Light Drives Optic Glioma Formation in a Cancer-Predisposition Syndrome

2021 ◽  
Keyword(s):  
Cancer Predisposition ◽  
Optic Glioma ◽  
Cancer Predisposition Syndrome

scholarly journals LGG-01. NF1 MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i31-i31
Author(s):  
Yuan Pan ◽  
Jared Hysinger ◽  
Nicki Schindler ◽  
Olivia Cobb ◽  
Xiaofan Guo ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Tumor Progression ◽  
Neuronal Activity ◽  
Cancer Predisposition ◽  
Optic Glioma ◽  
Optic Pathway ◽  
Tumor Initiation ◽  
Nerve Activity ◽  
Cancer Predisposition Syndrome

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic gliomas) during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1 optic glioma to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing optic nerve activity via light deprivation prevents tumor formation and maintenance. By manipulating environmental light to modulate optic pathway (retinal) neuron activity, we show that Nf1 optic glioma initiation depends on neuronal activity during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacologic inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce optic glioma incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.

TAMI-69. NF1 MUTATION DRIVES NEURONAL ACTIVITY-DEPENDENT OPTIC GLIOMA INITIATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi212-vi212
Author(s):  
Yuan Pan ◽  
Jared Hysinger ◽  
Tara Barron ◽  
Nicki Schindler ◽  
Olivia Cobb ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Tumor Progression ◽  
Neuronal Activity ◽  
Visual Experience ◽  
Cancer Predisposition ◽  
Optic Glioma ◽  
Optic Pathway ◽  
Nerve Activity ◽  
Cancer Predisposition Syndrome

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis-1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic pathway gliomas [OPGs]), during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1-OPG to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience via light deprivation prevents tumor formation and maintenance. We show that Nf1-OPG initiation depends on visual experience during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.

scholarly journals Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

2021 ◽  
Author(s):  
Anna Byrjalsen ◽  
Illja J. Diets ◽  
Jette Bakhuizen ◽  
Thomas van Overeem Hansen ◽  
Kjeld Schmiegelow ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
Pediatric Cancer ◽  
Causal Relation ◽  
Evaluation Criteria ◽  
Cancer Predisposition ◽  
Gene Panel ◽  
Childhood Onset ◽  
Children With Cancer ◽  
Cancer Predisposition Syndrome ◽  
A Prospective Study

AbstractIncreasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated.

An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population-Based Evidence for a Cancer Predisposition Syndrome?

2015 ◽  
Vol 63 (2) ◽  
pp. 196-201 ◽  
Author(s):  
Natasha M. Archer ◽  
Renata Parada Amorim ◽  
Rafaela Naves ◽  
Simone Hettmer ◽  
Lisa R. Diller ◽  
...  
Keyword(s):  
Population Based ◽  
Cancer Predisposition ◽  
Malignant Neoplasms ◽  
Cancer Predisposition Syndrome ◽  
Increased Risk ◽  
Second Malignant Neoplasms

To test or not to test: genetic cancer predisposition testing in paediatric patients with cancer

2020 ◽  
pp. medethics-2020-106656
Author(s):  
Sapna Mehta ◽  
Dennis John Kuo
Keyword(s):  
Healthcare Providers ◽  
Paediatric Population ◽  
Cancer Predisposition ◽  
Decision Making Process ◽  
Open Future ◽  
Human Flourishing ◽  
Ethical Considerations ◽  
Knowledge Of Results ◽  
Cancer Predisposition Syndrome ◽  
Patients With Cancer

Genetic cancer predisposition testing in the paediatric population poses unique ethical dilemmas. Using the hypothetical example of a teenager with cancer with a high probability of having an underlying cancer predisposition syndrome, we discuss the ethical considerations that affect the decision-making process. Because legally these decisions are made by parents, genetic testing in paediatrics can remove a child’s autonomy to preserve his or her own ‘open future’. However, knowledge of results confirming a predisposition syndrome can potentially be beneficial in modifying treatment and surveillance plans and enabling at-risk family members to obtain cascade testing for themselves. Considering virtue ethics to envision the best characters of the patient, parents and healthcare providers can guide them to the better choice to test or not to test, with the ultimate goal of achieving the best outcome for survival and eudaimonia, human flourishing reliably sought out.

