Diagnostic approach of tumors with neurotrophic tropomyosin receptor tyrosine kinase gene fusions

The neurotrophic tropomyosin receptor tyrosine kinase (NTRK) gene family members (NTRK1, NTRK2, NTRK3), encoding tropomyosin receptor tyrosine kinase proteins (TrkA, TrkB, TrkC), physiologically, are responsible for the maturation, proliferation and maintenance of neurons. The genetic alterations of the NTRK family, mostly caused by chromosomal translocation, can lead to the development of several malignant tumors. These gene rearrangements can be detected in rare tumors, like infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, with very high frequency, but also in very common malignancies - colorectal carcinoma, lung cancer - with relatively low incidence rate. Given the newly discovered, highly selective Trk inhibitors, used with high overall response rate, we highlight the growing importance of an appropriate diagnostic approach for tumors harboring NTRK gene alterations. This review discusses all diagnostic methods, their advantages and disadvantages, that can be used to identify NTRK gene fusions, and we make diagnostic considerations, that can help in these cases to choose the proper technique.