Case Report: A novel LHFPL3::NTRK2 fusion in dysembryoplastic neuroepithelial tumor

Abstract

Neurotrophic tyrosine receptor kinase (NTRK) rearrangements are oncogenic drivers of various types of adult and pediatric tumors, including gliomas. However, NTRK rearrangements are extremely rare in glioneuronal tumors. Here, we report a novel NTRK2 rearrangement in a 24-year-old female with dysembryoplastic neuroepithelial tumor (DNT), a circumscribed WHO grade I benign tumor associated with epilepsy. By utilizing targeted RNA next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), reverse transcriptase PCR (RT-PCR), and Sanger sequencing, we verified an in-frame fusion between NTRK2 and the lipoma HMGIC fusion partner-like 3 (LHFPL3). This oncogenic gene rearrangement involves 5’ LHFPL3 and 3’ NTRK2, retaining the entire tyrosine kinase domain of NTRK2 genes. Moreover, the targeted DNA NGS analysis revealed an IDH1 (p.R132H) mutation, a surprising finding in this type of tumor. The pathogenic mechanism of the LHFPL3::NTRK2 in this case likely involves aberrant dimerization and constitutive activation of RTK signaling pathways.

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

“…A classic example of transcription factor fusion is the EWSR1::FLI1 fusion, which is a common driver in Ewing sarcoma [79,80]. The most notable protein kinases involved in fusions include the MAST kinases in breast cancer [81], present in 3 to 5% of cases, as well as RET in various cancers (particularly lung and thyroid) [76,[82][83][84] and other RTKs in a variety of tumors [36,36,[85][86][87][88][89][90][91][92][93][94][95][96][97]. Such rearrangements are occasionally cancer-specific, or may be observable in distinctly different cancer types.…”

“…The vast majority of fusions identified in MPS studies are non-recurring, and, as such, have been identified as stochastic events [19]. While large-scale MPS efforts have been enormously productive in identifying fusion break points, novel oncofusions and their acting mechanisms are still being identified from MPS data at an accelerating pace [85][86][87][88][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120], and while multiple fusion databases are available [64,121,122], a centralized and standardized hub akin to, for example, IntAct [123] for interaction data or UniProt [124] for protein information has yet to emerge.…”