Abstract 208: Epigenomic characterization of keratinocyte carcinomas in xeroderma pigmentosum

Keratinocyte carcinomas (KCs), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), arise in the epidermis due to chronic exposure to solar ultraviolet (UV) radiation. KCs account for 99% of skin neoplasms and represent the most prevalent form of cancer worldwide. DNA methylation, an epigenetic modification of CpG dinucleotides, modulates gene expression, thereby defining cell identity and mediating cellular responses to external stimuli. Aging and environmental stressors, including UV radiation, progressively alter epidermal methylomes, thus influencing KC development and progression. Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by mutations in genes of major cellular response mechanisms to UV-induced DNA damage, such as the nucleotide excision repair (NER) system or the translesion synthesis (TLS) DNA polymerase η. Consequently, XP patients exhibit a more than 10,000-fold increase in KC incidence, with tumors potentially manifesting as early as childhood. Epigenomic analysis of tumors derived from XP patients could provide valuable insights into the deregulation of DNA methylation in KC tumorigenesis, thereby contributing to the development of novel antitumor therapies for both XP patients and the broader population. Here, we used Infinium MethylationEPIC BeadChips to assess the DNA methylation status of 30 epidermal samples from XP patients with mutations in the XPC and POLH genes, representing roughly 50% of all XP cases and significantly impacted by KCs. Our sample set comprised BCC and cSCC tumors, non-tumorous epidermis, and actinic keratosis (AK), a precancerous lesion that frequently progresses to cSCC. DNA methylation analysis of XP samples clearly distinguished between BCC and cSCC tumors, whereas non-tumorous epidermis unexpectedly clustered with AK samples, reflecting substantial methylome dysregulation that is consistent with the heightened risk of KC development in XP patients. In line with this, further examination of non-tumorous XP methylomes relative to non-XP counterparts revealed features indicative of premature aging, including significant erosion of DNA methylation profiles and increased mitotic rates. Analysis of XP-derived BCC and cSCC methylation profiles also identified a higher frequency of copy number variation (CNV) events and a potential bias towards an epidermal stem cell (EpSC)-like cell-of-origin in cSCC tumors. These findings may suggest an elevated aggressiveness of XP tumors, which we now aim to verify using cellular models of KC deficient in key XP genes. Citation Format: Bea Riebesehl,Lea S. Beensen,Felix Bormann,Wilfried Roth,Carlos F. Menck,Thomas G. Hofmann,Frank Lyko,Manuel Rodríguez Paredes. Epigenomic characterization of keratinocyte carcinomas in xeroderma pigmentosum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 208.