Genetic landscape of non‐ <scp>UV</scp> ‐induced cutaneous squamous cell carcinomas

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.