addition, 19% of the slides with missing tissue showed no indication of loss of fidelity in the digital image itself; the missing tissue could only be appreciated upon review of the glass slides. These results highlight a potential liability in the use of digital images for primary diagnosis in CUSA-resected brain tumor specimens.
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http://dx.doi.org/10.1111/bpa.12938DOI Listing
February 2021

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa142. Epub 2020 Oct 22.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.

Methods: Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.

Results: Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus ( = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the gene and an absence of mutations in , which are present in approximately one-third of pediatric DMGs. Accompanying mutations in , , , , and were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.

Conclusions: Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.
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http://dx.doi.org/10.1093/noajnl/vdaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739048PMC
October 2020

Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1.

Acta Neuropathol 2021 02 14;141(2):281-290. Epub 2020 Dec 14.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
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http://dx.doi.org/10.1007/s00401-020-02247-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847462PMC
February 2021

Preferentially Expressed Antigen in Melanoma (PRAME) Expression in Malignant, but Not Benign, Peripheral Nerve Sheath Tumors.

J Neuropathol Exp Neurol 2021 Mar;80(4):384-386

Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, California.

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http://dx.doi.org/10.1093/jnen/nlaa125DOI Listing
March 2021

Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Brain Pathol 2020 Nov 3:e12918. Epub 2020 Nov 3.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.
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http://dx.doi.org/10.1111/bpa.12918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089120PMC
November 2020

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.

Acta Neuropathol Commun 2020 10 28;8(1):173. Epub 2020 Oct 28.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, USA.

Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case-control data from three studies: a population-based pediatric and adolescent ependymoma case-control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case-control study from Toronto's Hospital for Sick Children and the Children's Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case-control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case-control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12-19 (P = 4.0 × 10), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (OR = 1.67; 95% CI 1.18-2.37; P = 3.97 × 10) and adult-onset ependymoma (P = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94-1.34; P = 0.21), nor with EPN-PF-A (P = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.
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http://dx.doi.org/10.1186/s40478-020-01038-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592366PMC
October 2020

Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma.

Nat Commun 2020 09 23;11(1):4803. Epub 2020 Sep 23.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.
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http://dx.doi.org/10.1038/s41467-020-18582-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511976PMC
September 2020

The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma.

Acta Neuropathol 2020 12 6;140(6):907-917. Epub 2020 Sep 6.

Division of Neuropathology, Department of Pathology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.
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http://dx.doi.org/10.1007/s00401-020-02221-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682537PMC
December 2020

A Prognostic Gene-Expression Signature and Risk Score for Meningioma Recurrence After Resection.

Neurosurgery 2020 12;88(1):202-210

Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

Background: Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.

Objective: To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.

Methods: Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.

Results: We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis.

Conclusion: The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence.
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http://dx.doi.org/10.1093/neuros/nyaa355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735867PMC
December 2020

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta Neuropathol Commun 2020 08 28;8(1):151. Epub 2020 Aug 28.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
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http://dx.doi.org/10.1186/s40478-020-01027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456392PMC
August 2020

Histologic Changes Following Continuous Wave and Micropulse Transscleral Cyclophotocoagulation: A Randomized Comparative Study.

Transl Vis Sci Technol 2020 04 28;9(5):22. Epub 2020 Apr 28.

Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.

Purpose: To compare the macroscopic and microscopic histologic changes in eyes treated with micropulse transscleral cyclophotocoagulation (MP-TCP) versus continuous wave transscleral cyclophotocoagulation (CW-TCP).

Methods: Twelve halves of globes from three pairs of adult cadaveric eyes were randomly assigned to nontreated control, CW-TCP, single MP-TCP treatment, or double MP-TCP treatments, and then sectioned for histologic analysis. Presence or absence of the following four unique histologic changes was recorded: splitting within the ciliary process epithelium (splitting), separation of the pigmented ciliary process epithelium from the stroma (separation), coagulation of collagen and destruction of ciliary process stroma (coagulation), and full-thickness destruction of ciliary process epithelium (destruction).

