Understanding NTRK Fusions and Their Role in Tumorigenesis
Posted: Monday, November 29, 2021
A review article published by a group of scientists at the Children’s Hospital of Philadelphia described the molecular biology and tumorigenesis of NTRK fusions along with their prevalence and clinical significance. Yiming Zhong, PhD, and his colleagues published this article in Cancer Genetics, providing insight into these genes that encode a class of TRK receptors.
The TRK receptors encoded by NTRK genes play critical roles in cell survival, proliferation, and differentiation. These TRK proteins are predominantly found in neuronal tissues, and germline mutations in the NTRK genes have been associated with neurodevelopmental disorders. Somatic alterations have been identified in malignancies including acute myeloid leukemia, thyroid carcinoma, salivary gland carcinoma, nonsmall cell lung cancer, melanoma, colorectal cancer, glioma, and neuroblastoma. The most common mechanism of oncogenic activation of TRKs is through chromosomal rearrangement, creating a fusion protein that becomes constitutively active. As a result of the mutation, cells experience uninterrupted growth, a lack of apoptosis, indefinite survival, and tumorigenesis. These fusions are rare, occurring in less than 1% of all solid tumors. However, the incidence of NTRK fusions is higher in pediatric tumors (possibly around 2.3%) than adult tumors.
To detect these mutations, immunohistochemistry fluorescence in situ hybridization, polymerase chain reaction, and next-generation sequencing have all been employed. The authors noted that next-generation sequencing has nearly 100% sensitivity and specificity for identifying these mutations; however, it has the highest cost and longest turnaround time of the aforementioned tests.
Identifying these mutations is of clinical importance, as NTRK fusions have been shown to be either the primary or sole driver of oncogenic in tumors. Currently, two drugs, entrectinib and larotrectinib, have been approved by the U.S> Food and Drug Administration for the treatment of tumors with NTRK fusions.
Disclosure: The authors reported no conflicts of interest.