Abstract

Background

Significant gene fusions with diagnostic and therapeutic importance have been identified in a variety of tumors including melanocytic lesions. TFG fusions to partner genes with targeted therapies have been described in prior studies in tumors. However, TFG fusions have yet to be evaluated in the setting melanocytic lesions which this study investigates.

Material and Methods

Cases of melanocytic lesions profiled by targeted RNA-based next generation sequencing (NGS) were retrospectively identified from 2016-2024. Demographic and clinical information were collected along with the identification of significant gene fusions.

Results

In a total of 105 melanomas, atypical melanocytic nevi, and melanocytomas with significant gene fusions, TFG fusions were detected in 7.6% (eight cases). Specifically, a TFG::ADGRG7 mutation was found in two nevi, one mucosal melanoma, and one desmoplastic melanoma; this fusion has been described as a non-driver in individuals of European ancestry. A TFG::GPR128 fusion was identified in two cutaneous melanomas and one ocular melanoma. While this fusion has been observed in cancers such as lymphoma and soft tissue tumors, it has also been detected in healthy individuals, suggesting a potential germ-line origin. Lastly, a TFG::NTRK3 fusion was discovered in one Spitz tumor. The fusion was previously reported in a high-grade sarcoma in a young man but not yet described in melanocytic lesions. This fusion might benefit from treatment with kinase inhibitors.

Conclusion

Our findings underscore the complexity of TRG fusions in melanocytic lesions highlighting the necessity to differentiate between oncogenic drivers amenable to targeted therapy versus those that are incidental occurrences.