MO_III_L: Molecular Sciences III. Lectures
Zoltán Lippai (1), Zoltán Sápi (1)
1: 1st Department of Pathology and Experimental Cancer Research
Introduction: The three member (NTRK1, NTRK2, NTRK3) of the NTRK gene family encode three tyrosine-kinase receptors (TrkA, TrkB, TrkC), which play important role in the apoptosis, proliferation, cell cycle regulation of neuronal and non-neuronal cells. Genetic abnormalities of the NTRK genes may lead to cell cycle dysregulation and tumorigenesis. Some rare tumors that have myogenic differentiation seems to have higher risk for NTRK gene alterations. Among the various types of NTRK gene alterations, the fusion is the best known and most described. In the case of gene fusion, the coding region of the tyrosine-kinase domain always remains intact, showing its importance. Given the newly discovered drugs, patients with tumors that harbor NTRK gene fusion can be treated. Unfortunately, the other types of gene rearrangements within the NTRK genes are not well investigated yet.
Aims: Our aim is to examine the tyrosine-kinase domain coding regions of the NTRK1-3 genes in soft tissue tumors that have myogenic differentiation, such as dedifferentiated liposarcoma and myofibroblastic sarcoma.
Methods: We performed pan-Trk antibody immunohistochemistry (Ventana, EPR17341 clone) on Bond-Max in order to select the likely positive cases. The immunohistochemistry-positive cases, after DNA isolation and PCR amplification of the tyrosine-kinase domain coding regions, were administered for Sanger-sequencing. In the cases, where nucleic acid substitution leading to amino acid substitution was observed, we executed FISH break-apart probes for NTRK1-3 genes, to rule out fusions.
Result: Among the 104 dedifferentiated liposarcomas, 66 were positive with immunohistochemistry. Then 36 cases (due to the lack of enough remaining material) were Sanger-sequenced for NTRK1 and NTRK3. Amidst these cases, 4 showed the same point mutation combination leading to amino acid substitutions within the NTRK1 gene. None of them have NTRK1-3 fusions, but interestingly, 2 represented amplification of the NTRK1 gene.
Conclusion: It is possible that the point mutation combination in NTRK1 or the amplification of NTRK1 may contribute to tumorigenesis. Further examinations are required to prove that. Hopefully, the drugs that are approved for tumors with NTRK gene fusions can be efficient in the cases of these gene alterations too.
Funding: This research was funded by EFOP-3.6.3-VEKOP-16-2017-00009.
Semmelweis University, Doctoral School of Pathological Sciences