Identification of a Novel, Recurrent SLC44A1‐PRKCA Fusion in Papillary Glioneuronal Tumor

Abstract

Mixed neuronal-glial tumors are rare and challenging to subclassify. One recently recognized variant, papillary glioneuronal tumor (PGNT), is characterized by prominent pseudopapillary structures and glioneuronal elements. We identified a novel translocation, t(9;17)(q31;q24), as the sole karyotypic anomaly in two PGNTs. A fluorescence in situ hybridization (FISH)-based positional cloning strategy revealed SLC44A1, a member of the choline transporter-like protein family, and PRKCA, a protein kinase C family member of serine/threonine-specific protein kinases, as the 9q31 and 17q24 breakpoint candidate genes, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) analysis using a forward primer from SLC44A1 exon 5 and a reverse primer from PRKCA exon 10 confirmed the presence of a SLC44A1-PRKCA fusion product in both tumors. Sequencing of each chimeric transcript uncovered an identical fusion cDNA junction occurring between SLC44A1 exon 15 and PRKCA exon 9. A dual-color breakpoint-spanning probe set custom-designed for interphase cell recognition of the translocation event identified the fusion in a third PGNT. These results suggest that the t(9;17)(q31;q24) with the resultant novel fusion oncogene SLC44A1-PRKCA is the defining molecular feature of PGNT that may be responsible for its pathogenesis. The FISH and RT-PCR assays developed in this study can serve as valuable diagnostic adjuncts for this rare disease entity.

The landscape of kinase fusions in cancer

“…Protein kinase C fusions have recently been described in papillary glioneuronal tumours32 and benign fibrous histiocytoma33. We found two new occurrences of PRKCA (protein kinase C, alpha) fusions in lung squamous cell carcinoma and three PRKCB (protein kinase C, beta) fusions in lung squamous cell carcinoma, lung adenocarcinoma and low-grade glioma (Fig.…”

Pigment-Synthesizing Melanocytic Neoplasm With Protein Kinase C Alpha (PRKCA) Fusion

“…13 Furthermore, PRKCA fusions have been identified as putative pathogenic events in other tumors, such as papillary glioneuronal tumor and lung squamous cell carcinoma. 14,15 …”

Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing

“…Although KIRREL has not been implicated in gene fusions before, Bridge and co-workers recently described a recurrent SLC44A1/PRKCA fusion in papillary glioneural tumor, with the same breakpoint in PRKCA as in the FH of the present study. 21 Further arguments for a pathogenetic significance of the KIRREL/PRKCA fusion in the context of FH is that KIRREL, like the previously identified aminoterminal partners PDPN, CD63, and LAMTOR1, is a membrane-associated protein, retaining its membranebinding part in the chimeric protein. 4 Abbreviations: CAFH, cellular/aneurysmal fibrous histiocytoma; CFH, cellular fibrous histiocytoma; LGFMS, low-grade fibromyxoid sarcoma; MLS, myxoid liposarcoma; PC, positive control; RFH, regular fibrous histiocytoma; Syn sarc, synovial sarcoma.…”