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To date it remains uncertain whether such neoplasms should be regarded as variants of smooth muscle or endometrial stromal neoplasm, or if they constitute a distinct tumour type. In this study we investigated DNA methylation patterns and copy number variations (CNVs) in a series of uterine tumours harboring\n                    <jats:italic>KAT6B\/A::KANSL1<\/jats:italic>\n                    gene fusions in comparison to other mesenchymal neoplasms of the gynecological tract. Unsupervised hierarchical clustering and t-SNE analysis of DNA methylation data (Illumina EPIC array) identified a distinct cluster for 8\/13\n                    <jats:italic>KAT6B\/A::KANSL1<\/jats:italic>\n                    tumours (herein referred to as core cluster). The other 5 tumours (herein referred to as outliers) did not assign to the core cluster but clustered near various other tumour types. CNV analysis did not identify significant alterations in the core cluster. In contrast, various alterations, including deletions at the\n                    <jats:italic>CDKN2A\/B<\/jats:italic>\n                    and\n                    <jats:italic>NF1<\/jats:italic>\n                    loci were identified in the outlier group. Analysis of the DNA methylation clusters in relation to histological features revealed that while tumours in the core\n                    <jats:italic>KAT6B\/A::KANSL1<\/jats:italic>\n                    cluster were histologically bland, outlier tumours frequently exhibited \u201chigh-grade\u201d histologic features in the form of significant nuclear atypia, increased mitotic activity and necrosis. Three of the five patients with outlier tumours died from their disease while clinical follow-up in the remaining two patients was limited (less than 12\u00a0months). In comparison, none of the 7 out of 8 patients with tumors in the core\n                    <jats:italic>KAT6B\/A::KANSL1<\/jats:italic>\n                    sarcoma cluster, where follow-up was available, died from disease. Furthermore, only 1 out of 7 patients recurred (mean follow-up of 30\u00a0months). In conclusion,\n                    <jats:italic>KAT6B\/A::KANSL1<\/jats:italic>\n                    uterine sarcoma is a molecularly unique type of uterine tumour that should be recognized as a distinct entity. These tumors typically exhibit low-grade histologic features but are occasionally morphologically high-grade; the latter have a DNA methylation profile different from the typical low-grade neoplasms and may be associated with aggressive behaviour.\n                  <\/jats:p>","DOI":"10.1007\/s00428-024-03935-0","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T05:01:59Z","timestamp":1728622919000},"page":"793-803","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Uterine mesenchymal tumours harboring the KAT6B\/A::KANSL1 gene fusion represent a distinct type of uterine sarcoma based on DNA methylation profiles"],"prefix":"10.1007","volume":"485","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0876-9087","authenticated-orcid":false,"given":"Felix K. 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All other authors state no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}