Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan–Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS.

NUT carcinoma is a rare malignant neoplasm characterised by recurrent NUTM1 rearrangements, initially reported in the midline. Recently, 10 cases of cutaneous NUT carcinoma with adnexal differentiation harbouring BRD3::NUTM1, NSD3::NUTM1, BRD4::NUTM1 or BRD3::NUTM2B fusions have been reported. Accordingly, ‘NUT adnexal carcinoma’ (NAC) has been introduced as a provisional tumour entity to the fifth edition of the WHO Classification of Skin Tumours.Aims: We report the histopathological, molecular genetic and epigenetic features of seven additional cases of NAC.Methods and results: The cohort consisted of four female and three male patients with a median age of 58 years. Follow‐up was available for six cases, and documented diffuse metastatic spreading leading to death at 18 months after diagnosis for one case. Histopathological examination in all cases revealed dermal/subcutaneous neoplasms composed of poorly differentiated cells with large irregular vesicular nuclei and at least focally prominent nucleoli. All cases showed areas of duct/gland formation. Using immunohistochemistry, all tumours showed diffuse NUT expression with co‐expression of SOX10 in five cases. P63 and P40 were diffusely positive in one case and confined to the periphery of the tumour nests in five cases. Molecular analysis showed BRD4::NUTM1 fusions (n = 3), BRD3::NUTM1 fusions (n = 3) and NSD3::NUTM1 (n = 1). Although being close to this latter group, methylation and transcriptional analysis revealed that NAC formed a unique cluster distinct from extracutaneous NUT carcinoma and NUTM1‐rearranged porocarcinoma.Conclusions: Our results further support the existence of primary cutaneous NAC and suggest that it may represent an entity distinct from extracutaneous NUT carcinoma.

Aims: Sebaceous neoplasms constitute a group of adnexal tumours, including sebaceous adenoma, sebaceoma and sebaceous carcinoma. Although mismatch repair deficiency may be observed, the nature of the genetic alterations contributing to the development of most of these tumours is still unknown. In the present study, we describe the clinical, microscopic, and molecular features of eight sebaceomas with GRHL gene rearrangement.Methods and results: Among these sebaceomas, four occurred in women and four in men; the median age was 63 years (range = 29–89). The tumours were located in the head and neck area in all cases. Microscopic examination revealed a well‐demarcated lesion located in the dermis with focal extension into the subcutaneous tissue (three cases). The neoplasms displayed macronodular (eight cases), cribriform (seven cases) and organoid (six cases) growth patterns, occurring in combination. The tumours were mainly composed of immature basophilic cells associated with scattered mature sebocytes. Numerous small infundibular cysts were present in seven cases. Mitotic activity was low (none/one to four mitoses/mm²). Immunohistochemistry showed positivity for androgen receptor and p63. Preserved expression of MLH1, PMS2, MSH2 and MSH6 was observed in all cases. RNA‐sequencing revealed RCOR1::GRHL2 (three cases), BCL6::GRHL1 (two cases), a BCOR::GRHL2 (one case), RCOR1::GRHL1 (one case) and TLE1::GRHL1 (one case) fusion transcript. Methylation analysis demonstrated that GRHL‐fused sebaceomas form an independent cluster and highlight the proximity of such tumours with poromas with folliculo‐sebaceous differentiation.Conclusions: In conclusion, we report recurrent fusions of the GRHL genes in a distinctive subset of sebaceomas harbouring infundibulocystic differentiation, a frequent organoid growth pattern and lack of mismatch repair deficiency.