Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

Abstract

Background The use of next‐generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long‐term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. Methods Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. Results We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI‐MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB‐ALK, CIC‐LEUTX, FGFR2‐KIAA159, and MN1‐CXXC5 and detail their morphological features. Conclusions Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

Genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma

“…It was first reported in a 3-month-old female with HGG who did well with gross total resection alone but 4 years later had a recurrence/new tumor of a LGG (ganglioglioma) with the identical fusion [ 11 , 12 ]. This fusion was also observed in an 8-year-old female with a myxopapillary ependymoma in the cauda equina who underwent gross total resection and had been disease free for over 8 years [13] . A recent study detected PPP1CB-ALK fusion in a 10month-old infant with a low-grade glioma and in a newborn with a congenital HGG [3] .…”

“…Recent in vitro and in vivo studies have demonstrated that the PPP1CB-ALK fusions were tumorigenic, and tumor cells and xenograph tumors harboring PPP1CB-ALK fusion exhibited sensitivity to ALK-inhibitors [ 3 , 24 ] . The majority of the few PPP1CB-ALK fusion positive brain tumors are reported to have relatively good outcomes by gross total resection [11][12][13] . Unfortunately, our patient passed away on day two of the life because the size of the tumor, the age of the patient and the neurological comprise at birth made the risk of surgery prohibitive.…”

“…PPP1CB-ALK fusions have been observed in a few case reports including a 3-month old female with a high-grade glioma (HGG) and later a low-grade glioma (LGG) [ 11 , 12 ], an 8-year old female with a myxopapillary ependymoma [13] , and a 66-year-old female with IMT of the uterus [14] . A recent study detected this fusion in infantile LGG and HGG, and demonstrated its tumorigenic potential in vivo [3] .…”

Case Report: A Unique Case of Pediatric Central Nervous System Embryonal Tumor Harboring the CIC–LEUTX Fusion, Germline NBN Variant and Somatic TSC2 Mutation: Expanding the Spectrum of CIC-Rearranged Neoplasia

“…However, a CIC – NUTM1 gene fusion or a CIC frameshift deletion, not a CIC – LEUTX gene fusion and a CIC amplification, were detected in CNS EFT– CIC . In review of the literature, we found only three cases of the CIC – LEUTX gene fusion were reported in CNS, namely a case of CNS angiosarcoma, a case of anaplastic ganglioglioma, and a case of anaplastic astrocytoma with epithelioid GBM features ( 7 , 8 ) ( Table 1 ), and this is the first case of CIC – LEUTX gene fusion in a CNS embryonal tumor.…”

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…Pediatric diffuse low and high-grade gliomas are undergoing significant changes in terms of diagnostic assessment, due to the increasing importance of molecular markers for classification and stratification [10,112,113]. These tumors also harbor peculiar molecular profiles which vary significantly from adult tumors, even in cases with similar histological features.…”