Nucleotide Excision Repair (NER) is a vital mechanism for maintaining genomic integrity by repairing a broad spectrum of DNA lesions, including those caused by UV light and bulky chemical adducts. While Xeroderma Pigmentosum Group C (XP-C) is primarily known for an extreme sensitivity to sunlight and a high risk of skin cancer, patients also exhibit a significantly elevated risk for internal malignancies. This study aims to characterize the mutational signatures and mechanisms arising from endogenous and exogenous DNA damage in XPC-deficient systems

We integrated clinical genomics with mouse models and isogenic human cell lines. The study analyzed the mutational landscapes of 25 internal tumors from XP-C patients across diverse tissue types, alongside 103 in-vivo samples (including various organs and primary hematopoietic stem cells from XPC-/- mice) and 162 in-vitro samples from three isogenic cell line pairs (HepG2, RPE1, and RPE1 TP53-/-). Analytical frameworks included Whole Genome Sequencing (WGS), duplex sequencing, de-novo mutational signature extraction, and evaluation of transcriptional strand bias. Models were exposed to diverse genotoxic stressors, including tobacco metabolites (BaP and/or BPDE), platinum agents (cisplatin, carboplatin, and oxaliplatin), oxidative stress inducers (KBrO3, H2O2), and Acetaldehyde.

XPC deficiency establishes a systemic mutator phenotype across tumors and non-cancerous models, characterized by two distinct mutational signatures: the ubiquitous SBS-XPC_1 and the hematologic-specific SBS-XPC_2. These signatures, driven partially by reactive oxygen species (ROS), represent a baseline product of endogenous DNA damage. Exogenous challenges significantly exacerbated this burden; tobacco metabolites and platinum compounds amplified mutagenesis and reshaped mutational profiles in XPC-/- models. Furthermore, frequent TP53 mutations enriched in internal XP-C tumors were found to act synergistically with NER deficiency, driving profound genomic instability and chromosomal alterations.

These findings establish that XPC deficiency confers a potent, systemic mutator phenotype extending far beyond UV-induced risks. The presence of strong transcriptional strand bias in internal tumors reveals that the mutagenic process is driven by bulky purine lesions that are substrates for Global-Genome NER but are only partially managed by Transcription-Coupled NER. Ultimately, this work identifies germline XPC deficiency as a predisposition to a broad spectrum of internal malignancies, where cells are uniquely vulnerable to damage ranging from daily metabolic byproducts to potent environmental genotoxins. These data underscore the need for modified clinical management and recognition of XP-C as an internal cancer predisposition syndrome.