The distribution of NTRK mutations and their relationship with pathogenesis of the local agresive spindle cell tumors

NTRK gene fusions are rare but therapeutic target genomic changes in common tumors. Tyrosine kinase inhibitors targeting NTRK fusions are of great importance as they are the second tumor and tissue agnostic drug approved by the FDA. In the current literature, which method and which algorithm should be used to investigate NTRK fusions in different tumor groups constitutes the biggest problem and is still currently being discussed. In this thesis, the presence of NTRK gene fusion was investigated in Dermatofibrosaroma protuberans (DFSP), Solitary fibrous tumor (SFT) and Inflammatory myofibroblastic tumor (IMT) groups, which are included in the group of locally aggressive spindle cell tumors of soft tissue. For this research, immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) and targeted RNA sequencing (RNA-Seq) methods used in the literature were used. In addition, unlike the literature, it has been examined whether fusion detection can be performed with 3'5' imbalance analysis in quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis. It was tried to determine what would be the most ideal method among these four methods. In the evaluation of all four methods together, 1 (5.8%) case with fibrosarcomatous transformation among 17 DFSP cases, 2 (22.2%) of 9 SFT cases with central nervous system and 1 (3.4%) of 29 IMT cases. NTRK gene fusion has been detected. NTRK gene fusion was not observed in any of the 21 peripherally located SFT cases. As a result of comparing the methods with each other, it was concluded that FISH analysis is the most ideal method in the case of examining the NTRK gene fusion from old archive material, and the RNA-based NGS method is not an ideal method due to its low negative predictive values. It was seen that the imbalance analysis gave healthier results in the last 2 years archive material, and it was thought that it could be used as an alternative method for detecting NTRK gene fusion if it could be improved by increasing the number of primers.