Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a NovelVIM-RETFusion

Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting inETV6-NTRK3gene fusion. Recently, alternativeETV6-RET,ETV6-MAML3, andETV6-METfusions have been found in a subset of SCs lacking the classicETV6-NTRK3fusion transcript, but still harboringETV6gene rearrangements. Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested forETV6,RET, andNTRK3break by fluorescence in situ hybridization and for the commonETV6-NTRK3fusions using reverse transcription polymerase chain reaction. Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classicETV6-NTRK3fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for theETV6-NTRK3fusion, 8 cases presented withETV6-RETfusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novelVIM-RETfusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for bothETV6-NTRK3andMYB-SMR3Bfusion transcripts. Conclusions: A novel finding in our study was the discovery of aVIM-RETfusion in 1 patient with SC of the parotid gland who could possibly benefit fromRET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely,ETV6-NTRK3andMYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV65 ' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.