LGG-28. NOVEL BRAF INTRAGENIC DELETION IN A GLIOMA: A CASE REPORT OF A PEDIATRIC PATIENT

Abstract BACKGROUND Numerous variant BRAF genetic alterations have been associated with malignancies. BRAF activating fusions/mutations are frequently present in low grade gliomas. BRAF intragenic deletions have been reported in melanoma, but have not previously been reported in gliomas. OBJECTIVE To report a BRAF intragenic deletion in a pediatric patient with recurrent low-grade glioma. RESULTS A 3-year-old female underwent a complete resection of a posterior fossa pilocytic astrocytoma. She had recurrences at age 4, and then at age 9; pathology was consistent with pilocytic astrocytoma. Microarray analysis on sample from the first recurrence showed one region of loss encompassing 86 Kbp within the BRAF gene. The deletion breakpoints are within intron 1 and 9, resulting in loss of exons 2 through 9, inclusive. This has been previously described melanoma, but appears to be a novel finding in glioma. It is hypothesized that, since the loss retains the kinase and ATP binding pocket domains but deletes the N-terminal conserved region 1 and 2 (CR1, CR2) of the BRAF gene, it is likely functionally similar to the loss and activation resulting from the more usually described KIAA1549 and BRAF gene fusion. CONCLUSION This is the first BRAF intragenic deletion involving exons 2–9 reported in a glioma. Although 86kbp is small using whole genome microarray technology, it is large using sequencing strategies, and a targeted sequencing approach to investigate the BRAF gene would not readily identify this deletion. It is speculated that the deletion may be under ascertained in the pediatric population.

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Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) Alterations in Low-Grade Gliomas: Report of a Novel Gene Fusion Partner in a Pilocytic Astrocytoma and Review of the Literature

Case Reports in Pathology ◽

10.1155/2020/5903863 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Siobhan S. Pattwell ◽

Eric Q. Konnick ◽

Yajuan J. Liu ◽

Rebecca A. Yoda ◽

Laligam N. Sekhar ◽

...

Keyword(s):

Pilocytic Astrocytoma ◽

Gene Fusion ◽

Pediatric Population ◽

Neurofibromatosis Type ◽

Genetic Alterations ◽

Neurotrophin Receptor ◽

Low Grade ◽

Fusion Partner ◽

Tyrosine Kinase 2 ◽

Cns Neoplasms

Pilocytic astrocytoma is a low-grade glial neoplasm of the central nervous system (CNS) that tends to occur in the pediatric population and less commonly presents in adults. Hereditary pilocytic astrocytoma is often associated with germline genetic alterations in the tumor suppressor NF1, the gene responsible for the syndrome neurofibromatosis type 1. Sporadic pilocytic astrocytoma frequently harbors somatic alterations in BRAF, with rare pilocytic astrocytomas containing alterations in FGFR1 and NTRK2. NTRK2 encodes for the protein tropomyosin receptor kinase B (TrkB), which is a neurotrophin receptor with high affinity for Brain-Derived Neurotrophic Factor (BDNF), and plays a role in several physiological functions of neurons, including cell survival and differentiation. In this report, we describe a novel PML-NTRK2 gene fusion occurring in an adult sporadic pilocytic astrocytoma and review the biology and implications of specific NTRK2 mutations occurring in CNS neoplasms.

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NovelBRAFAlteration in a Sporadic Pilocytic Astrocytoma

Case Reports in Medicine ◽

10.1155/2012/418672 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 13

Author(s):

Sonika Dahiya ◽

Jinsheng Yu ◽

Aparna Kaul ◽

Jeffrey R. Leonard ◽

David H. Gutmann

Keyword(s):

Pilocytic Astrocytoma ◽

Fusion Transcript ◽

Genetic Alterations ◽

Causative Mutation ◽

Low Grade ◽

Glial Tumor ◽

Serine Threonine Kinase ◽

Kinase Gene ◽

Genetic Changes ◽

Erk Activation

Pilocytic astrocytoma (PA) is the most frequently encountered glial tumor (glioma or astrocytoma) in children. Recent studies have identified alterations in theBRAFserine/threonine kinase gene as the likely causative mutation in these childhood brain tumors. The majority of these genetic changes involve chromosome 7q34 tandem duplication, resulting in aberrantBRAFfusion transcripts. In this paper, we describe a novelKIAA1549:BRAFfusion transcript in a sporadic PA tumor associated with increased ERK activation and review the spectrum ofBRAFgenetic alterations in this common pediatric low-grade central nervous system neoplasm.

