PhD Scientific Days 2022

Budapest, 6-7 July 2022

Pathology and Oncology I. (Poster discussion will take place in the Aula during the Coffee Break)

NTRK Gene Alterations in Soft Tissue Tumors

Dr. Zoltán Lippai (1)
Prof. Dr. Zoltán Sápi (1)

(1): 1st Department of Pathology and Experimental Cancer Research, Semmelweis University

Text of the abstract

Introduction: The three members (NTRK1, NTRK2, NTRK3) of the NTRK gene family encode three receptor tyrosine kinases (TrkA, TrkB, TrkC), which play important role in the proliferation, differentiation, apoptosis, survival, cell cycle regulation of neuronal and non-neuronal cells. Genetic abnormalities of the NTRK genes may lead to tumorigenesis owing to the dysregulation of the above mentioned functions. Among the various types of NTRK gene alterations, fusions are well known. Patients with tumors harboring NTRK gene fusion can be treated effectively with the newly discovered anti-Trk drugs. Unfortunately, the non-fusion gene alterations of the NTRK genes have not been investigated so far.
Aims: Our aim is to examine the tyrosine kinase domain coding regions of the NTRK genes in soft tissue tumors, such as dedifferentiated liposarcoma.
Methods: We performed pan-Trk antibody immunohistochemistry in order to select the likely positive cases. The immunohistochemistry-positive cases, after PCR amplification of the tyrosine kinase domain coding regions, were administered for Sanger sequencing. In the missense mutation harboring cases, we executed Sanger sequencing of the normal tissue, to rule out the possibility of germline mutations and FISH assays, to rule out fusions. We performed NGS of these mutated cases to further deepen our knowledge of these mutations.
Result: Among the 111 dedifferentiated liposarcomas, 70 were positive with immunohistochemistry. Then 41 cases amongst the positive ones were Sanger sequenced. Amidst these cases, 4 showed the same missense point mutation pair within the NTRK1 gene. These are proved to be somatic mutations. None of them have NTRK fusions, but interestingly, 2 represented amplification of the NTRK1 gene. Based on the NGS data, 3 cases are homozygote for both mutation, and the fourth one is heterozygote for both. The two mutations are in cis position.
Conclusion: We discovered a new point mutation pair in dedifferentiated liposarcoma. We think that this point mutation pair may contribute to tumorigenesis and further examinations are in process to prove this. We expect that the anti-Trk drugs can be also efficient in those cases harboring the point mutations we discovered.
Funding: This research was funded by EFOP-3.6.3-VEKOP-16-2017-00009.