Results: A total of 498 slides were analyzed, and laser scars in all treated specimens were located in the pars plana. Logistic regression analysis showed that compared with controls, CW-TCP-treated specimens were significantly more likely to experience separation (odds ratio [OR] = 11.1, = 0.02), coagulation (OR = 24.3, = 0.002), and destruction (OR = 11.1, = 0.03). Destruction of the ciliary process epithelium was observed exclusively in CW-TCP-treated sections. No significant differences in histologic features were observed between controls and MP-TCP.

Conclusions: MP-TCP does not produce significant histologic changes in cadaveric eyes, whereas CW-TCP treatment does.

Translational Relevance: These findings improve understanding of the mechanism of MP-TCP, help explain the increased rates of adverse effects following CW-TCP treatment compared with MP-TCP, and describe effects of MP-TCP at various doses.
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http://dx.doi.org/10.1167/tvst.9.5.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401863PMC
April 2020

Pediatric meningioma: a clinicopathologic and molecular study with potential grading implications.

Brain Pathol 2020 11 6;30(6):1134-1143. Epub 2020 Aug 6.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

Meningiomas are common in adults (~35% of brain tumors) but rare in children, where they exhibit unique clinical, pathological and molecular features compared to adult counterparts. Thus, data generated from adult cohorts may be imperfectly suited to guiding diagnostic, prognostic and treatment decisions for children. We studied 50 meningioma patients ≤18 years with available clinical and pathological data to address the need for data obtained in the pediatric setting. As previously described, we noted a slight bias toward male patients and a higher proportion of spinal tumors compared to adults. Thirty-eight of 50 specimens were further analyzed by next generation sequencing. Loss-of-function mutations in NF2 and chromosome 22 losses were common, but pathogenic variants in other genes (SMARCB1, FUBP1, BRAF, TERT promoter, CHEK2, SMAD and GATA3) were identified in a minority of cases. Copy number variants outside of chromosomes 22 and 1 were infrequent. H3K27 hypomethylation, a useful biomarker in adult tumors, was not found in our cohort. In exploring the correlation between mitotic count and recurrence-free survival, we found a threshold of six mitoses per 10 high powered fields as the optimal cutoff in predicting recurrence-free survival. If independently validated in larger studies, adjusted grading thresholds could enhance the clinical management of pediatric meningiomas.
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http://dx.doi.org/10.1111/bpa.12884DOI Listing
November 2020

The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies.

Cancer Discov 2020 Nov 23;10(11):1722-1741. Epub 2020 Jul 23.

Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, California.

Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior efficacy to treatment based upon the genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth . Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies. SIGNIFICANCE: Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0160DOI Listing
November 2020

Meningioma cells express primary cilia but do not transduce ciliary Hedgehog signals.

Acta Neuropathol Commun 2020 07 20;8(1):114. Epub 2020 Jul 20.

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.

Meningiomas are the most common primary intracranial tumors, but treatment options for meningioma patients are limited due to incomplete understanding of tumor biology. A small percentage of meningiomas harbor somatic variants in the Hedgehog pathway, a conserved gene expression program that is essential for development and adult stem cell homeostasis. Hedgehog signals are transduced through primary cilia, and misactivation of the Hedgehog pathway is known to underlie cancer. Nevertheless, the mechanisms of Hedgehog signaling in meningioma are unknown. Here, we investigate mechanisms of ciliary Hedgehog signaling in meningioma using tissue microarrays containing 154 human meningioma samples, NanoString transcriptional profiling, primary meningioma cells, pharmacology, and CRISPR interference. Our results reveal that meningiomas of all grades can express primary cilia, but that cilia are less prevalent among anaplastic tumors. Moreover, we find that expression of Smoothened alleles that are oncogenic in other contexts fail to activate the Hedgehog transcriptional program or promote proliferation in primary meningioma cells. These data reveal that meningiomas can express the subcellular structure necessary for canonical Hedgehog signaling, but suggest that they do not transduce ciliary Hedgehog signals.
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http://dx.doi.org/10.1186/s40478-020-00994-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370519PMC
July 2020

Whole exome sequencing reveals the maintained polyclonal nature from primary to metastatic malignant peripheral nerve sheath tumor in two patients with NF1.

Neurooncol Adv 2020 Jul 10;2(Suppl 1):i75-i84. Epub 2019 Sep 10.

