Novel FGFR2::ZCCHC24 Fusion in Dysembryoplastic Neuroepithelial Tumor

To the Editor:

Dysembryoplastic neuroepithelial tumor (DNT) is a morphologically unique low-grade tumor first reported in a series of young patients with resectable intracortical lesions that had multinodular architecture, and a heterogeneous cellular composition (1). DNTs have a strong association with drug-resistant seizures and may be found in as many as 20% of patients who undergo surgical resection for chronic epilepsy. The tumor commonly involves the temporal lobe (mesial structures, 67.3%); however, tumors in the frontal, parietal, occipital lobes, and infratentorial regions have been reported (1–3). On neuroimaging, the tumors exhibit a lobulated architecture with sharply defined margins. Cystic or multicystic changes with septa generate a characteristic soap-bubble appearance. Peritumoral edema, calcifications, and hemorrhage are rare. A nodular pattern and/or peripheral rim enhancement are noted in one-third of patients after gadolinium administration (3). Although most DNTs are CNS WHO grade 1 tumors, some have been reported to undergo malignant transformation (4, 5). Thus, comprehensive molecular characterization to better understand the tumor is warranted.

The exact driving factors for the development of DNTs are unknown. Mitogen-activated protein kinase (MAPK) signaling pathway activation was described in DNTs with pathogenic alterations predominantly involving fibroblast growth factor receptors (FGFR), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and platelet-derived growth factor receptor α (PDGFRA) (6, 7, 10). Activating FGFR1 variants are identified in the majority of DNTs, and a BRAF p. V600E mutation was present in up to 50% of DNT cases (7). More commonly reported FGFR1 alterations include internal tandem duplication of the tyrosine kinase domain and missense variants (6). FGFR family fusions are very rarely reported in DNTs (8–11). Here, we report a case of DNT with a novel FGFR2::ZCCHC24 fusion.

A 15-year-old boy presented with seizures manifesting as a visual aura affecting the left inferior temporal visual field (multiple times/day). T2-weighted magnetic resonance imaging revealed a hyperintense mass with a bubbly appearance in the right occipital lobe along the parieto-occipital lobe sulcus, measuring 3.7 cm × 3.7 cm × 3.6 cm (Fig. 1A, B). The patient underwent a right-sided occipital craniotomy with gross total resection of the lesion. Postoperatively, his visual symptoms improved as the left inferior temporal field became less blurry.

FIGURE 1.

Dysembryoplastic neuroepithelial tumor. (A) Horizontal view of magnetic resonance imaging shows an expansile cortically based T2 hyperintense mass with a bubbly appearance, measuring 3.7-cm transverse, in the right occipital lobe along the parieto-occipital lobe sulcus. (B) Sagittal view of the lesion in T1-weighted image. (C) The tumor is composed of small monotonous oligodenodroglia-like cells with delicate vasculature and focal calcifications. (D) A compact piloid glial component is also noted (H&E 200×). (E) The tumor cells are positive for glial fibrillary acidic protein by immunohistochemistry (280×). (F) In between the glial component are neuronal cells floating in a myxoid background (400×), as highlighted by NeuN staining (G) (400×). (H) Tumor proliferation index is low (<1%), as highlighted by Ki67 (100×).

Histological examination of the lesion showed a glioneuronal neoplasm composed of glial tumor cells with round uniform nuclei and perinuclear clearing (oligodendroglia like) in a myxoid/mucoid background (Fig. 1C). Multifocal piloid components were also evident (Fig. 1D). Many neurons appeared to “float” in the abundant myxoid matrix (highlighted by NeuN staining, Fig. 1F, G). No dysplastic ganglion cells, tumor necrosis, or microvascular proliferation were identified. There were no eosinophilic granular bodies or Rosenthal fibers. The tumor cells were positive for glial fibrillary acidic protein (Fig. 1E), negative for BRAF p. V600E, and negative for IDH1 p. R132H mutations (data not shown). The Ki67 proliferation index was less than 1% (Fig. 1H). The diagnosis of a DNT, CNS WHO grade 1, was rendered.

Next-generation sequencing (Illumina, TruSight Tumor 170) revealed an abnormal sequence transcript arising from a FGFR2:ZCCHC24 genomic fusion (Fig. 2A) and 2 other variants of uncertain significance (BRAF p. M23V, TFRC p. T658A). No other genetic mutation was detected. A chromosomal microarray (Affymetrix OncoScan assay) showed gains within multiple regions of chromosome 10 (Fig. 2B). Closer investigation confirmed the breakpoints in the tyrosine kinase domain 2 of FGFR2 and zinc finger binding domain of ZCCHC24 (Fig. 2C). DNA methylation profiling of the tumor was consistent with DNT (National Cancer Institute 850K methylation classifier; data not shown).

FIGURE 2.

