David H Gutmann

Ludwig Institute for Cancer Research, La Jolla, California, United States

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Publications (412)2406.86 Total impact

  • The Lancet Neurology 01/2015; 14(1):30-31. · 23.92 Impact Factor
  • David H Gutmann
    Neuro-oncology. 12/2014;
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    ABSTRACT: One of the potential etiologies for non-familial Neurofibromatosis Type 1 (NF1) is increasing parental age. We sought to evaluate recent evidence for parental age effects in NF1 in a large study. Individuals with NF1 and a comparison group from the U.S. general population born between 1994 and 2012 were ascertained from the NF1 Patient Registry Initiative (NPRI) and the National Center for Vital Statistics, respectively. Multiple linear regression analysis was employed to identify differences between familial NF1, non-familial NF1, and U.S. population subjects in the mean parental ages at the time of the birth of offspring in each group. In addition, we also evaluated the effect of parental age on NF1 offspring with and without a pediatric brain tumor history. A total of 313 subjects from the NPRI (including 99 brain tumor cases) matched by birth year at a 1:3 ratio to U.S. general population births (n = 939) were included. Compared to the U.S. general population and familial NF1 cases, the mean paternal age for non-familial NF1 cases was 4.34 years (95 % CI 3.23-5.46, p ≤ 0.0001) and 3.39 years (95 % CI 1.57-5.20, p ≤ 0.0001) older, respectively, after adjusting for birth year. A similar pattern was observed for maternal age. There were no statistically significant differences in the mean maternal or paternal ages between NF1 offspring with and without a pediatric brain tumor. In conclusion, these data support a parental age effect for non-familial NF1 cases, but not for pediatric brain tumors in NF1.
    Familial Cancer 12/2014; · 1.94 Impact Factor
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    ABSTRACT: Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues" chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collaborations directed towards the best practices and therapies for individuals with RASopathies. © 2014 Wiley Periodicals, Inc.
    American journal of medical genetics. Part A. 11/2014;
  • David H Gutmann
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    ABSTRACT: Plexiform neurofibromas are one of the most common tumors encountered in individuals with the neurofibromatosis type I (NF1) cancer predisposition syndrome. In this issue of Cancer Cell, Chen and colleagues define the cell of origin for murine Nf1 plexiform neurofibroma and leverage this finding to develop a platform for preclinical drug evaluation. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cancer cell. 11/2014; 26(5):596-599.
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    ABSTRACT: Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.
    Cancer research. 11/2014;
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    ABSTRACT: Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway.
    Neuro-oncology. 10/2014;
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    ABSTRACT: Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology.
    Neuro-oncology. 09/2014;
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    ABSTRACT: Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (P<0.001 for each). Expression of p75NTR was observed in 80% of malignant peripheral nerve sheath tumors compared with 31% of cellular schwannomas (P<0.001). Fourth, Ki-67 labeling indices ≥20% were highly predictive of malignant peripheral nerve sheath tumor (87% sensitivity and 96% specificity). Taken together, the combinations of these histopathological and immunohistochemical features provide useful criteria to distinguish between malignant peripheral nerve sheath tumor and cellular schwannoma with high sensitivity and specificity. Additional retrospective and prospective multicenter studies with larger data sets will be required to validate these findings.Modern Pathology advance online publication, 5 September 2014; doi:10.1038/modpathol.2014.109.
    Modern Pathology 09/2014; · 5.25 Impact Factor
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    American Journal of Medical Genetics Part A 09/2014; · 2.30 Impact Factor
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    ABSTRACT: Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures [fluorescence-activated cell sorting (FACS)] or from postnatal glial cultures by mechanic isolation. Given the highly dynamic and state-dependent functions of these cells, the use of FACS or short-term culture methods may not accurately capture the biology of brain microglia. In the current study, we performed RNA-sequencing using Cx3cr1+/GFP labeled microglia isolated from the brainstem of 6-week-old mice to compare the transcriptomes of FACS-sorted versus laser capture microdissection (LCM). While both isolation techniques resulted in a large number of shared (common) transcripts, we identified transcripts unique to FACS-isolated and LCM-captured microglia. In particular, ∼50% of these LCM-isolated microglial transcripts represented genes typically associated with neurons and glia. While these transcripts clearly localized to microglia using complementary methods, they were not translated into protein. Following the induction of murine experimental autoimmune encephalomyelitis, increased oligodendrocyte and neuronal transcripts were detected in microglia, while only the myelin basic protein oligodendrocyte transcript was increased in microglia after traumatic brain injury. Collectively, these findings have implications for the design and interpretation of microglia transcriptome-based investigations. GLIA 2014
    Glia 09/2014; · 5.07 Impact Factor
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    ABSTRACT: Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has become an attractive target for human cancer therapy. Hyperactivation of mTOR has been reported in both sporadic and syndromic (hereditary) brain tumors. In contrast to the large number of successful clinical trials employing mTOR inhibitors in different types of epithelial neoplasms, their use to treat intracranial neoplasms is more limited. In this review, we summarize the role of mTOR activation in brain tumor pathogenesis and growth relevant to new human brain tumor trials currently under way using mTOR inhibitors.
    Neuro-oncology. 08/2014;
  • Katherine E Schwetye, David H Gutmann
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    ABSTRACT: Cognitive and behavioral disorders affect nearly 80% of all children with the neurofibromatosis type 1 inherited cancer syndrome, and are among the most significant clinical manifestations for patients and their families. One of the barriers to successful therapeutic intervention is the wide spectrum of clinical phenotypic expression, ranging from visuospatial learning problems to social perceptual deficits (autism). Leveraging numerous small-animal models of neurofibromatosis type 1, several promising targets have been identified to treat the learning, attention, and autism spectrum phenotypes in this at-risk population. In this review, we provide an up-to-date summary of our current understanding of these disorders in NF1, and propose future research directions aimed at designing more effective therapeutic approaches and clinical trials.
