👤 M Bourdon

Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESSs]) uterine neoplasms. However, they may represent an emerging entity characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Here, we aimed to confirm that this neoplasm is a distinct clinicopathologic and molecular sarcoma and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. Therefore, we conducted a comprehensive clinical, histopathologic, immunohistochemical, and molecular study, including array comparative genomic hybridization, whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analyses of 16 tumors with KAT6B::KANSL1 fusion from 12 patients. At presentation, patients were peri-menopausal (median, 47.5 years), and the primary tumors were located in the uterine corpus (12/12, 100%), with an additional prevesical location in 1 (8.3%) of 12 cases. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphologic and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13 (81.3%) of 16 tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13 (81.3%) of 18 had large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16 (100%) of 16 and 14 (87.5%) of 16 tumors, respectively. Array comparative genomic hybridization performed on 10 tumors classified these neoplasms as simple genomic sarcomas. Whole RNA-sequencing on 16 samples and clustering analysis on primary tumors found that the KAT6B::KANSL1 fusion always occurred between exons 3 of KAT6B and 11 of KANSL1; no pathogenic variant was identified on cDNA, all neoplasms clustered together, close to LG-ESS, and pathway enrichment analysis showed cell proliferation and immune infiltrate recruitment pathway involvement. These results confirm that the sarcomas harboring a KAT6B/A::KANSL1 fusion represent a distinct clinicopathologic entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the molecular driver alteration. Show less

The epithelial to mesenchymal transition (EMT) has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch signaling, which could promote this EMT. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated EMT in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30, 60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5) and biomarkers of EMT (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T cells) at Day 60. Conversely, expression of the Cd19 marker (B cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for EMT were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and EMT markers in the early development of adenomyosis. Show less