Circumscribed Astrocytic Gliomas
2023-07-27 Scott Ryall, PhD Affiliation1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
The 2021 WHO guidelines for CNS tumor classification recognizes circumscribed astrocytic gliomas to acknowledge the characteristic solid growth pattern, in contrast to diffuse tumors. 1 Circumscribed astrocytic gliomas include 6 entities: i) Pilocytic astrocytoma, ii) High-grade astrocytoma with piloid features (HGAP), iii) Pleomorphic xanthoastrocytoma (PXA), iv) Subependymal giant cell astrocytoma (SEGA), v) Chordoid glioma, and vi) Astroblastoma, MN1-altered
| Circumscribed Astrocytic Gliomas | Genetic Event(s) |
|---|---|
| Pilocytic astrocytoma | The most frequent genetic abnormalities observed in pilocytic astrocytoma are rearrangements of approximately 2-Mb at chromosome 7q34 resulting in the KIAA1549::BRAF gene fusion involving various combinations of the KIAA1549 and BRAF exons. 2-5 Infrequently, alternate BRAF fusions have been observed 4,6-8, which, like KIAA1549::BRAF, all result in loss of the N-terminal regulatory domain of BRAF, leading to dysregulated MAPK signaling. 5,9,10 Other genetic abnormalities are in genes encoding other members of the MAPK pathway and include NF1 alterations (typically germline and associated with optic pathway glioma), BRAF mutations (most often p.V600E), FGFR1 mutations, FGFR1 fusions (most often FGFR1::TACC1), NTRK1/NTRK2/NTRK3 fusions, KRAS mutations, and RAF1 fusions. 5,9,11-13 |
| High-grade astrocytoma with piloid features | Currently, high-grade astrocytoma with piloid features (HGAP) can only be diagnosed via DNA methylation profiling. 14,15 Despite this, certain genetic markers suggestive of the diagnosis include CDKN2A and/or CDKN2B homozygous deletions (~80%), ATRX mutations and/or loss of expression (45%), KIAA1549::BRAF (20%), NF1 mutations or deletions (~30%), FGFR1 mutations (~20%), KRAS mutations (~3%), and BRAF mutations (~1%). 14 Total or partial loss of chromosome 19q is observed in approximately 50% of HGAP. 14,15 |
| Pleomorphic xanthoastrocytoma | All pleomorphic xanthoastrocytoma (PXA) harbor activating genetic alterations in a MAPK pathway gene. The most frequent of these is BRAF p.V600E which is seen in up to 80% of tumors. 5,16,17 >90% of BRAF p.V600E tumors have combined homozygous deletions of CDKN2A and/or CDKN2B. 16,18-20 Less frequently, these tumors may harbor TERT promoter mutations or amplifications. 16,21 Tumors without BRAF p.V600E can harbour a wide variety of alternative alterations in the MAPK pathway including non-canonical BRAF mutations and fusions, NTRK1/NTRK2/NTRK3 fusions, and NF1 alterations. Rare alterations in SMARCB1, BCOR, ARID1A,ATRX, PTEN, FANCA, PRKDC, NOTCH2/NOTCH3/NOTCH4, and BCL6 have also been described, but their significance is, as of now, unclear. 16,19,22 DNA methylation analysis classifies PXA as its own entity, which my help alleviate diagnsotic concern in cases with ambiguous morphology or non-canonical genetics. 15 |
| Subependymal giant cell astrocytoma | Subependymal giant cell astrocytoma (SEGA) is strongly associated with tuberous sclerosis. OMIM:191100 OMIM:613254 These tumors commonly harbor biallelic inactivation of TSC1 or TSC2, with the second hit frequenty being a deletion or loss of heterozygosity. 23-25 SEGA in the absence of tuberous sclerosis have been reported, but it is unclear whether they harbor undetectable TSC1/TSC2 variants or alternative mechanisms of inactivation. 25,26 BRAF p.V600E has been infrequently reported in SEGA, although these findings are disputed. 12,25,27 DNA methylation analysis classifies SEGA as its own tumor entity. 15 |
| Chordoid glioma | Chordoid glioma are near-ubiquitously defined by p.D463H mutations in PRKCA, which is a diagnostic hallmark in these lesions. 28,29 Although the precise mechanism of this mutation remains to be fully elucidated, it has been associated with elevated levels of phosphorylated ERK, suggesting that it activates the MAPK signaling pathway. 28 Mutations in other known glioma-related genes are not seen in these tumors. DNA methylation analysis classifies chordoid glioma as its own diagnostic entity, which can be helpful in histologically ambiguous cases. 15,30 |
