Molecular alterations in pediatric brainstem gliomas

Abstract

Background: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. Methods:We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). Results: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors.One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPAR , PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. Conclusions:Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration.Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas. K E Y W O R D SBrainstem glioma, diffuse intrinsic pontine glioma, next-generation sequencing, pediatric

High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

“…We have collected publicly available data from 23 recent pediatric and adult HGG cohorts with molecular data. 4,9,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] We were careful to subtract 321 AYA cases from this review in order to elucidate the distribution of molecular subgroups in this particular age group (15-25 y) and to compare them with purely pediatric (<15 y) and adult (>25 y) cases. Otherwise, we collected recent publicly available data from the largest pediatric 7 and 2 adult cohort 34,35 studies comprising globally 2646 cases: pediatric (<15 y, n = 1012), adolescent (15-25 y, n = 321), and adult (26-55 y, n = 1313).…”

Identification of Grade-associated MicroRNAs in Brainstem Gliomas Based on Microarray Data

“…Radiotherapy is the standard treatment for BSGs, and a total dose of 54 greys (Gy) in daily fractions of 1.8 Gy to 2.0 Gy is most commonly used; however, irradiation can only transiently alleviate tumour progression 8 , 9 . Chemotherapy does not have any significant effect on the outcome 10 . Moreover, there are some reports of salvage targeted therapy with bevacizumab and experimental treatments with etoposide, paclitaxel, and tamoxifen; the challenge comes from the lack of tumour-specific targets 6 , 11 .…”

Direct Involvement of Cranial Nerve V at Diagnosis in Patients With Diffuse Intrinsic Pontine Glioma: A Potential Magnetic Resonance Predictor of Short-Term Survival

“…In the 2016 revision of the WHO brain tumor classification, these neoplasms were termed as diffuse midline glioma, H3K27M-mutant (32). Imaging studies are currently directing toward highlighting correlations between the relevant imaging findings and the new molecular findings (33, 34). If involvement of CN V was confirmed to be a predictor of poor survival in DIPG, it could be hypothesized that such finding could also have prognostic significance for the newer entity of the diffuse midline glioma H3K27M mutant.…”