Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas

Abstract

Background The MAPK/ERK pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer. Previous studies found that BRAF mutations as well as KIAA1549-BRAF fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic changes in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG. Methods We retrospectively analyzed 46 spinal gliomas from patients age 1-25 years from Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (Sick Kids). CHCO utilized a 67 gene panel which assessed BRAF and additionally screened for other possible genetic abnormalities of interest. At Sick Kids, BRAFV600E was assessed by ddPCR and IHC. BRAF fusions were detected by FISH, RT-PCR or Nanostring platform. Data was correlated with clinical information. Results Of 31 samples with complete fusion analysis, 13 (42%) harbored KIAA1549-BRAF. All thirteen (100%) patients with confirmed KIAA1549-BRAF survived the entirety of the study period (median [interquartile range, IQR] follow-up time: 47 months [27-85 months]) and fifteen (83.3%) fusion negative patients survived (follow-up time: 37.5 (19.8-69.5 months). Other mutations of interest were also identified in this patient cohort including BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion. Conclusion KIAA1549-BRAF was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and experienced lower death rates compared to KIAA1549-BRAF negative patients, although this was not statistically significant.

Intradural Pediatric Spinal Tumors: An Overview from Imaging to Novel Molecular Findings

“…It has been largely investigated and demonstrated that KIAA1549-BRAF-fused cerebellar pLGGs have a better prognosis compared to the ones not carrying the fusion; the same evidence has been described for the spinal low-grade gliomas [ 13 , 15 ]. On the other hand, the presence of BRAF fusion in the tumor suggests the potential use of target therapy, such as MEK inhibitors [ 16 ], while the use of BRAF inhibitors are indicated and useful when the BRAFV600 mutation is present [ 17 ].…”

“…Mutations in genes encoding histone H3.1 (HIST1H3B) and H3.3 (H3F3A) have been considered as a hallmark of diffuse midline gliomas. Instead, histonic mutations are also rarely found in pediatric low-grade gliomas [ 19 ]; this concept is important in highlighting the pathological heterogeneity in gliomas and the overlapped genetic landscape between high- and low-grade gliomas [ 13 , 20 ].…”

“…The pHGG's prognosis remains bleak, with a mean survival of 12 months afte nosis and a range between 6-16 months [12]. The genetic landscape of pediatric spinal tumors has been less studied than that of intracranial localization: the involvement of KIAA1549-BRAF (v-raf murine sarcoma viral oncogene homolog B1), BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion has been detected in pediatric spinal tumors [13,14]. One of the most studied molecular alterations concerns LGG and it is KIAA1549-BRAF fusion that causes the hyperactivation of the MAPK/ERK pathway.…”

“…The presence of calcifications is closely related to the diagnosis of ganglioglioma [8], while solid components and cysts [1], as well as edema and enhancement, are non-specific [24,25]. Due to relative rarity, few studies have focused on The genetic landscape of pediatric spinal tumors has been less studied than that of intracranial localization: the involvement of KIAA1549-BRAF (v-raf murine sarcoma viral oncogene homolog B1), BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion has been detected in pediatric spinal tumors [13,14]. One of the most studied molecular alterations concerns LGG and it is KIAA1549-BRAF fusion that causes the hyperactivation of the MAPK/ERK pathway.…”

Analyses of DNA Methylation Profiling in the Diagnosis of Intramedullary Astrocytomas

“…Some studies have shown that the main recurrent molecular alterations are KIAA1549-BRAF fusions and H3F3A p . K27M (H3K27M) mutations ( 9 , 10 ), while others did not identify recurrent molecular alterations at all ( 11 ). Interestingly, the most frequent molecular alterations found in brain astrocytomas, such as IDH mutations, are generally not observed in IMAs or were not classic IDH1 p. R132H and IDH2 p. R172H mutations ( 9 , 11–17 ).…”