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Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermis samples from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed keratin and enhancer methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages. Citation Format: Manuel Rodríguez Paredes, Felix Bormann, Günter Raddatz, Julian Gutekunst, Carlota Lucena-Porcel, Florian Köhler, Elisabeth Wurzer, Katrin Schmidt, Joachim Röwert-Huber, Evgeniya Denisova, Lars Feuerbach, Esther Herpel, Ingo Nindl, Thomas G. Hofmann, Marc Winnefeld, Frank Lyko. Methylation profiling identifies two subclasses of cutaneous squamous cell carcinoma related to distinct cell types of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5333.