NTRK fusions and Trk proteins: what are they and how to test for them.

The NTRK genes include a family of three genes, NTRK1, NTRK2, and NTRK3, which are associated with fusions with a variety of partner genes, leading to upregulation of three proteins, TrkA, TrkB, and TrkC. NTRK fusions occur in a variety of solid tumors: at high incidence in secretory carcinoma of the breast and salivary glands, congenital mesoblastic nephroma, and infantile fibrosarcoma; at intermediate incidence in thyroid carcinoma, particularly postradiation carcinomas and a subset of aggressive papillary carcinomas, Spitzoid melanocytic neoplasms, pediatric midline gliomas (particularly pontine glioma), and KIT/PDGFRA/RAS negative gastrointestinal stromal sarcomas; and at a low incidence in many other solid tumors. With new FDA-approved treatments available and effective in treating patients whose tumors harbor NTRK fusions, testing for these fusions has become important. A variety of technologies can be used for testing, including FISH, PCR, DNA, and RNA-based next-generation sequencing, and immunohistochemistry. RNA-based next-generation sequencing represents the gold standard for the identification of NTRK fusions, but FISH using break-apart probes and DNA-based next-generation sequencing also represent adequate approaches. Immunohistochemistry to detect increased levels of Trk protein may be very useful as a screening technology to reduce costs, although it alone does not represent a definitive diagnostic methodology.