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

Abstract

Central nervous system (CNS) embryonal tumors (WHO grade IV) are a heterogeneous group of rare, poorly differentiated neuroepithelial malignant neoplasms that commonly occur in children, and they have a poor prognosis. The 2016 WHO (World Health Organization) classification of CNS tumors created a major shift in paradigm of the classification of embryonal tumors. However, some cases were still difficult to classify. Further integrative genomic analysis is needed to improve the precise classification, diagnosis and treatment of CNS embryonal tumors. Herein, we firstly report a case of CNS embryonal tumor harboring the pathogenic CIC–LEUTX gene fusion. A 2-year-old male infant presented with a solid cystic mass in the left temporal lobe-basal ganglia and left parietal lobe (maximum diameter, 75 mm) and underwent gross tumor resection. The tumor was classified as a poorly differentiated embryonal neoplasm of neuroectodermal origin that lacked specific features and rosettes. By immunohistochemistry, the tumor cells were strongly positive for synaptophysin, and the Ki67 proliferation index was high (>50%). FISH (Fluorescence in situ hybridization) results indicated no change in the copy number at the 19q13.42 C19MC locus. Next generation sequencing showed a CIC–LEUTX gene fusion, a somatic TSC2 c.G2714A mutation, and a heterozygous germline NBN c.C127T mutation. One month after surgery, there was recurrence of the intracranial tumor (maximum diameter, 55 mm) as well as spinal cord implantation metastasis. The patient received chemotherapy (CTX+CBP+VCR/DDP+VP-16), radiotherapy, and a drug targeting the TSC2 gene (everolimus). At the time of this writing, the patient is alive without evidence of disease for 11 months. This is the first report of the CIC–LEUTX gene fusion in a case of CNS embryonal tumor.

Imaging Characteristics of CNS Neuroblastoma-FOXR2: A Retrospective and Multi-Institutional Description of 25 Cases

“…Therefore, only a few case series describing its imaging features exist. 6,7,[10][11][12][13] In our international cohort of 25 patients, we found that these were supratentorial, often large, multilobulated tumors with little-orno perifocal edema. Tumors nearly always showed a mix of solid and cystic/necrotic components.…”

A case of CIC‐rearranged sarcoma with CIC‐LEUTX gene fusion in spinal cord

“…The other article was a case of an embryonal tumor of the central nervous system in a child. This case not only had the CIC‐LEUTX fusion gene but also had NBN germline mutations and TSC2 lineage mutations 18 . So far, there are only three reports on CIC‐LEUTX fusion tumors, with a total of four cases, and this case is the fifth case (Table 2).…”

A novel BRD4‐LEUTX fusion in a pediatric sarcoma with epithelioid morphology and diffuse S100 expression

“…LEUTX gene is expressed almost exclusively during embryonal life and plays an important role in embryonal genome activation through its N‐terminal highly conserved homeodomain (HD), which is responsible for promoter binding and consequent transcription of target genes 12,13 . LEUTX rearrangements with CIC and KAT6A as fusion partners have been described in CNS tumors and acute myeloid leukaemia, respectively 14‐16 . Recent studies have suggested that CIC‐LEUTX fusion may work similarly to CIC‐DUX4 , as both LEUTX and DUX4 contain HD domains, which may confer chimeric transcriptional regulatory properties to CIC, likely enhancing its transcriptional activity 17‐19 …”

“…12,13 LEUTX rearrangements with CIC and KAT6A as fusion partners have been described in CNS tumors and acute myeloid leukaemia, respectively. [14][15][16] Recent studies have suggested that CIC-LEUTX fusion may work similarly to CIC-DUX4, as both LEUTX and DUX4 contain HD domains, which may confer chimeric transcriptional regulatory properties to CIC, likely enhancing its transcriptional activity. [17][18][19] BRD4 is a regulator of gene transcription, DNA replication and repair, and has been involved in numerous forms of human cancers, for example, BRD4-NUT driven NUT midline carcinoma, and its role as therapeutic target has been recently investigated.…”