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Identification of fusions with potential clinical significance in melanoma

Abstract

Though uncommon in melanoma, gene fusions may have therapeutic implications. Next generation sequencing-based clinical assays, designed to detect relevant gene fusions, mutations, and copy number changes, were performed on 750 melanomas (375 primary and 375 metastases) at our institution from 2014–2021. These included 599 (80%) cutaneous, 38 (5%) acral, 11 (1.5%) anorectal, 23 (3%) sinonasal, 27 (3.6%) eye (uveal/ conjunctiva), 11 (1.5%) genital (vulva/penile), and 41 (5.5%) melanomas of unknown primary. Sixteen fusions (2%) were detected in samples from 16 patients: 12/599 (2%) cutaneous, 2/38 (5%) acral, 1/9 (11%) vulva, 1/23(4.3%) sinonasal; and 12/16 (75%) fusions were potentially targetable. We identified two novel rearrangements: NAGS::MAST2 and NOTCH1::GNB1; and two fusions that have been reported in other malignancies but not in melanoma: CANT1::ETV4 (prostate cancer) and CCDC6::RET (thyroid cancer). Additional fusions, previously reported in melanoma, included: EML4::ALK, MLPH::ALK, AGAP3::BRAF, AGK::BRAF, CDH3::BRAF, CCT8::BRAF, DIP2B::BRAF, EFNB1::RAF1, LRCH3::RAF1, MAP4::RAF1, RUFY1::RAF1, and ADCY2::TERT. Fusion positive melanomas harbored recurrent alterations in TERT and CDKN2A, among others. Gene fusions were exceedingly rare (0.2%) in BRAF/RAS/NF1-mutant tumors and were detected in 5.6% of triple wild-type melanomas. Interestingly, gene rearrangements were significantly enriched within the subset of triple wild-type melanomas that harbor TERT promoter mutations (18% versus 2%, p < 0.0001). Thirteen (81%) patients were treated with immunotherapy for metastatic disease or in the adjuvant setting. Six of 12 (50%) patients with potentially actionable fusions progressed on immunotherapy, and 3/6 (50%) were treated with targeted agents (ALK and MEK inhibitors), 2 off-label and 1 as part of a clinical trial. One patient with an AGAP3::BRAF fusion positive melanoma experienced a 30-month long response to trametinib. We show that, detecting fusions, especially in triple wild-type melanomas with TERT promoter mutations, may have a clinically significant impact in patients with advanced disease who have failed front-line immunotherapy.

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Fig. 1: Summary of fusion and next generation sequencing results of the fusion-positive cases.
Fig. 2: Schematic representation of three fusions not previously reported in melanoma.
Fig. 3: ALK and BRAF break apart fluorescence in situ hybridization.
Fig. 4: Histology of fusion-positive melanomas.
Fig. 5: Notch1 immunohistochemistry, and GNB1 and MAST2 immunofluorescence staining.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Conceptualization and supervision: D.D.S. and M.P.H; methodology: L.P.L., V.N., J.G., A.A.F., S.S., M.L.O., J.K.L., D.D.S. and M.P.H; acquisition, analysis and interpretation of data: J.M.T.M., L.P.L., V.N., J.G., A.A.F., S.S., M.L.O., R.K.F., L.M.D., D.P.L., J.K.L., D.D.S. and M.P.H; writing original draft: J.M.T.M., D.D.S. and M.P.H; review and edit manuscript: J.M.T.M., L.P.L., V.N., J.G., A.A.F., S.S., M.L.O., R.K.F., L.M.D., D.P.L., J.K.L., D.D.S and M.P.H. All authors read and approved the final version of the manuscript.

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Correspondence to Dora Dias-Santagata or Mai P. Hoang.

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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Partners Human Research Committee, the institutional review board of Partners HealthCare (protocol code 2011P0001665).

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Moran, J.M.T., Le, L.P., Nardi, V. et al. Identification of fusions with potential clinical significance in melanoma. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01138-z

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