👤 François Le Loarer

Recently, FN1 fusions to receptor tyrosine kinase genes have been identified in soft tissue tumors with calcified chondroid matrix named calcifying chondroid mesenchymal neoplasms (CCMNs). We collected 33 cases of CCMN from the French network for soft tissue and bone tumors. We performed whole-exome RNA sequencing, expression analysis, and genome-wide DNA methylation profiling in 33, 30, and 20 cases of CCMN compared with a control group of tumors, including noncalcified tenosynovial giant cell tumor (TGCT). Among them, 15 cases showed morphologic overlap with soft tissue chondroma, 8 cases with tophaceous pseudogout, and 10 cases with chondroid TGCT. RNA-sequencing revealed a fusion of FN1 in 76% of cases (25/33) with different 5' partners, including most frequently FGFR2 (14 cases), TEK or FGFR1. Among CCMN associated with FGFR1 fusions, 2 cases had overexpression of FGF23 without tumor-induced osteomalacia. Four CCMN had PDGFRA::USP8 fusions; 3 of which had histologic features of TGCT and were located in the hip, foot, and temporomandibular joint (TMJ). All cases with FN1::TEK fusion were located at TMJ and had histologic features of TGCT with or without chondroid matrix. They formed a distinct cluster on unsupervised clustering analyses based on whole transcriptome and genome-wide methylome data. Our study confirms the high prevalence of FN1 fusions in CCMN. In addition, through transcriptome and methylome analyses, we have identified a novel subgroup of tumors located at the TMJ, exhibiting TGCT-like features and FN1::TEK fusions. Show less

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