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Low-grade Osteosarcomatous Dedifferentiation of an Atypical Lipomatous Tumor in a Pediatric Patient

Pediatric and Developmental Pathology ◽

10.1177/1093526619889130 ◽

2019 ◽

Vol 23 (3) ◽

pp. 240-246

Author(s):

Benjamin J Kukull ◽

Mazdak A Khalighi ◽

Kenneth R Gundle ◽

Barry G Hansford ◽

Christopher L Corless ◽

...

Keyword(s):

Pediatric Patient ◽

Unusual Case ◽

Pediatric Population ◽

Low Grade ◽

Parosteal Osteosarcoma ◽

Atypical Lipomatous Tumor ◽

Lipomatous Tumor ◽

Well Differentiated ◽

Single Focus ◽

Shared Characteristic

Atypical and malignant lipomatous tumors are infrequent in the pediatric population. Within this uncommon cohort, the morphologically and genetically related spectrum of atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma (ALT/WDL/DDLS) is markedly rare. Their shared characteristic molecular aberration is a genomic amplicon of a region of chromosome 12q, including the oncogenes MDM2 and CDK4. We present an unusual case of a pediatric patient with an ALT, with recurrence after 2 years in the form of a bone-forming mass, radiologically and pathologically mimicking parosteal osteosarcoma, a tumor also molecularly characterized by amplification of MDM2 and CDK4. However, with ample histologic sampling, a single focus of lipogenic differentiation was identified, thus representing the first near complete low-grade osteosarcomatous dedififferentation reported within ALT/WDL/DDLS and the first ever in pediatric patient. The case serves a reminder of a diagnosis differential and pitfalls within MDM2-amplified tumors.

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LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.405 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii370-iii371

Author(s):

Stacy Chapman ◽

Demitre Serletis ◽

Colin Kazina ◽

Mubeen Rafay ◽

Sherry Krawitz ◽

...

Keyword(s):

Targeted Therapy ◽

Pilocytic Astrocytoma ◽

Clinical Symptoms ◽

Obstructive Hydrocephalus ◽

Braf V600e Mutation ◽

Braf V600e ◽

Low Grade ◽

Dramatic Improvement ◽

Chemotherapeutic Regimen ◽

Response To Chemotherapy

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

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The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes

Scientific Reports ◽

10.1038/s41598-021-95009-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ilona E. Grabowicz ◽

Bartek Wilczyński ◽

Bożena Kamińska ◽

Adria-Jaume Roura ◽

Bartosz Wojtaś ◽

...

Keyword(s):

Gene Expression ◽

Long Range ◽

Genetic Alterations ◽

Chromatin Organization ◽

Open Chromatin ◽

Low Grade ◽

Strong Impact ◽

Cell Matrix ◽

Topologically Associating Domains ◽

Genome Wide

AbstractGenome-wide studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different glioma types. We have recently created a unique atlas encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we intersected genome-wide atlas data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in WHO low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found the set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing specific glioma-related genes. Moreover, many genes associated with the cell–matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by long-range contacts with enhancers. Presented results demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy.

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LGG-31. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS: ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORT WITH 101 PAIRED TUMOR SAMPLES

Neuro-Oncology ◽

10.1093/neuonc/noaa222.413 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii372-iii372

Author(s):

Margot A Lazow ◽

Austin Schafer ◽

Mariko D DeWire-Schottmiller ◽

Adam Lane ◽

Daniel R Boué ◽

...

