Nicolas Ortonne

Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to the development of plexiform neurofibromas (pNF), benign tumors of the

BackgroundSkin adnexal carcinomas (SAC) comprise a rare and heterogeneous group of malignancies with variable prognosis. Due to the lack of established guidelines for initial staging and follow-up, this study aimed to analyse recurrence risks across SAC subtypes to provide a framework for subtype-specific treatments options and follow-up.MethodsThis nationwide multicentre prospective study, using the CARADERM database, included patients diagnosed with primary and localised SAC between March 2014 and March 2024. Subtypes with fewer than 15 cases were excluded from the prognostic analysis. Recurrence was classified as local, regional, or distant, with a three-year follow-up endpoint. Recurrence risks were stratified as low (<5%), moderate (5–15%), or high (≥15%) for local and regional recurrences and as low (0%), moderate (0–5%), or high (≥5%) for distant recurrences.ResultsAmong 980 eligible patients, distinct recurrence patterns were identified across subtypes. Subtypes with high global recurrence risk included adnexal carcinomas NOS, apocrine carcinomas, mucinous adenocarcinomas and squamoid eccrine ductal carcinomas, with three-year cumulative recurrence rate of 29.3%. In contrast, low-risk subtypes such as low-grade trichoblastic carcinomas, pilomatrical carcinomas, proliferating trichilemmal tumor and digital papillary adenocarcinomas, exhibited a global recurrence rate of 1.5%. Local, regional, and distant recurrence risks varied among subtypes, emphasising their heterogeneous clinical behavior.ConclusionThis is the first prospective multicentre study to define recurrence-based risk stratification across SAC subtypes. These findings underscore the need for subtype-specific strategies and provide the foundation for evidence-based staging and follow-up algorithms for rare skin carcinomas.

There is currently no effective treatment for malignant peripheral nerve sheath tumors (MPNSTs), half of which result from malignant progression of neurofibromas (NFs) in patients with neurofibromatosis type 1 (NF1). NFs are due to biallelic loss-of-function of NF1, which negatively regulates the RAS pathway, in the Schwann cell lineage. We generated a conditional Nf1-mutant mouse model where NFs spontaneously transform into MPNSTs, faithfully recapitulating the human situation. Single-cell transcriptomic profiling demonstrated progression of NFs into MPNSTs, with a glial-to-mesenchymal transition. Sox9 was identified as a marker of this transition and key player in tumor growth. The transition is followed by a loss of the tumor suppressor gene (TSG) Cdkn2a and acquisition of pathogenic variants of other TSGs. Finally, a proof-of-concept drug screen aimed at reducing Sox9 expression in tumor cells identified 12 FDA-approved drugs. Notably, several of these agents target the RAS signaling cascade, suggesting that multi-targeted inhibition of this pathway may represent a promising therapeutic strategy against MPNSTs.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin damage like chronic ulcers, scars, Recessive Dystrophic Epidermolysis Bullosa (RDEB), and inflammatory skin diseases such as hidradenitis suppurativa (HS). Little is known about non‐UV‐induced skin carcinomas. We aimed to describe the clinical, pathological, and genetic features, of non‐UV‐induced cSCC. We collected clinical and pathologic data corresponding to 31 patients with non‐UV‐induced cSCC, including 5 cSCC on HS, 4 on chronic leg ulcers and 8 on RDEB. DNA was extracted from FFPE samples and analysed using a NGS assay targeting 523 cancer genes. A comparison was performed with published genetic data obtained in non‐UV‐induced and UV‐induced cSCC. We found that the Tumour Mutational Burden (TMB) of non‐UV‐induced cSCC was 6‐times lower than the published TMB of UV‐induced cSCC. The predominant mutational signature was a clock‐wise signature. By comparing the frequency of driver mutations, we found TP53 and NOTCH1 to be significantly less frequently mutated than in UV‐mutated cSCC. Interestingly, KMT2B (a histone methyl transferase) was mutated in 11/31 non‐UV‐induced cSCC and this proportion was significantly higher than in UV‐mutated cSCC. These mutations were high impact loss‐of‐function mutations. We found that knocking down KMT2B expression using siRNA did not affect cell proliferation of SCC‐13 and A‐431 cell lines, however, it significantly increased cell migration in vitro . Taken together, this study provides a comprehensive description of non‐UV‐induced cSCC and identifies that KMT2B is mutated and involved in non‐UV‐induced cSCC carcinogenesis. © 2025 The Pathological Society of Great Britain and Ireland.