| Astroblastoma, MN1-altered | Astroblastoma, MN1-altered is defined by structural rearrangements of MN1, most commonly as MN1::BEND2 fusions, although other rare fusion partners have been reported. 31-34 Typically, MN1 alterations do not co-occurr with secondary oncogenic alterations, however, a rare subset of tumors have been shown to also harbor CDKN2A homozygous deletions. 31,33 Cytogenetically, astroblastomas often harbor monosomy 16 and partial losses of 22q and X. 31-33,35 DNA methylation analysis shows that astroblastoma have a unique profile as compared to other tumors with astroblastomatous rosettes, which can be helpful in diagnostically differentiating these cases. 15 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 34185076 | 2021 | The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. | Louis DN et al |
| 2 | 18974108 | 2008 | Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. | Jones DT et al |
| 3 | 18398503 | 2008 | BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. | Pfister S et al |
| 4 | 19373855 | 2009 | Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. | Forshew T et al |
| 5 | 32289278 | 2020 | Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas. | Ryall S et al |
| 6 | 21424530 | 2011 | Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. | Cin H et al |
| 7 | 28448514 | 2017 | A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma. | Tomić TT et al |
| 8 | 29141672 | 2017 | A novel GIT2-BRAF fusion in pilocytic astrocytoma. | Helgager J et al |
| 9 | 23817572 | 2013 | Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. | Jones DT et al |
| 10 | 23583981 | 2013 | Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. | Zhang J et al |
| 11 | 17712732 | 2007 | Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. | Janzarik WG et al |
| 12 | 21274720 | 2011 | Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. | Schindler G et al |
| 13 | 23222849 | 2013 | Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. | Gutmann DH et al |
| 14 | 29564591 | 2018 | Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. | Reinhardt A et al |
| 15 | 29539639 | 2018 | DNA methylation-based classification of central nervous system tumours. | Capper D et al |
| 16 | 30051528 | 2019 | The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. | Phillips JJ et al |
| 17 | 3261930 | 1988 | Use of aspirin for prevention of cardiovascular disease--1981-82 to 1985-86: the Minnesota Heart Survey. | Folsom AR et al |
| 18 | 26454767 | 2015 | BRAF mutation and anaplasia may be predictive factors of progression-free survival in adult pleomorphic xanthoastrocytoma. | Tabouret E et al |
| 19 | 28181325 | 2018 | Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. | Vaubel RA et al |
| 20 | 30496796 | 2019 | Molecular features of pleomorphic xanthoastrocytoma. | Zou H et al |
| 21 | 30240866 | 2018 | BRAF V600E, TERT, and IDH2 Mutations in Pleomorphic Xanthoastrocytoma: Observations from a Large Case-Series Study. | Ma C et al |
| 22 | 32619305 | 2021 | Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it? | Vaubel R et al |
| 23 | 9403714 | 1997 | Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. | Henske EP et al |
| 24 | 9007104 | 1996 | Loss of tuberin from cerebral tissues with tuberous sclerosis and astrocytoma. | Mizuguchi M et al |
| 25 | 29221145 | 2017 | Subependymal giant cell astrocytomas in Tuberous Sclerosis Complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations. | Bongaarts A et al |
| 26 | 25978531 | 2015 | Subependymal giant cell astrocytoma in the absence of tuberous sclerosis complex: case report. | Beaumont TL et al |
| 27 | 25346165 | 2015 | BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas. | Lee D et al |
| 28 | 29476136 | 2018 | A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. | Goode B et al |
| 29 | 29915258 | 2018 | A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. | Rosenberg S et al |
| 30 | 29967940 | 2018 | Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. | Capper D et al |
| 31 | 28960623 | 2018 | Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. | Wood MD et al |
| 32 | 28990708 | 2018 | Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement. | Hirose T et al |
| 33 | 30876455 | 2019 | Genomic analysis demonstrates that histologically-defined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis. | Lehman NL et al |
| 34 | 31111274 | 2019 | MN1 rearrangement in astroblastoma: study of eight cases and review of literature. | Mhatre R et al |
| 35 | 26919435 | 2016 | New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. | Sturm D et al |
Citation
Scott Ryall, PhD
Circumscribed Astrocytic Gliomas
Atlas Genet Cytogenet Oncol Haematol. 2023-07-27
Online version: http://atlasgeneticsoncology.org/solid-tumor/209195/circumscribed-astrocytic-gliomas