    Expert Review of Neurotherapeutics 08/2014; · 2.96 Impact Factor
  • Angela C Hirbe, David H Gutmann
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    ABSTRACT: Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to different medical and surgical specialists and, therefore, the association of clinical symptoms with neurofibromatosis type 1 might not be appreciated. Thus, for prompt diagnosis and to provide optimum care for patients with neurofibromatosis type 1, clinicians must be aware of the diverse clinical features of this disorder. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient. As our understanding of this disorder deepens through basic laboratory and clinical investigations, swift implementation of new effective treatments becomes feasible.
    The Lancet Neurology 08/2014; 13(8):834–843. · 23.92 Impact Factor
  • Corina Anastasaki, David H Gutmann
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder in which affected individuals are prone to learning, attention, and behavioral problems. Previous studies in mice and flies have yielded conflicting results regarding the specific effector pathways responsible for NF1 protein (neurofibromin) regulation of neuronal function, with both cyclic AMP (cAMP)- and RAS-dependent mechanisms described. Herein, we leverage a combination of induced pluripotent stem cell (iPSC)-derived NF1-patient neural progenitor cells (NPCs) and Nf1 genetically-engineered mice to establish, for the first time, that neurofibromin regulation of cAMP requires RAS activation in human and mouse neurons. However, instead of involving RAS-mediated MEK/AKT signaling, RAS regulation of cAMP homeostasis operates through the activation of atypical Protein Kinase C (PKCζ), leading to GRK2-driven Gs inactivation. These findings reveal a novel mechanism by which RAS can regulate cAMP levels in the mammalian brain.
    Human Molecular Genetics 07/2014; · 7.69 Impact Factor
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    ABSTRACT: Glioblastoma (GBM) frequently displays amplification and/or mutation of the epidermal growth factor receptor (EGFR) gene. Highlighting the importance of EGFR in the pathogenesis of GBM, aberrant EGFR (ΔEGFR, also known as EGFRvIII) confers a variety of biological effects upon its expression, including resistance to radiation and chemotherapeutic agents, promotion of tumor cell motility and invasion, enhancement of tumorigenicity in vivo, and maintenance of GBM growth and heterogeneity. We hypothesized that this diverse oncogenic pathophysiology exerted by ΔEGFR is regulated, in part, through the modulation of microRNA (miR) activity, widely shown to be involved in many biological processes including cancer initiation, maintenance and progression.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii14-iii15. · 6.18 Impact Factor
  • David H Gutmann
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    ABSTRACT: With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders.
    Neurology 06/2014; · 8.30 Impact Factor
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    ABSTRACT: Purpose:Neurofibromatosis type 1 has been linked to several neurological conditions, including epilepsy, Parkinson disease, headache, multiple sclerosis, and sleep disturbances, predominantly through case reports and patient series that lack comparison groups. Our objective was to assess whether specific neurological conditions occur more frequently in individuals with neurofibromatosis type 1 versus those without neurofibromatosis type 1.Methods:We used the 2006-2010 MarketScan Commercial Claims and Encounters database to examine associations between neurological conditions and neurofibromatosis type 1. The neurofibromatosis type 1 group was identified through ≥2 International Classification of Diseases, Ninth Revision, Clinical Modification neurofibromatosis codes (237.70, 237.71) occurring ≥30 days apart or one inpatient neurofibromatosis code. A nonneurofibromatosis type 1 comparison group was frequency matched to the neurofibromatosis type 1 group on age and enrollment length at a 10:1 ratio. Unconditional logistic regression was employed to calculate adjusted odds ratios and 95% confidence intervals for associations between neurofibromatosis and neurological conditions.Results:Compared with the nonneurofibromatosis type 1 group (n = 85,790), the neurofibromatosis type 1 group (n = 8,579) had significantly higher odds of health insurance claims for epilepsy (odds ratio: 7.3; 95% confidence interval: 6.4-8.3), Parkinson disease (odds ratio: 3.1; 95% confidence interval: 1.3-7.5), headache (odds ratio: 2.9; 95% confidence interval: 2.6-3.1), multiple sclerosis (odds ratio: 1.9; 95% confidence interval: 1.2-2.9), and sleep disturbances/disorder (odds ratio: 1.4; 95% confidence interval: 1.2-3.6).Conclusion:This large study provides strong evidence for positive associations between several neurological conditions and neurofibromatosis type 1.Genet Med advance online publication 05 June 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.70.
    Genetics in medicine: official journal of the American College of Medical Genetics 06/2014; · 3.92 Impact Factor
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    ABSTRACT: Background Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamcyin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity.ProcedureWe conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry.ResultsNo subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus.Conclusions This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes. Pediatr Blood Cancer 2014;61:982–986. © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 06/2014; 61(6). · 2.35 Impact Factor
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    ABSTRACT: The use of massively parallel sequencing for studying RNA expression has greatly enhanced our understanding of the transcriptome through the myriad ways these data can be characterized. In particular, clinical samples provide important insights about RNA expression in health and disease, yet these studies can be complicated by RNA degradation that results from the use of formalin as a clinical preservative and by the limited amounts of RNA often available from these precious samples. In this study we describe the combined use of RNA sequencing with an exome capture selection step to enhance the yield of on-exon sequencing read data when compared with RNA sequencing alone. In particular, the exome capture step preserves the dynamic range of expression, permitting differential comparisons and validation of expressed mutations from limited and FFPE preserved samples, while reducing the data generation requirement. We conclude that cDNA hybrid capture has the potential to significantly improve transcriptome analysis from low-yield FFPE material.
    The Journal of molecular diagnostics: JMD 05/2014; · 3.48 Impact Factor

