Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association

Abstract

Neurofibromatosis type-1 is a familial genetic syndrome associated with a predisposition to develop peripheral and central nervous system neoplasms. We have previously reported on a subset of gliomas developing in these patients with morphologic features resembling subependymal giant cell astrocytoma, but the molecular features of these tumors remain undefined. A total of 14 tumors were studied and all available slides were reviewed. Immunohistochemical stains and telomere-specific FISH were performed on all cases. In addition, next-generation sequencing was performed on 11 cases using a platform targeting 644 cancer-related genes. The average age at diagnosis was 28 years (range: 4-60, 9F/5M). All tumors involved the supratentorial compartment. Tumors were predominantly low grade (n = 12), with two high-grade tumors, and displayed consistent expression of glial markers. Next-generation sequencing demonstrated inactivating NF1 mutations in 10 (of 11) cases. Concurrent TSC2 and RPTOR mutations were present in two cases (1 sporadic and 1 neurofibromatosis type-1-associated). Interestingly, alternative lengthening of telomeres was present in 4 (of 14) (29%) cases. However, an ATRX mutation associated with aberrant nuclear ATRX expression was identified in only one (of four) cases with alternative lenghtening of telomeres. Gene variants in the DNA helicase RECQL4 (n = 2) and components of the Fanconi anemia complementation group (FANCD2, FANCF, FANCG) (n = 1) were identified in two alternative lenghtening of telomere-positive/ATRX-intact cases. Other variants involved genes related to NOTCH signaling, DNA maintenance/repair pathways, and epigenetic modulators. There were no mutations identified in DAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots of IDH1, IDH2, or BRAF. A subset of subependymal giant cell astrocytoma-like astrocytomas are alternative lenghtening of telomere-positive and occur in the absence of ATRX alterations, thereby suggesting mutations in other DNA repair/maintenance genes may also facilitate alternative lenghtening of telomeres. These findings suggest that subependymal giant cell astrocytoma-like astrocytoma represents a biologically distinct group that merits further investigation.

Alternative lengthening of telomeres, ATRX loss and H3‐K27M mutations in histologically defined pilocytic astrocytoma with anaplasia

“…Next Generation Sequencing (NGS) studies were performed by various methods at referring institutions as part of the clinical workup (n=4). In two additional H3-K27M positive cases and one H3-K27M negative case, NGS was performed at Johns Hopkins as previously described (32). Briefly, DNA libraries were prepared using Agilent SureSelect-XT reagents (Agilent Technologies, Inc., Santa Clara, CA) with genomic regions of interest captured by means of an Agilent custom-designed bait set covering the full coding regions of 644 cancer-associated genes (exon 1 is poorly covered for some genes).…”

Telomere alterations in neurofibromatosis type 1-associated solid tumors

“…To study genetic alterations associated with the development of ALT, we performed NGS in 4 MPNSTs (3 ALT-positive and 1 ALT-negative) and 6 ALT-positive gliomas, 4 of which were also analyzed as part of a prior study [31]. Sequencing results of ALT-positive cases are provided by case in Additional file 1: Table S2.…”

Mutations of the MAPK/TSC/mTOR pathway characterize periventricular glioblastoma with epithelioid SEGA-like morphology-morphological and therapeutic implications

“…However, in testing for direct phosphorylation of the mTOR target 4E-BP1, only a subset of neoplastic cells showed mTOR activation, correlating with the subclonal presence of the TSC1 mutation. The fact that the activation of mTORC1 by the PI3K/PTEN/Akt pathway alone does not correlate with epithelioid morphology is supported by the astrocytic/fibrillary appearance of the overwhelming majority of glioblastoma cases, which belong to the so-called “classic” variant and exhibit PI3K/PTEN/Akt pathway activation, mainly via inactivation of PTEN tumor suppressor [26–30]. It is important, however, to recognize that the PI3K/PTEN/Akt pathway is not a linear pathway and it branches into different growth promoting pathways, of which only one is mTOR [25].…”

“…Syndromic NF1 germline mutations, similar to syndromic TSC1/2 mutations, are associated with low-grade gliomas that nevertheless differ in morphological appearance, with NF1 usually associated with pilocytic astrocytoma, and TSC with SEGA [1]. Surprisingly, the rare glioblastomas arising in patients with NF1 syndrome exhibit an epithelioid morphology, indistinguishable from epithelioid glioblastoma [37, 38]. The epithelioid morphology may result from inactivation of both NF1 alleles in the presence of an intact downstream pathway resulting in strong activation of mTOR similar to SEGA, where a germline TSC mutation is accompanied by LOH [7].…”