Abstract
The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.
Highlights
Tumor diagnosis and prognostic evaluation, as well as therapeutic management, were addressed by histological examination alone, which was based on tumor morphology and complementary immunohistochemical profiling
TThheeOonnccooggenenicicRaocletiovfaNtiTonRKof: FNuTsRioKnscVanerosucscuOrtihnerseAvleterraaltiwonasys, including structural chromosomal rearrangements leading to gene fusions, splice variants, mutations, copy number alterations and The oncogenic activation of neurotrophic tropomyosin receptor kinase (NTRK) can occur in several ways, including structural chromosomal rearrangements leading to gene fusions, splice variants, mutations, copy number alterations and increased expression
Considered that NTRK was discovered as a potential oncogene in colorectal cancer (CRC) [27,88], and that tumors in which NTRK fusions can be considered pathognomonic belong to non-central nervous system (CNS) cell-lineages as well, the oncogenic potential of this signaling pathway is not restricted to tissues with NTRK physiological expression [76,77,78,79,80]
Summary
Tumor diagnosis and prognostic evaluation, as well as therapeutic management, were addressed by histological examination alone, which was based on tumor morphology and complementary immunohistochemical profiling. Since NTRK fusions have been found at significant frequencies in CNS tumors, which typically lack effective therapies, their detection is expected to soon become a mainstay in the diagnostic assessment of these tumors, and specific expertise in this topic will become mandatory. In this Review, we will discuss the biology and physiological role of TRK receptors as well as their role in pathological conditions, focusing on the recently collected knowledge in brain tumors
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