Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering the molecular mechanisms driving resistance has been the subject of intense research. Recent in vitro and clinical data have suggested a link between expression of telomerase and resistance to targeted therapy in melanoma. TERT promoter mutations are the main mechanism for the continuous upregulation of telomerase in melanoma and co-occur frequently with BRAF alterations. To understand how TERT promoter mutations could be associated with resistance to targeted therapy in melanoma, we conducted translational and in vitro studies. In a cohort of V600E-BRAF-mutated melanoma patients, we showed that the TERT promoter mutation status and TERT expression tended to be associated with response to BRAF and MEK inhibitors. We demonstrated that TERT overexpression in BRAF-mutated melanoma cells reduced sensitivity to BRAF and MEK independently of TERT’s telomer maintenance activity. Interestingly, inhibition of TERT reduced growth of BRAF-mutated melanoma including resistant cells. TERT expression in melanoma can therefore be a new biomarker for resistance to MAPK inhibitors as well as a novel therapeutic target.

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.

In BRAF^V600mut metastatic melanoma, the combination of BRAF and MEK inhibitors (BRAFi, MEKi) has undergone multiple resistance mechanisms, limiting its clinical benefit and resulting in the need for response predicting biomarkers. Based on phase III clinical trial data, several studies have previously explored baseline genomic features associated with response to BRAFi + MEKi. Using a targeted approach that combines the examination of mRNA expression and DNA alterations in a subset of genes, we performed an analysis of baseline genomic alterations involved in MAPK inhibitors’ resistance in a real-life cohort of BRAF^V600mut metastatic melanoma patients. Twenty-seven patients were included in this retrospective study, and tumor samples were analyzed when the BRAFi + MEKi therapy was initiated. The clinical characteristics of our cohort were consistent with previously published studies. The BRAFi + MEKi treatment was initiated in seven patients as a following-line treatment, and had a specific transcriptomic profile exhibiting 14 genes with lower mRNA expression. However, DNA alterations in CCND1, RB1, and MET were only observed in patients who received BRAFi + MEKi as the first-line treatment. Furthermore, KIT mRNA expression was significantly higher in patients showing clinical benefit from the combined therapy, emphasizing the tumor-suppressor role of KIT already described within the context of BRAF-mutant melanoma.

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.