Publication Stats

13k Citations
2,406.86 Total Impact Points

Institutions

  • 2014
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2006–2014
    • Otto-von-Guericke-Universität Magdeburg
      • Institute for Neuropathology
      Magdeburg, Saxony-Anhalt, Germany
    • Duke University Medical Center
      • Department of Pharmacology and Cancer Biology
      Durham, NC, United States
  • 1995–2014
    • Washington University in St. Louis
      • • Department of Neurology
      • • Department of Pathology and Immunology
      • • Department of Pediatrics
      San Luis, Missouri, United States
  • 2013
    • Guy's and St Thomas' NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1994–2013
    • University of Washington Seattle
      • • Department of Neurology
      • • Division of General Internal Medicine
      • • Department of Pathology
      Seattle, WA, United States
  • 2012
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
    • The Children's Hospital of Philadelphia
      • Division of Oncology
      Philadelphia, PA, United States
  • 1991–2011
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of Pennsylvania
      • Department of Neurology
      Philadelphia, PA, United States
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 2009
    • University of California, Davis
      • Department of Surgical and Radiological Sciences (VM)
      Davis, CA, United States
  • 1996–2009
    • University of Toronto
      • • Hospital for Sick Children
      • • Division of Neurology
      • • Division of Neurosurgery
      Toronto, Ontario, Canada
    • Universitair Medisch Centrum Groningen
      Groningen, Groningen, Netherlands
  • 2007–2008
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
    • St. Jude Children's Research Hospital
      • Department of Developmental Neurobiology
      Memphis, TN, United States
  • 1997–2008
    • National Cancer Institute (USA)
      • • Mouse Cancer Genetics Program
      • • Laboratory of Cellular Oncology
      Maryland, United States
  • 2004–2007
    • Oregon Health and Science University
      Portland, Oregon, United States
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 2001–2007
    • Emory University
      • • Department of Pathology and Laboratory Medicine
      • • Department of Dermatology
      Atlanta, GA, United States
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 1997–2007
    • Children's Memorial Hospital
      Chicago, Illinois, United States
  • 2000–2006
    • SickKids
      • Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC)
      Toronto, Ontario, Canada
    • National Institutes of Health
      • Branch of Genetic Epidemiology
      Bethesda, MD, United States
  • 2003
    • Mount Sinai Hospital
      New York City, New York, United States
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States
  • 2002
    • King's College London
      Londinium, England, United Kingdom
  • 1998–2001
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1989–1997
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Philadelphia, Pennsylvania, United States
  • 1992–1994
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States