Sequencing and chromosomal microarray results of the DNT. (A) Next-generation sequencing reveals a novel FGFR2::ZCCHC24 in-frame fusion transcript. The result was called using Manta containerized in the TST170 local app v1 (Illumina). The fusion was supported by a total of 8346 reads—5375 split reads and 2971 paired reads. This generated a “high confidence fusion” score of 0.933 (minimum acceptable value is 0.3). (B) Whole genome view of the chromosome microarray with a graphical representation of copy number probes on top and SNP probes on the bottom. Only chromosome 10 exhibits abnormalities with multiple regions of gain. (C) Individual regions of gain are seen in a close-up view of chromosome 10. In particular, 1 region of gain (arr[GRCh37] 10q22.3q26.13 (80930697_123725466)x3) contains both fusion partners FGFR2 and ZCCHC24 at its breakpoints.

FGFR2 fusion is relatively infrequent, accounting for approximately 15% of all FGFR2 genetic aberrations (9). In the context of low-grade neuroepithelial tumors (LGNTs), FGFR2::INA was reported in several cases of ganglioglioma (11, 12), multinodular and vacuolating neuronal tumors (11, 13), and polymorphous low-grade neuroepithelial tumor of the young (PLNTY) (11). Other reported fusion partners include ACTR1A (11), SHTN1 (previously KIAA1598) (12), and OPTN (11), which correspond to PLNTY, ganglioglioma, and LGNET, respectively (Table). To the best of our knowledge, no FGFR2 fusion has yet been reported in DNT. Moreover, the fusion partner we report here, FGFR2::ZCCHC24, is novel in cancer.

TABLE.

Reported Brain Tumors with FGFR2 Fusion

Report (Reference) (Number of Cases)	Age/Sex	Location	Presenting Symptoms	Diagnosis	FGFR2 Fusion	Other Genetic Alteration
Current report	15/M	Occipital	Visual field deficit	DNT	FGFR2::ZCCHC24	BRAF, TFRC
(# cases: 1)
Gupta et al (11)	17/M	Temporal	Chronic seizures	PLNTY	FGFR2::ACTR1A	–
(# cases: 1)
Gupta et al (11)	10/F and 38/M	Temporal	Chronic seizures and seizures	PLNTY	FGFR2::INA	–
(# cases: 2)
Gupta et al (11)	35/M	occipital	Chronic seizures	Ganglioglioma	FGFR2::INA	–
(# cases: 1)
Pekmezci et al (12)	35/M	Parietal	Unknown	Ganglioglioma	FGFR2::INA	–
(# cases: 1)
Pekmezci et al (12)	7/M	Temporal	Seizures	Ganglioglioma	FGFR2::SHTN1	–
(# cases: 1)
Gupta et al (11)	12/M	Temporal	Chronic seizures	Mixed MVNT/Ganglioglioma	FGFR2::INA	–
(# cases: 1)
Pekmezci et al (13)	12/M	Temporal	Seizures	Mixed MVNT/ganglioglioma	FGFR2::INA	BRAF
(# cases: 1)
Gupta et al (11)	6/M	Parietal	Chronic seizures	LGNET, NOS (favor DNT)	FGFR2::OPTN	–
(# cases: 1)

DNT, dysembryoplastic neuroepithelial tumor; PLNTY, polymorphous low-grade neuroepithelial tumor of the young; MVNT, multinodular and vacuolating neuronal tumors; LGNET, low-grade neuroepithelial tumor; NOS, not otherwise specified; F, female; M, male.

The extracellular domain of FGFR interacts with a fibroblast growth factor to initiate a downstream cascade that influences cellular mitogenesis, proliferation, and differentiation. Activated FGFR2 can phosphorylate fibroblast growth factor receptor substrate 2 (FRS2), which in turn mediates the activation of MAPK and PI-3K/AKT signaling (8). These pathways are thought to be involved in the pathogenesis of DNT (10, 11). Zinc finger CCHC-type 24 (ZCCHC24) is a poorly studied member of the ZCCHC superfamily proteins. In humans, the family encompasses 25 RNA binding proteins with multifaceted roles in RNA metabolism, including transcription, alternative splicing, translation, and RNA degradation (14). Interestingly, ZCCHC24 is ubiquitously expressed in the brain, especially in oligodendrocyte precursor cells and oligodendrocytes (15). In-frame fusion of FGFR2 and ZCCHC24 thus raises the possibility that the dysregulated FGFR signaling could aberrantly affect critical RNA metabolism in this tumor.

In conclusion, we describe the first case of DNT with a novel FGFR2::ZCCHC24 fusion. This underscores the role of the MAPK pathway in the pathogenesis of this disease, which is consistent with prior FGFR2 fusions described in LGNTs (10). The molecular result provides reasonable mechanistic evidence for the use of FGFR2-targeted therapies in the treatment of DNTs.

 

The authors acknowledge the support of the Laboratory for Clinical Genomics and Advanced Technology in the Department of Pathology and Laboratory Medicine of the Dartmouth Hitchcock Health System. The authors also acknowledge the Pathology Shared Resource, at the Norris Cotton Cancer Center at Dartmouth with NCI Cancer Center Support Grant 5P30 CA023108-37.

The authors have no duality or conflicts of interest to declare.