ORCID Profile
0000-0002-3812-4418
Current Organisation
University of Helsinki
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Publisher: Springer Science and Business Media LLC
Date: 07-09-2022
DOI: 10.1038/S41389-022-00425-3
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.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2023
Publisher: Wiley
Date: 08-2022
DOI: 10.1002/GCC.23088
Abstract: Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be ided into distinct molecular subtypes. We have previously shown that 3′RNA‐sequencing is highly effective in classifying archival formalin‐fixed paraffin‐embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3′RNA‐sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 ( MED12 ), high mobility group AT‐hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2 ‐ positive tumors, including overexpression of PLAG1 . We explored 12 such leiomyomas by whole‐genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein‐level served as controls. We identified chromosomal rearrangements targeting either HMGA2 , HMGA1 , or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5–COL4A6 deletion. These observations suggest that instead of only HMGA2‐positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2 , HMGA1 , or PLAG1. The results indicate that the frequency of HMGA2‐positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Siiri Reinikka.