Keyword(s):

Genetic Alterations ◽

Rapid Progression ◽

Low Grade ◽

Valuable Insight ◽

Histologic Diagnosis ◽

Low Grade Gliomas ◽

Genomic Landscape ◽

Cdkn2a Deletion ◽

Diagnostic Biopsy ◽

Over Time

Abstract INTRODUCTION Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries. RESULTS 101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]). CONCLUSIONS Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

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RADT-29. EFFECT OF RADIATION THERAPY ON OVERALL SURVIVAL FOLLOWING SUBTOTAL RESECTION OF ADULT PILOCYTIC ASTROCYTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.782 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii187-ii188

Author(s):

Adham Khalafallah ◽

Adrian Jimenez ◽

Henry Brem ◽

Debraj Mukherjee

Keyword(s):

Overall Survival ◽

Radiation Therapy ◽

Pilocytic Astrocytoma ◽

Radiation Treatment ◽

Cox Proportional Hazards Model ◽

Adult Patients ◽

Subtotal Resection ◽

Adjuvant Radiation ◽

Low Grade ◽

Risk Of Death

Abstract BACKGROUND Pilocytic astrocytoma (PCA) is a low-grade glioma common in children but also rarely diagnosed in adults. The role of adjuvant radiation therapy (RT) in treating these tumors remains unclear. OBJECTIVE We investigated the effect of RT on overall survival, specifically among adult patients who had undergone subtotal PCA resection. METHODS Information on adult patients (age 18 years old) who had undergone subtotal PCA resection between 2004 and 2016 was collected from the National Cancer Database (NCDB). A multivariate Cox proportional hazards model was utilized to determine factors independently associated with overall survival. RESULTS A total of 451 patients were identified. The mean age of our patient cohort was 36.8 years old, and the majority of patients (83.4%) did not receive radiation treatment following subtotal PCA resection. Overall median survival was 93.8 months. Survival was longer (p < 0.001) in the patients who did not receive post-surgical RT (median: 98.3 months) compared to patients who did (median: 54.8 months). Patients who had older age at diagnosis (hazard ratio [HR]=1.05, 95% confidence interval [CI]=1.03-1.07, p < 0.01), were Black or African American (HR=2.76, CI=1.12-6.46, p=0.019), received radiation during their initial treatment (HR=4.53, CI=2.08-9.89, p < 0.01), or had a Charlson/Deyo score of > 1 (HR=3.68, CI=1.55, p=0.003) had a significantly higher risk of death following subtotal PCA resection. CONCLUSION Postoperative RT is independently associated with a significantly higher risk of death among adults who underwent subtotal PCA resection. Our findings provide a rationale for further investigation into the efficacy and safety of RT within this patient population.

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LGG-50. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF 1,000 PEDIATRIC LOW-GRADE GLIOMAS UNCOVERS NOVEL SUBGROUPS FOR CLINICAL RISK STRATIFICATION

Neuro-Oncology ◽

10.1093/neuonc/noaa222.428 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii375-iii376

Author(s):

Uri Tabori ◽

Scott Ryall ◽

Michal Zapotocky ◽

Julie Bennett ◽

Liana Nobre ◽

...

Keyword(s):

