PhD Scientific Days 2025

Pathological and Oncological Sciences III.

NTRK amplification occurs frequently in pan-TRK immunopositive dedifferentiated liposarcomas

Name of the presenter

Lippai Zoltán

Institute/workplace of the presenter

Semmelweis University Department of Orthopedic Surgery; Budapesti Bajcsy-Zsilinszky Kórház - Onkopatológiai Diagnosztikai Kft

Authors

Dr. Zoltán Lippai, PhD¹

1: Semmelweis Egyetem ÁOK Patológiai és Kísérleti Rákkutató Intézet

Text of the abstract

Introduction: The neurotrophic tyrosine kinase receptor (NTRK) gene family is of rising importance as their fusions are oncogenic, and specific target drugs are available to inhibit the chimera proteins. Pan-TRK antibody, which shows the overexpression of the NTRK1-2-3 genes, is a useful tool to detect tumors with or without NTRK gene alterations, due to high negative predictive value. Though it is well known that pan-TRK immunopositivity is usually not connected to NTRK fusion, the role of other possible genetic alterations is under-researched. In our previous work, we found 3 NTRK1 amplified cases out of 6 cases with recurrent NTRK1 tyrosine kinase domain mutation pair, so we extended our investigation to a larger series to estimate amplification frequency.

Aims: We aimed to investigate the relation between pan-TRK immunopositivity and possible genetic alterations by using NTRK1/2/3 locus specific break apart probe set in order to estimate the frequency of genomic rearrangement of NTRK1-2-3 genes in dedifferentiated liposarcomas.

Methods: 132 individual cases of dedifferentiated liposarcomas with myogenic heterologous differentiation were selected. Immunohistochemistry with pan-TRK antibody was performed on tumor samples from these cases. Pan-TRK immunopositive cases were analyzed by FISH using NTRK1-2-3 break apart probes. Publicly available data sets were analysed for the presence of structural variants involving NTRK1/2/3 gene loci, in which 265 liposarcomas samples were included.

Result: Pan-TRK immunopositivity was seen in 76 of the 132 dedifferentiated liposarcoma cases. None of the pan-TRK immunopositive dedifferentiated liposarcomas showed absolutely certain sign of fusion, however, 18 (27.7%) cases showed amplification of one of the genes, 13 had polysomy, 34 were normal, 11 were not evaluable by NTRK1-2-3 break apart FISH. Analyzing publicly available data from large series of 265 liposarcoma samples, 23 (8.6%) cases showed a mutual exclusive amplification of the NTRK genomic loci in a non-preselected, independent patient population.

Conclusion: Our results underline the so far not revealed frequent occurrence of NTRK amplifications in pan-TRK immunpositive tumors which might be important in the TRK inhibition therapy.

Funding: One member of the research group received grant via EKÖP.