Long read sequencing identifies complex structural variant landscape and recurrent TERT rearrangements in mucoepidermoid carcinoma.

Autor: Gensterblum-Miller E; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA., Bhangale A; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., Majid DA; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., Pienkowski VM; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Rydzanicz M; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Janiszewska J; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland., Kostrzewska-Poczekaj M; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland., Chang C; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., Brummel C; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., Michmerhuizen NL; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA., Wang J; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA., Sandford E; Department of Int Med-Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA., Tewari M; Department of Int Med-Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Wierzbicka M; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland., Birkeland AC; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., McHugh JB; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Spector ME; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Giefing M; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland., Jarmuz-Szymczak M; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland., Heft Neal ME; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., Brenner JC; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: chadbren@umich.edu.
Jazyk: angličtina
Zdroj: Oral oncology [Oral Oncol] 2024 Dec; Vol. 159, pp. 107108. Date of Electronic Publication: 2024 Nov 15.
DOI: 10.1016/j.oraloncology.2024.107108
Abstrakt: Mucoepidermoid Carcinoma (MEC) is a common salivary malignant neoplasm. Approximately 60 % of MECs harbor translocations between CRTC1 or CRTC3 and MAML2, which are thought to drive disease pathogenesis. However, the precise structural mechanism driving this rearrangement remains uncharacterized. Here, we performed multi-omic and long read genomic sequencing, discovering a chain of alterations that created the CRTC1::MAML2 fusion, but also an unexpected MAML2 to MYBL1 rearrangement, suggesting that MYBL1 may play a larger role in salivary gland cancers than previously recognized. Furthermore, we discovered and validated recurrent TERT rearrangements and amplifications in MEC models. 5/5 MEC cell lines and 36/39 (92 %) primary MEC tumors harbored a TERT rearrangement or copy number amplification. Custom sequencing of the TERT locus confirmed translocation breakpoints in 13/33 (39 %) MECs, while exome sequencing confirmed frequent TERT amplifications. Critically, TERT knockdown in NCI-H292, a cell line with TERT promoter rearrangement, reduced clonogenic cell survival, supporting a critical role of this gene in MEC tumorigenesis. Overall, our data suggest that complex chromothripsis rearrangement mechanisms drive the formation of structural variation in CRTC1::MAML2 fusion positive and negative tumors and reveal highly recurrent structural variation driving TERT rearrangement in MEC.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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