Temporal, spatial, and genetic constraints contribute to the patterning and penetrance of murine neurofibromatosis-1 optic glioma

Abstract Background Brain tumors are the most common solid tumors of childhood, but little is understood about the factors that influence their development. Pediatric low-grade gliomas in particular display unique temporal and spatial localization associated with different genetic mutations (eg, BRAF genomic alterations, mutations in the neurofibromatosis type 1 [NF1] gene) for reasons that remain unclear. NF1 low-grade gliomas typically arise in the optic pathway of young children as optic pathway gliomas (OPGs), likely from a cell of origin that resides within the third ventricular zone (TVZ). However, the factors that contribute to their distinct temporal patterning and penetrance have not been adequately explored. Methods TVZ neuroglial progenitor cells (NPCs) were analyzed over the course of mouse brain development. Progenitors isolated by fluorescence-activated cell sorting (FACS) were assessed for functional and molecular differences. The impact of different germline Nf1 mutations on TVZ NPC properties was analyzed using genetically engineered mice. Results We identify 3 individual factors that could each contribute to Nf1 optic glioma temporal patterning and penetrance. First, there are 3 functionally and molecularly distinct populations of mouse TVZ NPCs, one of which (“M” cells) exhibits the highest clonogenic incidence, proliferation, and abundance during embryogenesis. Second, TVZ NPC proliferation dramatically decreases after birth. Third, germline Nf1 mutations differentially increase TVZ NPC proliferation during embryogenesis. Conclusions The unique temporal patterning and penetrance of Nf1 optic glioma reflects the combined effects of TVZ NPC population composition, time-dependent changes in progenitor proliferation, and the differential impact of the germline Nf1 mutation on TVZ NPC expansion.

Download Full-text

PDTM-07. DEFINING THE MECHANISMS UNDERLYING NF1 OPTIC GLIOMA PENETRANCE

Neuro-Oncology ◽

10.1093/neuonc/noz175.783 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi188-vi188

Author(s):

Nicole Brossier ◽

Olivia Cobb ◽

David Gutmann

Keyword(s):

Ventricular Zone ◽

Gene Mutations ◽

Cell Populations ◽

Optic Glioma ◽

Low Grade ◽

Optic Pathway ◽

Cell Of Origin ◽

Cells Of Origin ◽

Nf1 Gene ◽

The Impact

Abstract While most children develop cancer without a clear etiology, some pediatric cancers arise in the context of tumor predisposition syndromes, typically caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), affects ~1:3,000 individuals worldwide, 15% of whom will develop low-grade tumors of the optic pathway (optic pathway gliomas; OPGs). However, it is currently unclear which children with NF1 will develop an OPG, making risk assessment for each individual child difficult. Recent evidence suggests that the specific NF1 germline mutation that each child is born with may be one factor that modulates tumor penetrance. To address the hypothesis that specific germline NF1 gene mutations differentially increase the risk of optic glioma formation through cell-intrinsic effects on the tumor cell of origin, we designed a series of studies to examine the impact of different NF1 germline gene mutations on neuroglial progenitor cell populations in the developing brain. We first defined the putative cells of origin – neuroglial progenitor cells within the third ventricular zone (TVZ) – over normal mouse brain development using Nestin-CFPnuc reporter mice. Three cell populations were identified, and these populations display distinct spatial localizations and are dynamic over the course of late embryonic and early postnatal development. Functional differences were identified between these populations in vitro (e.g., differential clonogenic incidence and proliferation), and additional differences were identified by RNA sequencing. After characterizing these populations, we evaluated their spatiotemporal dynamics in mice genetically engineered to harbor different NF1 patient-derived germline Nf1 gene mutations. Interestingly, some, but not all, Nf1 gene mutations resulted in increased GFAP+ progenitor content and progenitor proliferation. Taken together, these findings provide early experimental evidence for mutational specificity in specific putative brain tumor cells of origin relevant to glioma penetrance.

Download Full-text

Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice

Carcinogenesis ◽

10.1093/carcin/bgy139 ◽

2018 ◽

Vol 40 (1) ◽

pp. 194-201

Author(s):

Joseph L Sottnik ◽

Vandana Mallaredy ◽

Ana Chauca-Diaz ◽

Carolyn Ritterson Lew ◽

Charles Owens ◽

...

Keyword(s):

Glycogen Storage Disease Type ◽

Gene Signature ◽

Glycogen Storage ◽

Genetically Engineered ◽

Normal Bladder ◽

Populations At Risk ◽

Genetically Engineered Mice ◽

Patient Prognosis ◽

The Impact

AbstractAmylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis. However, the impact of low AGL expression on the susceptibility of normal bladder to carcinogenesis is unknown. We address this gap by developing a germline Agl knockout (Agl−/−) mouse that recapitulates biochemical and histological features of GSDIII. Agl−/− mice exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had a higher BC incidence compared with wild-type mice (Agl+/+). To determine if the increased BC incidence observed was due to decreased Agl expression in the urothelium specifically, we developed a urothelium-specific conditional Agl knockout (Aglcko) mouse using a Uroplakin II-Cre allele. BBN-induced carcinogenesis experiments repeated in Aglcko mice revealed that Aglcko mice had a higher BC incidence than control (Aglfl/fl) mice. RNA sequencing revealed that tumors from Agl−/− mice had 19 differentially expressed genes compared with control mice. An ‘Agl Loss’ gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL loss in promoting carcinogenesis and provide a rationale for evaluating Agl expression levels, or Agl Loss gene signature scores, in normal urothelium of populations at risk of BC development such as older male smokers.

