NTRK Fusions Across Solid Tumours: Biology, Prevalence, and Testing Strategies
With FDA-approved TRK inhibitors now available, detecting NTRK gene fusions has become clinically essential across a wide range of solid tumours, from high-frequency cancers like secretory carcinoma to low-frequency occurrences in common malignancies. RNA-based NGS represents the gold standard for fusion identification, though FISH and DNA-based NGS are adequate alternatives. Pan-Trk immunohistochemistry offers a cost-effective screening strategy, although it is not definitive and must be confirmed by molecular testing.
The original study
NTRK fusions and Trk proteins: what are they and how to test for them.
- Authors
- Weiss LM, Funari VA
- Journal
- Human pathology
- Type
- Journal Article, Review
- PMID
- 33794242
Original abstract
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.