While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.

Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. Previously surgery was the standard primary treatment modality; however, in recent years a paradigm shift towards a more conservative management has been introduced and an effort to harmonise the strategy amongst clinicians has been made. We present herein an evidence-based, joint global consensus guideline approach to the management of this disease focussing on: molecular genetics, indications for an active treatment, and available systemic therapeutic options. This paper follows a one-day consensus meeting held in Milan, Italy, in June 2018 under the auspices of the European Reference Network for rare solid adult cancers, EURACAN, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) as well as Sarcoma Patients Euro-Net (SPAEN) and The Desmoid tumour Research Foundation (DTRF). The meeting brought

CIC-fused sarcomas represent an emerging family of tumors, for long connected to the Ewing family group of tumors, but underlined by distinct CIC fusions with different partners. 3′ Fusion partners include DUX4, FOXO4, and, as recently emphasized, NUTM1. In this study, we report the clinicopathologic and molecular features of a series of 6 CIC-NUTM1 sarcomas. Mean age at diagnosis was 6 years (2 to 27 y), and 4 patients were male individuals. Primary tumors were located in the central nervous system (n=3), paravertebral soft tissue and epidural spaces (n=1, each), and lung (n=1). Median overall survival was 17.5 months (7 to 37 mo), and all but one patient died of disease. All tumors displayed classic features of CIC-DUX4 sarcomas with round cell to epithelioid microscopic appearance. Most tumors expressed ETV4 and NUTM1 (n=5/6 and 6/6, respectively), whereas WT1cter was positive in only 2 cases. All tested tumors were positive for break-apart fluorescence in situ hybridization for CIC and NUTM1. Apart from CIC or NUTM1 genomic breakpoints, no other recurrent copy number alteration was seen on genomic profiles. Fusion transcripts were identified by RNA-sequencing on either formalin-fixed paraffin-embedded or frozen material. CIC and NUTM1 breakpoints were located between exons 16 and 20 and exons 2 and 5, respectively. Altogether, CIC-NUTM1 sarcomas represent a new molecular variant of CIC-fused sarcomas with a predilection for the central nervous system and younger pediatric population. Its phenotype may be confused with NUT carcinomas.