Identification of fusions with potential clinical significance in melanoma.

Autor: Moran JMT; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Le LP; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Nardi V; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Golas J; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Farahani AA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Signorelli S; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Onozato ML; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Foreman RK; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Duncan LM; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Lawrence DP; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Lennerz JK; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Dias-Santagata D; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ddiassantagata@mgh.harvard.edu., Hoang MP; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. mhoang@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2022 Dec; Vol. 35 (12), pp. 1837-1847. Date of Electronic Publication: 2022 Jul 23.
DOI: 10.1038/s41379-022-01138-z
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
Databáze: MEDLINE
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