Division of Medical Oncology, Department of Medicine Washington University School of Medicine, St. Louis, Missouri.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with high metastatic rates and poor overall patient survival. There are currently no effective therapies, underscoring the pressing need to define the molecular etiologies that underlie MPNST progression. The aim of this study was to examine clonal progression and identify the molecular events critical for MPNST spread.

Methods: In two patients with temporally and spatially distinct metastatic lesions, we employed whole exome sequencing (WES) to elucidate the genetic events of clonal progression, thus identifying the molecular events critical for MPNST spread.

Results: First, we demonstrated shared clonal origins for the metastatic lesions relative to the primary tumors, which were maintained throughout the course of MPNST progression, supporting the conclusion that cancer cells with metastatic potential already exist in the primary neoplasm. Second, we discovered TRIM23, a member of the Tripartite Motif family of proteins, as a regulator of MPNST lung metastatic spread in vivo.

Conclusions: The ability to track the genomic evolution from primary to metastatic MPNST offers new insights into the sequence of genetic events required for tumor progression and has identified TRIM23 as a novel target for future study in this rare cancer.
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http://dx.doi.org/10.1093/noajnl/vdz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317063PMC
July 2020

Pathology of meningiomas.

Handb Clin Neurol 2020 ;169:87-99

Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, CA, United States.

Meningiomas are a diverse group of neoplasms that exhibit a wide range of morphologies and clinical behavior. They are generally accepted to originate from arachnoid cap cells within the leptomeninges. Classic histologic features include whorl formations, psammoma bodies, nuclear holes, and nuclear pseudoinclusions. Meningiomas are classified as benign, atypical, or anaplastic (grades I, II, or III) based on histologic features including mitotic activity, brain invasion, and presence of other minor criteria. There are numerous histologic variants of meningiomas, and some are associated with worse clinical outcomes and therefore are assigned a higher grade. The majority of meningiomas show diffuse positivity for vimentin and epithelial membrane antigen, supporting the dual mesenchymal and epithelial nature of meningothelial cells. The presence of an elevated proliferation index (as measured by Ki-67 immunohistochemical stain) and loss of progesterone receptor expression are associated with the higher grade. Pathologic features including histologic variants, grading criteria, and ancillary tests such as special and immunohistochemical stains are discussed.
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http://dx.doi.org/10.1016/B978-0-12-804280-9.00005-6DOI Listing
April 2021

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.

Neuro Oncol 2020 11;22(11):1602-1613

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype.

Methods: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8.

Results: Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10).

Conclusions: Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.
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http://dx.doi.org/10.1093/neuonc/noaa117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690366PMC
November 2020

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Acta Neuropathol 2020 06 17;139(6):1071-1088. Epub 2020 Apr 17.

Division of Hematology/Oncology, Department of Pediatrics, Nicklaus Children's Hospital, Miami, FL, USA.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
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http://dx.doi.org/10.1007/s00401-020-02155-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792550PMC
June 2020

Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features.

Ophthalmology 2020 06 12;127(6):804-813. Epub 2019 Dec 12.

Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Purpose: To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.

Design: Cohort study.

Participants: Thirty-two children with retinoblastoma.

Methods: We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.

Main Outcome Measures: Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.

Results: Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.

Conclusions: Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246167PMC
June 2020

Loss of H3K27 trimethylation by immunohistochemistry is frequent in oligodendroglioma, IDH-mutant and 1p/19q-codeleted, but is neither a sensitive nor a specific marker.

Acta Neuropathol 2020 03 7;139(3):597-600. Epub 2020 Jan 7.

Department of Pathology, University of California, San Francisco (UCSF), 505 Parnassus Ave, Room M551, San Francisco, CA, 94143, USA.

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http://dx.doi.org/10.1007/s00401-019-02123-8DOI Listing
March 2020

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors.

Brain Pathol 2020 03 29;30(2):213-225. Epub 2019 Dec 29.

Department of Pathology, University of California, San Francisco, CA.

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6-25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma-like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1-WT1 fusion provides a definitive diagnosis of DSRCT. Genome-wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.
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http://dx.doi.org/10.1111/bpa.12809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780368PMC
March 2020

Intracapsular High-Grade Ductal Carcinoma In-Situ Ex Pleomorphic Adenoma of the Lacrimal Gland.

