Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association. (December 2018)

• Record Type: Journal Article
• Authors: Palsgrove, Doreen; Brosnan-Cashman, Jacqueline; Giannini, Caterina; Raghunathan, Aditya; Jentoft, Mark; Bettegowda, Chetan; Gokden, Murat; Lin, Doris; Yuan, Ming; Lin, Ming-Tseh; Heaphy, Christopher; Rodriguez, Fausto
• Is Part Of: Modern pathology. Volume 31:Number 12(2018)
• Page Start: 1787
• Page End: 1800
• Publication Date: 2018-12
• Subjects: Pathology -- Periodicals; Diagnosis, Laboratory -- Periodicals; Pathologie -- Périodiques; Diagnostics biologiques -- Périodiques; Diagnosis, Laboratory; Pathology; Pathology -- Abstracts; Pathology -- Periodicals; Periodicals; Electronic journals; 616.07
• DOI: 10.1038/s41379-018-0103-x
• Languages: English
• ISSNs: 0893-3952

Abstract

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 inactivatingNF1 mutations in 10 (of 11) cases. ConcurrentTSC2 andRPTOR 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, anATRX 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 helicaseRECQL4 (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 inDAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots ofIDH1, IDH2, orBRAF . 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.