Download Full-text

The Role of Extent of Resection in IDH1 Wild-Type or Mutant Low-Grade Gliomas

Neurosurgery ◽

10.1093/neuros/nyx265 ◽

2017 ◽

Vol 82 (6) ◽

pp. 808-814 ◽

Cited By ~ 20

Author(s):

Toral Patel ◽

Evan D Bander ◽

Rachael A Venn ◽

Tiffany Powell ◽

Gustav Young-Min Cederquist ◽

...

Keyword(s):

Cox Regression ◽

Extent Of Resection ◽

World Health ◽

Low Grade ◽

Wild Type ◽

Who Grade ◽

Cox Regression Analysis ◽

Low Grade Gliomas ◽

Grade Ii ◽

The Impact

Abstract BACKGROUND Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (WHO) grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. OBJECTIVE To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan–Meier method. RESULTS Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {CI} 0.000-0.074] and HR = 0.001 [95% CI 0.00-0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17-4.13] and HR = 2.99 [95% CI 0.15-61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wtLGGs, but the impact on IDH1 mtLGGs requires further study.

Download Full-text

Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

Cancer Informatics ◽

10.1177/1176935120915839 ◽

2020 ◽

Vol 19 ◽

pp. 117693512091583 ◽

Cited By ~ 1

Author(s):

Mohammed Amine Bendahou ◽

Housna Arrouchi ◽

Wiame Lakhlili ◽

Loubna Allam ◽

Tarik Aanniz ◽

...

Keyword(s):

Isocitrate Dehydrogenase ◽

Computational Analysis ◽

Catalytic Site ◽

Dimensional Structure ◽

Low Grade ◽

Isocitrate Dehydrogenase 1 ◽

Modeling Tools ◽

Low Grade Gliomas ◽

Isocitrate Dehydrogenase 2 ◽

The Impact

Introduction: The emergence of new omics approaches, such as genomic algorithms to identify tumor mutations and molecular modeling tools to predict the three-dimensional structure of proteins, has facilitated the understanding of the dynamic mechanisms involved in the pathogenesis of low-grade gliomas including oligodendrogliomas and astrocytomas. Methods: In this study, we targeted known mutations involved in low-grade gliomas, starting with the sequencing of genomic regions encompassing exon 4 of isocitrate dehydrogenase 1 ( IDH1) and isocitrate dehydrogenase 2 ( IDH2) and the four exons (5-6 and 7-8) of TP53 from 32 samples, followed by computational analysis to study the impact of these mutations on the structure and function of 3 proteins IDH1, IDH2, and p53. Results: We obtain a mutation that has an effect on the catalytic site of the protein IDH1 as R132H and on the catalytic site of the protein IDH2 as R172M. Other mutations at p53 have been identified as K305N, which is a pathogenic mutation; R175 H, which is a benign mutation; and R158G, which disrupts the structural conformation of the tumor suppressor protein. Conclusion: In low-grade gliomas, mutations in IDH1, IDH2, and TP53 may be the key to tumor progression because they have an effect on the function of the protein such as mutations R132H in IDH1 and R172M in IDH2, which change the function of the enzyme alpha-ketoglutarate, or R158G in TP53, which affects the structure of the generated protein, thus their importance in understanding gliomagenesis and for more accurate diagnosis complementary to the anatomical pathology tests.

Download Full-text

Impact of Resolvin E1 on Murine Neutrophil Phagocytosis in Type 2 Diabetes

Infection and Immunity ◽

10.1128/iai.02444-14 ◽

2014 ◽

Vol 83 (2) ◽

pp. 792-801 ◽

Cited By ~ 46

Author(s):

Bruno S. Herrera ◽

Hatice Hasturk ◽

Alpdogan Kantarci ◽

Marcelo O. Freire ◽

Olivia Nguyen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Transgenic Animals ◽