Ophthalmic Plast Reconstr Surg 2020 Jan/Feb;36(1):e1-e3

Department of Ophthalmology, University of California, San Francisco.

Primary ductal adenocarcinoma of the lacrimal gland is an aggressive neoplasm and can be seen either as a de novo malignancy or in the setting of a carcinoma ex pleomorphic adenoma. Carcinoma ex pleomorphic adenoma carries an overall unfavorable outcome; however, prognosis depends on the type and grade of the malignant component, presence of retained myoepithelial component, and extend of invasion beyond the capsule. Herein, the authors describe a 78-year-old man diagnosed with an incidental, intracapsular, high-grade ductal adenocarcinoma in situ ex pleomorphic adenoma, who is free of disease at 9 months subsequent to complete resection. It is important to recognize the morphologic features of intraductal and intracapsular neoplasms to prevent unnecessary morbidities due to extensive surgical interventions or radiotherapy.Morphologic features of intracapsular ductal carcinoma in situ ex pleomorphic adenoma, which shows better clinical outcomes with complete excision than its invasive counterpart.
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http://dx.doi.org/10.1097/IOP.0000000000001491DOI Listing
March 2021

Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features.

Brain Pathol 2020 05 6;30(3):479-494. Epub 2019 Nov 6.

Department of Pathology, University of California, San Francisco, CA.

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
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http://dx.doi.org/10.1111/bpa.12797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780370PMC
May 2020

Integrated models incorporating radiologic and radiomic features predict meningioma grade, local failure, and overall survival.

Neurooncol Adv 2019 May-Dec;1(1):vdz011. Epub 2019 Aug 28.

Department of Radiation Oncology, University of California San Francisco, California.

Background: We investigated prognostic models based on clinical, radiologic, and radiomic feature to preoperatively identify meningiomas at risk for poor outcomes.

Methods: Retrospective review was performed for 303 patients who underwent resection of 314 meningiomas (57% World Health Organization grade I, 35% grade II, and 8% grade III) at two independent institutions, which comprised primary and external datasets. For each patient in the primary dataset, 16 radiologic and 172 radiomic features were extracted from preoperative magnetic resonance images, and prognostic features for grade, local failure (LF) or overall survival (OS) were identified using the Kaplan-Meier method, log-rank tests and recursive partitioning analysis. Regressions and random forests were used to generate and test prognostic models, which were validated using the external dataset.

Results: Multivariate analysis revealed that apparent diffusion coefficient hypointensity (HR 5.56, 95% CI 2.01-16.7, = .002) was associated with high grade meningioma, and low sphericity was associated both with increased LF (HR 2.0, 95% CI 1.1-3.5, = .02) and worse OS (HR 2.94, 95% CI 1.47-5.56, = .002). Both radiologic and radiomic predictors of adverse meningioma outcomes were significantly associated with molecular markers of aggressive meningioma biology, such as somatic mutation burden, DNA methylation status, and expression. Integrated prognostic models combining clinical, radiologic, and radiomic features demonstrated improved accuracy for meningioma grade, LF, and OS (area under the curve 0.78, 0.75, and 0.78, respectively) compared to models based on clinical features alone.

Conclusions: Preoperative radiologic and radiomic features such as apparent diffusion coefficient and sphericity can predict tumor grade, LF, and OS in patients with meningioma.
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http://dx.doi.org/10.1093/noajnl/vdz011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777505PMC
August 2019

Telomere alterations in neurofibromatosis type 1-associated solid tumors.

Acta Neuropathol Commun 2019 08 28;7(1):139. Epub 2019 Aug 28.

Departments of Pathology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD, 21231, USA.

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p < 0.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p = 0.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT.
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http://dx.doi.org/10.1186/s40478-019-0792-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712691PMC
August 2019

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis.

Brain Pathol 2020 01 10;30(1):46-62. Epub 2019 Jun 10.

Department of Pathology, University of California, San Francisco, CA.

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.
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http://dx.doi.org/10.1111/bpa.12747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859193PMC
January 2020