Overview
NTRK gene fusion refers to chromosomal rearrangements involving the neurotrophic tyrosine receptor kinase genes NTRK1, NTRK2, and NTRK3. These genes encode the TRKA, TRKB, and TRKC receptor tyrosine kinases, which are essential for neuronal growth, survival, and differentiation. Gene fusion events lead to the formation of abnormal TRK fusion proteins with constitutive kinase activity, resulting in uncontrolled cell proliferation and oncogenesis. Although NTRK gene fusions are rare in most common solid tumors, with an overall prevalence of less than one percent, they are highly prevalent in certain rare tumors such as secretory breast carcinoma, mammary analogue secretory carcinoma of salivary glands, and congenital infantile fibrosarcoma, where fusion prevalence can approach one hundred percent. NTRK gene fusions are recognized as important pan-cancer biomarkers with tumor-agnostic therapeutic relevance.
Symptoms
NTRK gene fusion itself does not produce specific symptoms. Clinical manifestations depend on the type, location, and stage of the underlying malignancy. Patients may present with symptoms related to brain tumors, head and neck cancers, thyroid malignancies, soft tissue sarcomas, lung cancer, or colorectal cancer. These symptoms can include localized mass effects, pain, neurological deficits, respiratory symptoms, gastrointestinal disturbances, or systemic features such as weight loss and fatigue. In many cases, NTRK gene fusions are identified during molecular profiling of tumors rather than through symptom-based suspicion.
Causes
NTRK gene fusions arise due to chromosomal rearrangements that join the kinase domain of an NTRK gene with a partner gene. This fusion leads to constitutive activation of the TRK kinase domain independent of ligand binding. The activated fusion protein continuously stimulates downstream oncogenic signaling pathways, including RAS, MAPK, PI3,K AKT, PLC gamma, and STAT pathways. These pathways promote cell proliferation, survival, angiogenesis, and resistance to apoptosis. The resulting persistent signaling drives tumor initiation and progression across multiple tissue types.
Risk Factors
Risk factors for NTRK gene fusion positivity include the presence of specific rare tumors such as infantile fibrosarcoma, secretory carcinomas of the breast and salivary gland, and certain pediatric malignancies. NTRK fusions may also be detected in more common cancers, including non-small cell lung carcinoma, colorectal cancer, melanoma, central nervous system tumors, and sarcomas, although at low frequency. Patients with advanced, metastatic, or treatment-resistant cancers are often candidates for NTRK fusion testing. Technical factors such as tumor heterogeneity, sample quality, and detection method may influence test sensitivity and interpretation.
Prevention
There are no preventive measures to avoid the development of NTRK gene fusions, as they represent acquired genetic alterations driving cancer. Prevention in a clinical context focuses on early identification through appropriate molecular testing. Accurate detection using immunohistochemistry as a screening tool followed by confirmatory methods such as fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or next-generation sequencing, is essential. Proper sample collection, handling, and timely transportation help preserve nucleic acid integrity. Identification of NTRK gene fusions enables selection of targeted TRK inhibitor therapy, supports personalized treatment decisions, and significantly improves outcomes in patients with fusion-positive tumors.