Genetically Engineered ◽

Mitogen Activated Protein Kinase ◽

Air Pouch ◽

Content Type ◽

Genetically Engineered Mice ◽

The Impact

Diabetic complications involve inflammation-mediated microvascular and macrovascular damage, disruption of lipid metabolism, glycosylation of proteins, and abnormalities of neutrophil-mediated events. Resolution of inflamed tissues to health and homeostasis is an active process mediated by endogenous lipid agonists, including lipoxins and resolvins. This proresolution system appears to be compromised in type 2 diabetes (T2D). The goal of this study was to investigate unresolved inflammation in T2D. Wild-type (WT) and genetically engineered mice, including T2D mice (db/db), transgenic mice overexpressing the human resolvin E1 (RvE1) receptor (ERV1), and a newly bred strain ofdb/ERV1mice, were used to determine the impact of RvE1 on the phagocytosis ofPorphyromonas gingivalisin T2D. Neutrophils were isolated and incubated with fluorescein isothiocyanate-labeledP. gingivalis, and phagocytosis was measured in a fluorochrome-based assay by flow cytometry. Mitogen-activated protein kinase (MAPK) (p42 and p44) and Akt (Thr308 and Ser473) phosphorylation was analyzed by Western blotting. The mouse dorsal air pouch model was used to evaluate thein vivoimpact of RvE1. Results revealed that RvE1 increased the neutrophil phagocytosis ofP. gingivalisin WT animals but had no impact indb/dbanimals. InERV1-transgenic andERV1-transgenic diabetic mice, phagocytosis was significantly increased. RvE1 decreased Akt and MAPK phosphorylation in the transgenic animals.In vivodorsal air pouch studies revealed that RvE1 decreases neutrophil influx into the pouch and increases neutrophil phagocytosis ofP. gingivalisin the transgenic animals; cutaneous fat deposition was reduced, as was macrophage infiltration. The results suggest that RvE1 rescues impaired neutrophil phagocytosis in obese T2D mice overexpressingERV1.

Download Full-text

Unique Molecular Features in High-Risk Histology Endometrial Cancers

Cancers ◽

10.3390/cancers11111665 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1665 ◽

Cited By ~ 3

Author(s):

Pooja Pandita ◽

Xiyin Wang ◽

Devin E. Jones ◽

Kaitlyn Collins ◽

Shannon M. Hawkins

Keyword(s):

Endometrial Cancer ◽

High Risk ◽

Early Stage ◽

Standard Of Care ◽

The United States ◽

Model Systems ◽

Low Grade ◽

Cell Of Origin ◽

Molecular Features ◽

The Impact

Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes.

Download Full-text

PROGRESS IN CLINICAL NEUROSCIENCES: Advances in the Management of Low-Grade Gliomas

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100016838 ◽

2005 ◽

Vol 32 (1) ◽

pp. 18-26 ◽

Cited By ~ 8

Author(s):

Warren P. Mason

Keyword(s):

Natural History ◽

Optimal Timing ◽

Low Grade ◽

Low Grade Gliomas ◽

Response Profile ◽

History Of ◽

Evidence Based Guidelines ◽

The Impact ◽

Extensive Surgery

The management of low-grade gliomas represents one of the most challenging and controversial areas in neuro-oncology. Many aspects of the treatment of low-grade gliomas are debated, including the optimal timing of surgery and radiotherapy, the benefit of extensive surgery, and the impact of these variables on the natural history of these indolent and generally incurable tumours. The recently published results of several large multicentre trials addressing the timing and dose of radiotherapy have provided solid evidence for delayed and reduced dose irradiation. These studies have also confirmed prognostic variables that can be used to guide management of individual patients. Among these variables is the observation that tumours with oligodendroglial features have a better natural history and response profile. The recognition that as many as two thirds of low-grade gliomas have oligodendroglial features, advances in molecular diagnostics making accurate pathologic diagnosis of oligodendroglial tumours possible, and the established chemosensitivity of malignant oligodendrogliomas, have raised new issues surrounding the potential value of chemotherapy for low-grade gliomas. This review will be restricted to low-grade diffuse astrocytomas, oligodendrogliomas, and low-grade mixed oligoastrocytomas in adults, and provide evidence-based guidelines for the management of these tumours, including the emerging role of chemotherapy as initial treatment.

Download Full-text

Treatment of Adult Lower-Grade Glioma in the Era of Genomic Medicine

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_158869 ◽

2016 ◽

pp. 75-81 ◽

Cited By ~ 3

Author(s):

Susan M. Chang ◽

Daniel P. Cahill ◽

Kenneth D. Aldape ◽

Minesh P. Mehta

Keyword(s):

Molecular Genetic ◽

Genomic Medicine ◽

Genetic Alterations ◽

World Health ◽

Low Grade ◽

Lower Grade ◽

Cell Of Origin ◽

Low Grade Gliomas ◽

Molecular Features ◽

Anaplastic Gliomas

By convention, gliomas are histopathologically classified into four grades by the World Health Organization (WHO) legacy criteria, in which increasing grade is associated with worse prognosis and grades also are subtyped by presumed cell of origin. This classification has prognostic value but is limited by wide variability of outcome within each grade, so the classification is rapidly undergoing dramatic re-evaluation in the context of a superior understanding of the biologic heterogeneity and molecular make-up of these tumors, such that we now recognize that some low-grade gliomas behave almost like malignant glioblastoma, whereas other anaplastic gliomas have outcomes comparable to favorable low-grade gliomas. This clinical spectrum is partly accounted for by the dispersion of several molecular genetic alterations inherent to clinical tumor behavior. These molecular biomarkers have become important not only as prognostic factors but also, more critically, as predictive markers to drive therapeutic decision making. Some of these, in the near future, will likely also serve as potential therapeutic targets. In this article, we summarize the key molecular features of clinical significance for WHO grades II and III gliomas and underscore how the therapeutic landscape is changing.

Download Full-text