A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase

Autor: Miika Mehine, Terhi Ahvenainen, Sara Khamaiseh, Jouni Härkönen, Siiri Reinikka, Tuomas Heikkinen, Anna Äyräväinen, Päivi Pakarinen, Päivi Härkki, Annukka Pasanen, Anna-Liisa Levonen, Ralf Bützow, Pia Vahteristo
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Oncogenesis, Vol 11, Iss 1, Pp 1-10 (2022)
Druh dokumentu: article
ISSN: 2157-9024
DOI: 10.1038/s41389-022-00425-3
Popis: Abstract Uterine leiomyomas, or fibroids, are the most common tumors in women of reproductive age. Uterine leiomyomas can be classified into at least three main molecular subtypes according to mutations affecting MED12, HMGA2, or FH. FH-deficient leiomyomas are characterized by activation of the NRF2 pathway, including upregulation of the NRF2 target gene AKR1B10. Here, we have identified a novel leiomyoma subtype showing AKR1B10 expression but no alterations in FH or other known driver genes. Whole-exome and whole-genome sequencing revealed biallelic mutations in key genes involved in neddylation of the Cullin 3-RING E3 ligase, including UBE2M, NEDD8, CUL3, and NAE1. 3′RNA sequencing confirmed a distinct molecular subtype with activation of the NRF2 pathway. Most tumors displayed cellular histopathology, perivascular hypercellularity, and characteristics typically seen in FH-deficient leiomyomas. These results suggest a novel leiomyoma subtype that is characterized by distinct morphological features, genetic alterations disrupting neddylation of the Cullin 3-RING E3 ligase, and oncogenic NRF2 activation. They also present defective neddylation as a novel mechanism leading to aberrant NRF2 signaling. Molecular characterization of uterine leiomyomas provides novel opportunities for targeted treatment options.
Databáze: Directory of Open Access Journals
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