Abstract
We discovered a uniquely high spontaneous somatic mutational load in peripheral blood mononuclear cells (PBMCs) of Xeroderma Pigmentosum group C (XP-C) patients, characterized by elevated single nucleotide variants associated with mutation signatures SBS8 and SBS32, as well as an enrichment of single-nucleotide cytosine deletions. This hypermutability was markedly lower in fibroblasts, suggesting a replication-dependent mechanism of mutagenesis due to deficient global genome nucleotide excision repair (GG-NER). Our findings reveal distinct molecular subtypes within XP defined by spontaneous mutational load in normal blood cells and demonstrate that the exceptionally high mutation burden in XP-C leukemia originates from mutations already present prior to malignant transformation.