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They can be divided into distinct molecular subtypes. We have previously shown that 3\u2032RNA\u2010sequencing is highly effective in classifying archival formalin\u2010fixed paraffin\u2010embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3\u2032RNA\u2010sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (<jats:italic>MED12<\/jats:italic>), high mobility group AT\u2010hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2<jats:italic>\u2010<\/jats:italic>positive tumors, including overexpression of <jats:italic>PLAG1<\/jats:italic>. We explored 12 such leiomyomas by whole\u2010genome 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\u2010level served as controls. We identified chromosomal rearrangements targeting either <jats:italic>HMGA2<\/jats:italic>, <jats:italic>HMGA1<\/jats:italic>, or <jats:italic>PLAG1<\/jats:italic> in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18\u2009years. Furthermore, two tumors displayed biallelic loss of <jats:italic>DEPDC5<\/jats:italic> and one tumor harbored a <jats:italic>COL4A5\u2013COL4A6<\/jats:italic> deletion. These observations suggest that instead of only HMGA2\u2010positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either <jats:italic>HMGA2<\/jats:italic>, <jats:italic>HMGA1<\/jats:italic>, or <jats:italic>PLAG1.<\/jats:italic> The results indicate that the frequency of HMGA2\u2010positive 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.<\/jats:p>","DOI":"10.1002\/gcc.23088","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T08:40:20Z","timestamp":1657701620000},"page":"27-38","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["3\u2032<scp>RNA<\/scp> and whole\u2010genome sequencing of archival uterine leiomyomas reveal a tumor subtype with chromosomal rearrangements affecting either <i>HMGA2<\/i>, <i>HMGA1<\/i>, or <i>PLAG1<\/i>"],"prefix":"10.1002","volume":"62","author":[{"given":"Vilja","family":"Jokinen","sequence":"first","affiliation":[{"name":"Applied Tumor Genomics Research Program University of Helsinki  Helsinki Finland"},{"name":"Department of Medical and Clinical Genetics University of Helsinki  Helsinki 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