Experts Uncover Atypical Gene Fusions in TGCT Via Molecular Profiling

In an interview with Oncology Learning Network, George Jour, MD, Assistant Professor of Pathology and Dermatology at New York University (NYU) School of Medicine - Langone Health System, discussed the findings of a study involving the molecular profiling of atypical tenosynovial giant cell tumors (TGCT; Cancers [Basel]. 2019 Dec 31;12[1]:E100).

Dr Jour is a bone and soft tissue pathologist, dermatopathologist, and molecular pathologist who also currently serves as Associate Director for Molecular Diagnostics at the NYU Langone Department of Pathology.

What led you and your co-investigators to conduct this study?

TGCT, also known as giant cell tumor of tendon sheath, is a benign soft tissue lesion that is catalogued among the so-called fibrohistiocytic tumors. A subset of these tumors, however, exhibit unusual histologic features and show aggressive clinical behavior.

This subset of tumors is referred to as "atypical TGCT". Distinction of these unconventional tumors often renders a diagnostic challenge. Overexpression of CSF1 in the neoplastic cell population through recurrent gene fusion involving CSF1 gene is believed to result in abnormal recruitment of CSF1R-expressing macrophages to the tumor site.

In the present study, we pursued further expansion of our current understanding of atypical TGCTs at the molecular level in order to identify specific fusions that would highlight the underlying biological mechanism responsible for tumorigenesis and enables accurate diagnosis of these tumors in the clinical setting.

Please briefly describe your study and its findings.

We identified novel non-CSF1-implicated gene fusions using anchored multiplex PCR (AMP) technology in the atypical TGCTs which showed evidence of recurrence. These fusions included NIPBL-ERG, FN1-ROS1, and YAP1-MAML2. All fusions were and subsequently validated by reverse transcriptase-PCR (RT-PCR) and Sanger sequencing.

Following these findings, we further compared the transcriptome landscape of conventional TGCTs using RNA sequencing and found distinct differences among the 2 groups.

Our findings reveal that atypical TGCTs harbor gene fusions not implicating CSF1 and suggest that non-CSF1 fusions potentially confer greater propensity to recurrences and local aggressiveness while indicating the presence of alternate pathogenic mechanisms that warrant further investigation.

What are the possible real-world applications of these findings in clinical practice?

These findings can be used as part of the diagnostic armamentarium in cases with unusual morphology that are suspicious to represent atypical TGCT.

Detection of the aforementioned fusions along with the atypical morphology would enable stratification of those patients who are at risk of having an aggressive course and treating them accordingly.

Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

We are in the process of expanding the tested cohort to include more patient cases that will be tested using the same methodologies referenced in our paper.

We will also pursue functional studies using cell lines in order to investigate and validate the putative tumorigenic role of these identified fusions.