A1 Refereed original research article in a scientific journal
Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a NovelVIM-RETFusion
Authors: Skálová Alena, Banečkova Martina, Thompson Lester D.R., Ptáková Nikola, Stevens Todd M., Brcic Luka, Hyrcza Martin, Michal Michael Jr, Simpson Roderick H.W., Santana Thalita, Michal Michal, Vaněček Tomas, Leivo Ilmo
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Publication year: 2020
Journal: American Journal of Surgical Pathology
Journal name in source: AMERICAN JOURNAL OF SURGICAL PATHOLOGY
Journal acronym: AM J SURG PATHOL
Volume: 44
Issue: 10
First page : 1295
Last page: 1307
Number of pages: 13
ISSN: 0147-5185
eISSN: 1532-0979
DOI: https://doi.org/10.1097/PAS.0000000000001535
Abstract
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.
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.
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