Risk Stratification ◽

Clinical Presentation ◽

Mapk Pathway ◽

Clinical Analysis ◽

Genetic Alterations ◽

Low Grade ◽

Who Grade ◽

Low Grade Gliomas ◽

Younger Age ◽

Risk Categories

Abstract Pediatric low-grade gliomas (pLGG) are primarily driven by genetic alterations in the RAS/MAPK pathway, most commonly involving BRAF of NF1. Despite their molecular convergence, pLGG often show unexplained variability in their clinical outcome. To address this, we molecularly characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harbored a detectable driver mutation. The remaining 16% of patients nonetheless showed RAS/MAPK pathway up-regulation at the RNA level. The clinical presentation and outcome of pLGG appeared highly variable and linked to the alteration type: re-arrangement or SNV. Re-arrangement-driven tumors were diagnosed at a younger age (6.6 versus 10.9 years, p<0.0001), enriched for WHO grade I histology (88% versus 66%, p<0.0001), infrequently progressed (27% versus 46%, p<0.0001), and rarely resulted in death (3 versus 13%, p<0.0001) as compared to SNV-driven tumors. These included the rarest molecular drivers of pLGG, for which we now have the clinicopathologic features of including MYB, MYBL1, FGFR2 fusions, FGFR1-TACC1, FGFR1 SNVs, IDH1 p.R132H, and H3.3 p.K27M. Utilizing this information, we suggest novel risk categories of pLGG that effectively predicted patient outcome. Low-risk tumors progressed infrequently and rarely succumbed to their disease (10-year PFS of 71% and OS of 98%). Intermediate-risk pLGG had a 10-year PFS and OS of 35% and 90%, respectively. High risk pLGG almost invariably progressed (10-year PFS of 0%) and these patients often succumbed to their disease (10-year OS of 41%). These data highlight the biological and clinical differences between pLGG subtypes and offers molecular based risk stratification to these cancers.

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Pathobiology ofHelicobacter pyloriInfection in Children

Canadian Journal of Gastroenterology ◽

10.1155/1999/591767 ◽

1999 ◽

Vol 13 (7) ◽

pp. 599-603 ◽

Cited By ~ 25

Author(s):

Robert H Riddell

Keyword(s):

Intestinal Metaplasia ◽

Pediatric Population ◽

Paediatric Population ◽

Lymphoid Hyperplasia ◽

Host Responses ◽

Low Grade ◽

Cell Axis ◽

Age Related ◽

H Pylori ◽

Time Required

In the paediatric population, the associations ofHelicobacter pyloriwith gastritis, gastric ulcer, duodenitis and duodenal ulcer, and with duodenal gastric surface metaplasia and disorders of the D cell-G cell axis resulting in hypergastrinemia, are well established and in many ways resemble their counterparts in adults. Eradication ofH pyloriinvariably results in the reversal of these diseases with time. There are also suggestions that gastric surface metaplasia is more extensive in children withH pylori, and may be the site of duodenalH pyloriinfection and associated duodenal erosions or ulcers. There is no consensus as to whetherH pyloriin children is more or less severe than in adults. In one paediatric cohort,H pyloriwas associated with increased intensity of inflammation, while other studies suggest that acute inflammation may be less intense in children overall but that chronic inflammation may be increased in intensity, including lymphoid hyperplasia, which in turn may correlate with endoscopic nodularity. Lymphoid hyperplasia and nodular gastritis appear to be more frequent in children than in adults and usually regress followingH pylorieradication. However, in children, other diseases or morphological abnormalities, including some loss of glands (atrophy), occasionally intestinal metaplasia, lymphoproliferative diseases including low grade mucosal-associated lymphoid tissue lymphoma, lymphocytic gastritis and hypertrophic gastritis/Menetrier’s disease, are much less frequently associated withH pylorithan in adults. Other associations are rarely seen in children, primarily because the time required for these to develop takes the individual to adulthood; for example, while intestinal metaplasia occurs in the pediatric population, the complications of adenoma/dysplasia and carcinoma are rare. In adults, inflammatory and hyperplastic polyps, atrophic gastritis and pernicious anemia, and in some patients granulomas (granulomatous gastritis), may also be associated withH pyloriinfection. Greater awareness of the spectrum of diseases associated withH pylorimay well lead to their increased recognition in the paediatric population. Some diseases, particularly Crohn’s disease, but also human immunodeficiency virus infection, have a negative association withH pylorithat appears not to be simply a result of the excess antibiotic therapy that these patients receive. These variations in association and reactions toH pylori, some of which are age-related, may allow the different host responses toH pylorithat occur in humans to be examined.

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