Recognizing and Managing Children with a Pediatric Cancer Predisposition Syndrome: A Guide for the Pediatrician

2018 ◽  
Vol 47 (5) ◽  
pp. e204-e216 ◽  
Author(s):  
Stephanie A. Coury ◽  
Katherine A. Schneider ◽  
Jaclyn Schienda ◽  
Wen-Hann Tan
Keyword(s):  
Pediatric Cancer ◽  
Cancer Predisposition ◽  
Cancer Predisposition Syndrome

scholarly journals Molecular Causes for BUBR1 Dysfunction in the Human Cancer Predisposition Syndrome Mosaic Variegated Aneuploidy

2010 ◽  
Vol 70 (12) ◽  
pp. 4891-4900 ◽  
Author(s):  
Saskia J.E. Suijkerbuijk ◽  
Maria H.J. van Osch ◽  
Frank L. Bos ◽  
Sandra Hanks ◽  
Nazneen Rahman ◽  
...  
Keyword(s):  
Human Cancer ◽  
Cancer Predisposition ◽  
Cancer Predisposition Syndrome ◽  
Mosaic Variegated Aneuploidy

scholarly journals Characteristics of Nephroblastoma/Nephroblastomatosis in Children with a Clinically Reported Underlying Malformation or Cancer Predisposition Syndrome

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5016
Author(s):  
Nils Welter ◽  
Angelo Wagner ◽  
Rhoikos Furtwängler ◽  
Patrick Melchior ◽  
Leo Kager ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Clinical Features ◽  
Tumor Volume ◽  
Wilms Tumor ◽  
Cancer Predisposition ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Predisposition Syndrome ◽  
Wagr Syndrome ◽  
Drash Syndrome

(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

scholarly journals Factors Affecting Genetic Consultation in Adolescent and Young Adult Patients With Sarcoma

2021 ◽  
pp. 1-8
Author(s):  
Grace E. McKay ◽  
Anna L. Zakas ◽  
Fauzia Osman ◽  
Amanda Parkes
Keyword(s):  
Genetic Counseling ◽  
Genetic Testing ◽  
Young Adult ◽  
Chart Review ◽  
Univariate Analysis ◽  
Cancer Predisposition ◽  
Adolescent And Young Adult ◽  
Li Fraumeni Syndrome ◽  
Cancer Predisposition Syndrome ◽  
Genetic Consultation

Background: Given a link between sarcomas and hereditary cancer predisposition syndromes, including Li-Fraumeni syndrome, the consideration for genetic counseling is recommended for all adolescent and young adult (AYA) patients diagnosed with sarcoma. The aim of this study was to evaluate factors influencing genetic consultations in AYA patients with sarcoma at the University of Wisconsin (UW). Methods: A retrospective chart review was performed on AYA patients diagnosed with sarcoma between the ages of 15 and 39 years who were seen at least once between 2015 to 2019 at UW. Our chart review identified discussions regarding genetics, referrals to genetics, genetic consultations, and results of genetic testing. Variables hypothesized to affect patient referrals for genetic consultation were identified a priori. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. Results: We identified 87 AYA patients with sarcoma. Only 19 (22%) of these patients had documentation of a discussion about genetics, 15 (17%) of whom were subsequently referred for genetic consultation. Of these 15 patients, 9 (60%) were seen in consultation. All 9 patients seen by genetics underwent genetic testing, with 4 (44%) of these patients having identified heritable cancer predisposition syndromes. Likelihood for genetics referral was linked most strongly to documented genetics discussion with an oncology provider (P<.001). Conclusions: Despite the recommendation for consideration for genetic counseling in AYA patients with sarcoma, <25% of such patients in our study had a documented discussion about genetics. Supporting this need, all referred patients met criteria for genetic testing, and 44% of tested patients were found to have a heritable cancer predisposition syndrome. These data support the initial conversation by a provider as critical to genetic referral and suggest the need for more specific national recommendations for the genetic evaluation of all AYA patients with sarcoma.

Sign in / Sign up

Export Citation Format

Share Document