Duplications of KIAA1549 and BRAF screening by Droplet Digital PCR from formalin-fixed paraffin-embedded DNA is an accurate alternative for KIAA1549-BRAF fusion detection in pilocytic astrocytomas

Self Cite

Diffuse leptomeningeal glioneuronal tumor (DLGNT) was introduced, for the first time, as a provisional entity in the 2016 WHO classification of central nervous system tumors. DLGNT mainly occur in children and characterized by a widespread leptomeningeal growth occasionally associated with intraspinal tumor nodules, an oligodendroglial-like cytology, glioneuronal differentiation and MAP-Kinase activation associated with either solitary 1p deletion or 1p/19q codeletion in the absence of IDH mutation. We report here two unexpected DLGNTs adult cases, characterized by a unique supratentorial circumscribed intraparenchymal tumor without leptomeningeal involvement in spite of long follow-up. In both cases, the diagnosis of DLGNT was made after DNA-methylation profiling which demonstrated that one case belonged to the DLGNT class whereas the other remained not classifiable but showed on CNV the characteristic genetic findings recorded in DLGNT. Both cases harbored 1p/19q codeletion associated with KIAA1549:BRAF fusion in one case and with BRAF V600E and PIK3CA E545A mutations, in the other. Our study enlarges the clinical and molecular spectrum of DLGNTs, and points out that the terminology of DLGNTs is not fully appropriate since some cases could have neither diffuse growth nor leptomeningeal dissemination. This suggests that DLGNTs encompass a wide spectrum of tumors that has yet to be fully clarified.

Section: Casesupporting

confidence: 77%

Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases

Appay

Pagès

Colin

et al. 2020

Self Cite

“…In the present study, we revealed that the rate of TERT promoter mutations was 22.4% (13/ 58); additionally, this mutation was found mainly in H3wildtype tumors (9/13), and was associated with a poor prognosis for grade II/III spinal cord gliomas. The BRAF V600E mutation, KIAA1549-BRAF fusion, FGFR alterations, and MYB or MYBL1 rearrangements are key prognostic and therapeutic markers for diffuse brain gliomas with wildtype IDH and H3 in children or adolescents [3,14,15,30]. Here, we also found that BRAF V600E only occurred in H3-wildtype grade II/III spinal cord astrocytomas, and was associated with a good prognosis.…”

Section: Discussionsupporting

confidence: 58%

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation

Chai

Zhang

Liu

et al. 2020

Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. The BRAF V600E mutation (7/57) was only observed in H3-wildtype astrocytomas, and was associated with a better prognosis in all histological grade II/III astrocytomas. TERT promoter mutations were observed in both H3 K27M-mutant (4/25) and-wildtype (9/33) astrocytomas, and were associated with a poor prognosis in H3-wildtype histological grade II/III astrocytomas. In the 2016 WHO classification of CNS tumors, H3 K27M-mutant diffuse midline gliomas, including spinal cord astrocytomas, are categorized as WHO grade IV. Here, we noticed that the median overall survival of histological grade II/III H3 K27M-mutant cases (n = 28) was significantly longer than that of either the total histological grade IV cases (n = 12) or the H3 K27M-mutant histological grade IV cases (n = 7). We also directly compared H3 K27M-mutant astrocytomas to H3-wildtype astrocytomas of the same histological grade. In histological grade II astrocytomas, compared to H3-wildtype cases (n = 37), H3 K27M-mutant patients (n = 14) had showed a significantly higher Ki-67-positive rate and poorer survival rate. However, no significant differences in these parameters were observed in histological grade III and IV astrocytoma patients. In conclusion, these findings indicate that spinal cord astrocytomas are considerably different from hemispheric and brainstem astrocytomas in terms of their molecular profiles, and that the histological grade cannot be ignored when assessing the prognosis of H3 K27M-mutant spinal cord astrocytomas.

“…As each individual droplet is devoid of competition, each DNA fragment is amplified, allowing for unparalleled sensitivity. ddPCR can identify not only point mutations such as BRAF p.V600E [123], H3.3 p.K27M [187], IDH1 p.R132H [187], and FGFR1 p.N546K and p.K656E [58] but also CDKN2A deletions [123], KIAA1549-BRAF [5], and FGFR1 TKD-duplication [58] based on copy number comparisons. This technique is very robust on degraded DNA, including from FFPE material, and requires minimal technical hands-on time.…”

Section: Droplet Digital Pcrmentioning

confidence: 99%

Pediatric low-grade glioma in the era of molecular diagnostics

Ryall

Tabori

Hawkins

2020

255

251

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behaviorin particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.