NTRK Gene Fusions: A Compendium of Fusion Partners and Tumor Types.

Abstract

Purpose: NTRK gene fusions are oncogenic drivers for a variety of adult and pediatric tumors, making them a target for tumor-agnostic precision medicine. Tropomyosin receptor kinase (TRK) inhibitors are approved by the US Food and Drug Administration for cancers driven by TRK fusions. However, NTRK genes can fuse with many different partner genes, leading to diverse TRK fusion proteins, highlighting the importance of identifying the specific fusion partner with optimal pan-cancer diagnostics. This analysis aims to provide an updated descriptive compendium of NTRK gene fusions.

Methods: NTRK gene fusions were identified via literature searches (PubMed), a search of a clinical trials database (larotrectinib), and searches of two genomic databases (Memorial Sloan Kettering and Children's Hospital of Philadelphia).

Results: In total, 358 distinct NTRK gene fusion-tumor pairings were identified across 25 tumor types. Primary CNS tumors were observed to harbor 86 distinct NTRK gene fusions, followed by sarcomas (n = 73). Overall, 229 different fusion partners were identified across tumor types (regardless of NTRK gene). Twenty-three fusion partners were found to fuse with >1 NTRK gene across tumor types, while 183 fusion partners were associated with only a single NTRK gene in one tumor type. ETV6::NTRK3 was found in the highest number of different tumor types.

Conclusion: This analysis illustrates the diversity of NTRK gene fusion partners across various tumor types and highlights the importance of selecting a pan-tumor fusion-partner agnostic test that can identify both known and novel fusion partners to identify patients who may benefit from treatment with TRK inhibitors.